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Prevention and Control of Influenza with Vaccines

Recommendations of the Advisory Committee on Immunization Practices = (ACIP),=20 2010

Prepared by

Anthony E. Fiore, MD1

Timothy M. Uyeki, MD1

Karen Broder, MD2

Lyn Finelli, DrPH1

Gary L. Euler, DrPH3

James A. Singleton, MS3

John K. Iskander, MD4

Pascale M. Wortley, MD3

David K. Shay, MD1

Joseph S. Bresee, MD1

Nancy J. Cox, PhD1

1Influenza = Division,=20 National Center for Immunization and Respiratory Diseases

2Immunization Safety=20 Office, Division of Healthcare Quality Promotion, National Center for=20 Preparedness, Detection, and Control of Infectious Diseases

3Immunization Services=20 Division, National Center for Immunization and Respiratory = Diseases

4Office of = the Associate=20 Director for Science, Office of the Director

The material in this report originated in the = National=20 Center for Immunization and Respiratory Diseases, Anne Schuchat, MD, = Director;=20 the Influenza Division, Nancy Cox, PhD, Director; the Office of the = Associate=20 Director for Science, Harold Jaffe, MD, Director; the Immunization = Safety=20 Office, Division of Healthcare Quality Promotion, Denise Cardo, MD, = Director;=20 and the Immunization Services Division, Lance Rodewald, MD, = Director.

Corresponding preparer: Timothy Uyeki, = MD,=20 Influenza Division, National Center for Immunization and Respiratory = Diseases,=20 CDC, 1600 Clifton Road, N.E., MS A-20, Atlanta, GA 30333. Telephone:=20 404-639-3747; Fax: 404-639-3866; E-mail: tuyeki@cdc.gov.

Summary

This report updates the 2009 recommendations by CDC's Advisory = Committee=20 on Immunization Practices (ACIP) regarding the use of influenza vaccine = for the=20 prevention and control of influenza (CDC. = Prevention and=20 control of influenza: recommendations of the Advisory Committee on = Immunization=20 Practices [ACIP]. MMWR 2009;58[No. RR-8] and CDC. Use = of=20 influenza A (H1N1) 2009 monovalent vaccine---recommendations of the = Advisory=20 Committee on Immunization Practices [ACIP], 2009. MMWR 2009;58:[No. = RR-10]).=20 The 2010 influenza recommendations include new and updated information.=20 Highlights of the 2010 recommendations include 1) a recommendation that = annual=20 vaccination be administered to all persons aged =E2=89=A56 months for = the 2010--11=20 influenza season; 2) a recommendation that children aged 6 months--8 = years whose=20 vaccination status is unknown or who have never received seasonal = influenza=20 vaccine before (or who received seasonal vaccine for the first time in = 2009--10=20 but received only 1 dose in their first year of vaccination) as well as = children=20 who did not receive at least 1 dose of an influenza A (H1N1) 2009 = monovalent=20 vaccine regardless of previous influenza vaccine history should receive = 2 doses=20 of a 2010--11 seasonal influenza vaccine (minimum interval: 4 weeks) = during the=20 2010--11 season; 3) a recommendation that vaccines containing the = 2010--11=20 trivalent vaccine virus strains A/California/7/2009 (H1N1)-like (the = same strain=20 as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 = (H3N2)-like, and=20 B/Brisbane/60/2008-like antigens be used; 4) information about Fluzone=20 High-Dose, a newly approved vaccine for persons aged =E2=89=A565 years; = and 5)=20 information about other standard-dose newly approved influenza vaccines = and=20 previously approved vaccines with expanded age indications. Vaccination = efforts=20 should begin as soon as the 2010--11 seasonal influenza vaccine is = available and=20 continue through the influenza season. These recommendations also = include a=20 summary of safety data for U.S.-licensed influenza vaccines. These=20 recommendations and other information are available at CDC's influenza = website=20 (http://www.cdc.gov/flu); any = updates or=20 supplements that might be required during the 2010--11 influenza season = also=20 will be available at this website. Recommendations for influenza = diagnosis and=20 antiviral use will be published before the start of the 2010--11 = influenza=20 season. Vaccination and health-care providers should be alert to = announcements=20 of recommendation updates and should check the CDC influenza website=20 periodically for additional information.

Introduction

In the United States, annual epidemics of influenza occur typically = during=20 the late fall through early spring. Influenza viruses can cause disease = among=20 persons in any age group, but rates of infection are highest among = children=20 (1--3). During these annual epidemics, rates of serious illness = and death=20 are highest among persons aged =E2=89=A565 years, children aged <2 = years, and persons=20 of any age who have medical conditions that place them at increased risk = for=20 complications from influenza (1,4,5). Influenza epidemics were = associated=20 with estimated annual averages of approximately 36,000 deaths during = 1990--1999=20 and approximately 226,000 hospitalizations during 1979--2001 = (6,7).

Influenza A subtypes that are generated by a major genetic = reassortment=20 (i.e., antigenic shift) or that are substantially different from viruses = that=20 have caused infections over the previous several decades have the = potential to=20 cause a pandemic (8). In April 2009, a novel influenza A (H1N1) = virus,=20 2009 influenza A (H1N1), that is similar to but genetically and = antigenically=20 distinct from influenza A (H1N1) viruses previously identified in swine, = was=20 determined to be the cause of respiratory illnesses that spread across = North=20 America and were identified in many areas of the world by May 2009=20 (9,10). Influenza morbidity caused by 2009 pandemic influenza A = (H1N1)=20 remained above seasonal baselines throughout spring and summer 2009 and = was the=20 cause of the first pandemic since 1968. In the United States, the = pandemic was=20 characterized by a substantial increase in influenza activity, as = measured by=20 multiple influenza surveillance systems, that was well beyond historical = norms=20 in September 2009, peaking in late October 2009, and returning to = seasonal=20 baseline by January 2010 (Fi= gures=20 1 and 2<= /A>).=20 During this time, >99% of viruses characterized were the 2009 = pandemic=20 influenza A (H1N1) virus (11= ). Data=20 from epidemiologic studies conducted during the 2009 influenza A (H1N1) = pandemic=20 indicate that the risk for influenza complications among adults aged = 19--64=20 years who had 2009 pandemic influenza A (H1N1) was greater than = typically occurs=20 for seasonal influenza (12). Influenza caused by 2009 pandemic = influenza=20 A (H1N1) virus is expected to continue to occur during future winter = influenza=20 seasons in the Northern and Southern Hemispheres, but whether 2009 = pandemic=20 influenza A (H1N1) viruses will replace or co-circulate with one or more = of the=20 two seasonal influenza A virus subtypes (seasonal H1N1 and H3N2) that = have=20 co-circulated since 1977 is unknown. Influenza viruses undergo frequent=20 antigenic change as a result of point mutations and recombination events = that=20 occur during viral replication (i.e., antigenic drift). The extent of = antigenic=20 drift and evolution of 2009 pandemic influenza A (H1N1) virus strains in = the=20 future cannot be predicted.

Annual influenza vaccination is the most effective method for = preventing=20 influenza virus infection and its complications (8). Annual = vaccination=20 with the most up-to-date strains predicted on the basis of viral = surveillance=20 data is recommended. Influenza vaccine is recommended for all persons = aged =E2=89=A56=20 months who do not have contraindications to vaccination. Trivalent = inactivated=20 influenza vaccine (TIV) can be used for any person aged =E2=89=A56 = months, including=20 those with high-risk conditions (Box). Live, attenuated influenza = vaccine (LAIV)=20 may be used for healthy nonpregnant persons aged 2--49 years. No = preference is=20 indicated for LAIV or TIV when considering vaccination of healthy = nonpregnant=20 persons aged 2--49 years. Because the safety or effectiveness of LAIV = has not=20 been established in persons with underlying medical conditions that = confer a=20 higher risk for influenza complications, these persons should be = vaccinated only=20 with TIV. Although vaccination coverage has increased in recent years = for many=20 groups recommended for routine vaccination, considerable room for = improvement=20 remains (13= ), and=20 strategies to improve vaccination coverage in the medical home and in = nonmedical=20 settings should be implemented or expanded (14).

Antiviral medications are an adjunct to vaccination and are effective = when=20 administered as treatment and when used for chemoprophylaxis after an = exposure=20 to influenza virus. However, the emergence since 2005 of resistance to = one or=20 more of the four licensed antiviral agents (oseltamivir, zanamivir, = amantadine,=20 and rimantadine) among circulating strains has complicated antiviral = treatment=20 and chemoprophylaxis recommendations. CDC has revised recommendations = for=20 antiviral treatment and chemoprophylaxis of influenza periodically in = response=20 to new data on antiviral resistance patterns among circulating strains = and risk=20 factors for influenza complications (15). With few exceptions, = 2009=20 pandemic influenza A (H1N1) virus strains that began circulating in = April 2009=20 remained sensitive to oseltamivir (16).

Methods

CDC's Advisory Committee on Immunization Practices (ACIP) provides = annual=20 recommendations for the prevention and control of influenza. The ACIP = Influenza=20 Work Group (the Work Group)* meets every 2--4 weeks throughout the year = to=20 discuss newly published studies, review current guidelines, and consider = revisions to the recommendations. As the Work Group reviews the annual=20 recommendations for consideration by the full ACIP, its members discuss = a=20 variety of issues, including the burden of influenza illness; vaccine=20 effectiveness, vaccine safety, and coverage in groups recommended for=20 vaccination; feasibility; cost-effectiveness; and anticipated vaccine = supply.=20 Work Group members also request periodic updates on vaccine and = antiviral=20 production, supply, safety, and efficacy from vaccinologists, = epidemiologists,=20 and manufacturers. State and local vaccination program representatives = are=20 consulted. CDC's Influenza Division (available at http://www.cdc.gov/flu) provides = influenza=20 surveillance and antiviral resistance data. The Vaccines and Related = Biological=20 Products Advisory Committee provides advice on vaccine strain selection = to the=20 Food and Drug Administration (FDA), which selects the viral strains to = be used=20 in the annual trivalent influenza vaccines.

Published, peer-reviewed studies are the primary source of data used = by ACIP=20 in making recommendations for the prevention and control of influenza, = but=20 unpublished data that are relevant to issues under discussion also are=20 considered. Among studies discussed or cited, those of greatest = scientific=20 quality and those that measure influenza-specific outcomes are the most=20 influential. For example, population-based estimates of influenza = disease burden=20 supported by laboratory-confirmed influenza virus infection outcomes = contribute=20 the most specific data. The best evidence for vaccine or antiviral = efficacy=20 comes from randomized controlled trials that assess laboratory-confirmed = influenza infections as an outcome measure and consider factors such as = timing=20 and intensity of influenza viruses' circulation and degree of match = between=20 vaccine strains and wild circulating strains (17,18). However, = randomized=20 controlled trials cannot be performed ethically in populations for which = vaccination already is recommended, and in this context, observational = studies=20 that assess outcomes associated with laboratory-confirmed influenza = infection=20 also can provide important vaccine or antiviral safety and effectiveness = data.=20 Evidence for vaccine or antiviral safety also is provided by randomized=20 controlled studies; however, the number of subjects in these studies = often is=20 inadequate to detect associations between vaccine and rare adverse = events. The=20 best way to assess the frequency of rare adverse events after = vaccination is by=20 controlled studies after vaccines are used widely in the population. = These=20 studies often use electronic medical records from large linked clinical=20 databases and medical charts of persons who are identified as having a = vaccine=20 adverse event (19--21). Vaccine coverage data from a nationally=20 representative, randomly selected population that include verification = of=20 vaccination through health-care record review are superior to coverage = data=20 derived from limited population samples or from self-reported = vaccination=20 status; however, the former rarely is obtained in vaccination coverage = data for=20 children aged =E2=89=A55 years (22). Finally, studies that assess = vaccination=20 program practices that improve vaccination coverage are most influential = in=20 formulating recommendations if the study design includes a = nonintervention=20 comparison group. In cited studies that included statistical = comparisons, a=20 difference was considered to be statistically significant if the p-value = was=20 <0.05 or the 95% confidence interval around an estimate of effect = allowed=20 rejection of the null hypothesis (i.e., no effect).

Data presented in this report were current as of June 29, 2010, and = represent=20 recommendations presented to the full ACIP and approved on February 24, = 2010,=20 and June 24, 2010. Modifications were made to the ACIP statement during = the=20 subsequent review process at CDC to update and clarify wording in the = document.=20 Vaccine recommendations apply only to persons who do not have = contraindications=20 to vaccine use (see Contraindications and Precautions for Use of TIV and = Contraindications and Precautions for Use of LAIV). Further updates, if = needed,=20 will be posted at CDC's influenza website (http://www.cdc.gov/flu).

Primary Changes and Updates in the=20 Recommendations

The 2010 recommendations include five principal changes or = updates:

Routine influenza vaccination is recommended for all = persons=20 aged =E2=89=A56 months. This represents an expansion of the previous = recommendations=20 for annual vaccination of all adults aged 19---49 years and is = supported by=20 evidence that annual influenza vaccination is a safe and effective = preventive=20 health action with potential benefit in all age groups. By 2009, = annual=20 vaccination was already recommended for an estimated 85% of the U.S.=20 population, on the basis of risk factors for influenza-related = complications=20 or having close contact with a person at higher risk for = influenza-related=20 complications. The only group remaining that was not recommended for = routine=20 vaccination was healthy nonpregnant adults aged 18--49 years who did = not have=20 an occupational risk for infection and who were not close contacts of = persons=20 at higher risk for influenza-related complications. However, some = adults who=20 have influenza-related complications have no previously identified = risk=20 factors for influenza complications. In addition, some adults who have = medical=20 conditions or age-related increases in their risk for = influenza-related=20 complications or another indication for vaccination are unaware that = they=20 should be vaccinated. Further support for expansion of annual = vaccination=20 recommendations to include all adults is based on concerns that 2009 = pandemic=20 influenza A (H1N1)-like viruses will continue to circulate during the = 2010--11=20 influenza season and that a substantial proportion of young adults = might=20 remain susceptible to infection with this virus. Data from = epidemiologic=20 studies conducted during the 2009 pandemic indicate that the risk for=20 influenza complications among adults aged 19--49 years is greater than = is seen=20 typically for seasonal influenza (12,23,27= ).
As in previous recommendations, all children aged 6 = months--8=20 years who receive a seasonal influenza vaccine for the first time = should=20 receive 2 doses. Children who received only 1 dose of a seasonal = influenza=20 vaccine in the first influenza season that they received vaccine = should=20 receive 2 doses, rather than 1, in the following influenza season. In=20 addition, for the 2010--11 influenza season, children aged 6 months--8 = years=20 who did not receive at least 1 dose of an influenza A (H1N1) 2009 = monovalent=20 vaccine should receive 2 doses of a 2010--11 seasonal influenza = vaccine,=20 regardless of previous influenza vaccination history. Children aged 6=20 months--8 years for whom the previous 2009--10 seasonal or influenza A = (H1N1)=20 2009 monovalent vaccine history cannot be determined should receive 2 = doses of=20 a 2010--11 seasonal influenza vaccine.
The 2010--11 trivalent vaccines will contain=20 A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like, and=20 B/Brisbane/60/2008-like antigens. The influenza A (H1N1) vaccine virus = is=20 derived from a 2009 pandemic influenza A (H1N1) virus.
A newly approved inactivated trivalent vaccine = containing 60=20 mcg of hemagglutinin antigen per influenza vaccine virus strain = (Fluzone=20 High-Dose [sanofi pasteur]) is an alternative inactivated vaccine for = persons=20 aged =E2=89=A565 years. Persons aged =E2=89=A565 years can be = administered any of the=20 standard-dose TIV preparations or Fluzone High-Dose. Persons aged = <65 years=20 who receive inactivated influenza vaccine should be administered a=20 standard-dose TIV preparation.
Previously approved inactivated influenza vaccines = that were=20 approved for expanded age indications in 2009 include Fluarix=20 (GlaxoSmithKline), which is now approved for use in persons aged = =E2=89=A53 years, and=20 Afluria (CSL Biotherapies), which is now approved for use in persons = aged =E2=89=A56=20 months. A new inactivated influenza vaccine, Agriflu (Novartis), has = been=20 approved for persons aged =E2=89=A518 years.

Background and Epidemiology

Biology of Influenza

Influenza A and B are the two types of influenza viruses that cause = epidemic=20 human disease. Influenza A viruses are categorized into subtypes on the = basis of=20 two surface antigens: hemagglutinin and neuraminidase. During = 1977--2010,=20 influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B = viruses=20 have circulated globally. Influenza A subtypes and B viruses are = separated=20 further into groups on the basis of antigenic similarities. New = influenza virus=20 variants result from frequent antigenic change (i.e., antigenic drift) = caused by=20 point mutations and recombination events that occur during viral = replication=20 (8). Recent studies have explored the complex molecular evolution = and=20 epidemiologic dynamics of influenza A viruses (28--30).

New or substantially different influenza A subtypes have the = potential to=20 cause a pandemic when they are able to cause human illness and = demonstrate=20 efficient human-to-human transmission and when little or no previously = existing=20 immunity has been identified among humans (8). In April 2009, = human=20 infections with a novel influenza A (H1N1) virus were identified, and = this virus=20 subsequently caused a worldwide pandemic (9). The 2009 pandemic = influenza=20 A (H1N1) virus is derived from influenza A viruses that have circulated = in swine=20 during the past several decades and is antigenically distinct from human = influenza A (H1N1) viruses in circulation since 1977. The 2009 pandemic=20 influenza A (H1N) virus contains a combination of gene segments that had = not=20 been reported previously in animals or humans. The hemagglutination (HA) = gene,=20 which codes for the surface protein most important for immune response, = is=20 related most closely to the HA found in contemporary influenza viruses=20 circulating among pigs. This HA gene apparently evolved from the = avian-origin=20 1918 pandemic influenza H1N1 virus, which is thought to have entered = human and=20 swine populations at about the same time (28).

Currently circulating influenza B viruses are separated into two = distinct=20 genetic lineages (Yamagata and Victoria) but are not categorized into = subtypes.=20 Influenza B viruses undergo antigenic drift less rapidly than influenza = A=20 viruses. Influenza B viruses from both lineages have circulated in most = recent=20 influenza seasons (31).

Immunity to surface antigens, particularly hemagglutinin, reduces the = likelihood of infection (32). Antibody against one influenza = virus type=20 or subtype confers limited or no protection against another type or = subtype of=20 influenza virus. Furthermore, antibody to one antigenic type or subtype = of=20 influenza virus might not protect against infection with a new antigenic = variant=20 of the same type or subtype (33). Frequent emergence of antigenic = variants through antigenic drift is the virologic basis for seasonal = epidemics=20 and is the reason for annually reassessing the need to change one or = more of the=20 recommended strains for influenza vaccines.

More dramatic changes, or antigenic shifts, occur less frequently. = Antigenic=20 shift occurs when a new subtype of influenza A virus appears and can = result in=20 the emergence of a novel influenza A virus with the potential to cause a = pandemic. The 2009 pandemic influenza A (H1N1) virus is not a new = subtype, but=20 because most humans had no pre-existing antibody to key pandemic 2009 = influenza=20 A (H1N1) virus hemagglutinin epitopes, widespread transmission was = possible=20 (28).

Health-Care Use, Hospitalizations, and Deaths Attributed to = Influenza

In the United States, annual epidemics of influenza typically occur = during=20 the fall or winter months, but the peak of influenza activity can occur = as late=20 as April or May. Influenza-related complications requiring urgent = medical care,=20 including hospitalizations or deaths, can result from the direct effects = of=20 influenza virus infection, from complications associated with age or = pregnancy,=20 or from complications of underlying cardiopulmonary conditions or other = chronic=20 diseases. Studies that have measured rates of a clinical outcome without = a=20 laboratory confirmation of influenza virus infection (e.g., respiratory = illness=20 requiring hospitalization during influenza season) to assess the effect = of=20 influenza can be difficult to interpret because of circulation of other=20 respiratory pathogens (e.g., respiratory syncytial virus) during the = same time=20 as influenza viruses (34--36). However, increases in health-care = provider=20 visits for acute febrile respiratory illness occur each year during the = time=20 when influenza viruses circulate. Data from the U.S. Outpatient = Influenza-like=20 Illness Surveillance Network (ILINet) demonstrate the annual increase in = physician visits for influenza-like illness (ILI)=E2=80=A0 and for each influenza season; for = 2009, these data=20 also indicated the increase in respiratory illness associated with = circulation=20 of 2009 pandemic influenza A (H1N1) virus during Spring 2009 and the = resurgence=20 of cases in Fall 2009 (Fi= gure=20 2) (37,38= ).

In typical winter influenza seasons, an increase in deaths and=20 hospitalizations is observed during periods when influenza viruses are=20 circulating. Some persons whose hospitalization is attributed to = invasive=20 pneumococcal pneumonia are likely to have influenza as a co-pathogen, = based on=20 correlation between influenza activity and seasonal variations in = pneumococcal=20 pneumonia (39). The number of deaths or hospitalizations = attributable at=20 least partly to influenza can be estimated by applying modeling = techniques to=20 viral surveillance and national mortality or hospitalizations data and = includes=20 deaths and hospitalizations for which influenza infection is likely a=20 contributor to mortality but not necessarily the sole cause of death=20 (6,7,40,41).

Excess deaths and hospitalizations during influenza season that are = likely to=20 be caused at least partly by influenza are derived from the broad = category of=20 pulmonary and circulatory deaths or hospitalizations. Estimates that = include=20 only outcomes attributed to pneumonia and influenza underestimate the = proportion=20 of severe illnesses that are attributable at least partly to influenza = because=20 such estimates exclude deaths caused by exacerbations of underlying = cardiac and=20 pulmonary conditions that are associated with influenza infection=20 (6,7,40--42).

During seasonal influenza epidemics from 1979--1980 through = 2000--2001, the=20 estimated annual overall number of influenza-associated hospitalizations = in the=20 United States ranged from approximately 55,000 to 431,000 per annual = epidemic=20 (mean: 226,000) (7). In the United States, the estimated number = of=20 influenza-associated deaths increased during 1990--1999. This increase = was=20 attributed in part to the substantial increase in the number of persons = aged =E2=89=A565=20 years, including many who were at higher risk for death from influenza=20 complications (6). When mortality data that included deaths = attributable=20 to both the pneumonia and influenza as well as the respiratory and = circulatory=20 categories were used as a basis for estimating the influenza burden, an = average=20 of approximately 19,000 influenza-associated deaths per influenza season = occurred during 1976--1990 compared with an average of approximately = 36,000=20 deaths per season during 1990--1999 (6). On the basis of data = from the=20 pneumonia and influenza category alone, an estimated annual average of = 8,000=20 influenza-related deaths occurred. In addition, influenza A (H3N2) = viruses,=20 which have been associated with higher mortality (43), = predominated in=20 90% of influenza seasons during 1990--1999 compared with 57% of seasons = during=20 1976--1990 (6). From the 1990--91 influenza season through the = 1998--99=20 season, the estimated annual number of deaths attributed to influenza = ranged=20 from 17,000 to 51,000 per epidemic (6). Estimates of mortality = using a=20 variety of different modeling techniques generally have been similar, = although=20 estimates for more recent years, when influenza A (H1N1) viruses have=20 predominated more often, have been somewhat lower (40).

Influenza viruses cause disease among persons in all age groups=20 (1--5). Rates of infection are highest among children, but the = risks for=20 complications, hospitalizations, and deaths from seasonal influenza are = higher=20 among adults aged =E2=89=A565 years, children aged <5 years, and = persons of any age=20 who have medical conditions that place them at increased risk for = complications=20 from influenza (1,4,5,44--47). Estimated rates of = influenza-associated=20 hospitalizations and deaths varied substantially by age group in studies = conducted during different seasonal influenza epidemics. During = 1990--1999,=20 estimated average rates of influenza-associated pulmonary and = circulatory deaths=20 per 100,000 persons were 0.4--0.6 among persons aged 0--49 years, 7.5 = among=20 persons aged 50--64 years, and 98.3 among persons aged =E2=89=A565 years = (6).=20

During the 2009 influenza A (H1N1) pandemic, epidemiologic studies in = multiple countries indicated that hospitalization rates and deaths among = children and adults aged <65 years exceeded those observed during = typical=20 winter seasonal influenza epidemics (12,23,25,48,49). In one = analysis,=20 the mean age among persons who died in the United States during = May--December=20 2009 and who had laboratory-confirmed influenza was 37 years. In = contrast, the=20 estimated mean age among persons who died from seasonal influenza during = 1979--2001 was 76 years (50). The estimated number of = hospitalizations=20 and deaths among adults aged =E2=89=A565 years was below that observed = in most seasonal=20 epidemics. This difference was attributed to a lower risk for infection=20 (51) associated with a higher prevalence of partial or full = immunity=20 among older persons, presumably as a result of exposures to = antigenically=20 similar influenza A viruses that circulated in the early-mid 20th = century. One=20 indication of some degree of preexisting immunity was the presence of=20 cross-reacting antibody present among approximately one third of older = adults=20 (52), which has been attributed to similarities in the structure = of the=20 hemagglutinin protein among the 2009 H1N1 virus and those that = circulated=20 earlier in the 20th century (53).

Children

Among children aged <5 years, influenza-related illness is a = common cause=20 of visits to medical practices and emergency departments (EDs). During = two=20 influenza seasons (2002--03 and 2003--04), the percentage of visits = among=20 children aged <5 years with acute respiratory illness or fever caused = by=20 laboratory-confirmed influenza ranged from 10%--19% of medical office = visits to=20 6%--29% of ED visits. On the basis of these data, the rate of visits to = medical=20 clinics for influenza was estimated to be 50--95 visits per 1,000 = children, and=20 the rate of visits to EDs was estimated to be 6--27 visits per 1,000 = children=20 (54). In a multiyear study in New York City that used viral = surveillance=20 data to estimate influenza strain-specific illness rates among ED = visits, in=20 addition to the expected variation by season and age group, influenza B=20 epidemics were determined to be an important cause of illness among = school-aged=20 children in several seasons, and annual epidemics of both influenza A = and B=20 peaked among school-aged children before other age groups (55).=20 Retrospective studies using medical records data have demonstrated = similar rates=20 of illness among children aged <5 years during other influenza = seasons=20 (45,56,57). During an influenza season, seven to 12 additional = outpatient=20 visits and five to seven additional antibiotic prescriptions per 100 = children=20 aged <15 years have been estimated compared with periods when = influenza=20 viruses are not circulating, with rates decreasing with increasing age = of the=20 child (57). During 1993--2004 in the Boston area, the rate of ED = visits=20 for respiratory illnesses that were attributed to influenza virus on the = basis=20 of viral surveillance data among children aged =E2=89=A47 years during = the winter=20 respiratory illness season ranged from 22.0 per 1,000 children aged = 6--23 months=20 to 5.4 per 1,000 children aged 5--7 years (58).

Estimates of rates of influenza-associated hospitalization are = substantially=20 higher among infants and children aged <2 years compared with older = children=20 and are similar to rates for other groups considered at higher risk for=20 influenza-related complications (59--64), including persons aged = =E2=89=A565=20 years (57,61). During 1979--2001, the estimated rate of=20 influenza-associated hospitalizations among children aged <5 years in = the=20 United States was 108 hospitalizations per 100,000 person-years, based = on data=20 from a national sample of hospital discharges of influenza-associated=20 hospitalizations (7). Recent population-based studies that = measured=20 hospitalization rates for laboratory-confirmed influenza in young = children have=20 documented hospitalization rates that are similar to or higher than = rates=20 derived from studies that analyzed hospital discharge data=20 (54,56,63,65,66). Annual hospitalization rates for = laboratory-confirmed=20 influenza decrease with increasing age, ranging from 240--720 per = 100,000=20 children aged <6 months to approximately 20 per 100,000 children aged = 2--5=20 years (54). Hospitalization rates for children aged <5 years = with=20 high-risk medical conditions are approximately 250--500 per 100,000 = children=20 (45,47,67).

Influenza-associated deaths are uncommon among children. An estimated = annual=20 average of 92 influenza-associated deaths (0.4 deaths per 100,000 = persons)=20 occurred among children aged <5 years during the 1990s compared with = 32,651=20 deaths (98.3 per 100,000 persons) among adults aged =E2=89=A565 years = (6). Of 153=20 laboratory-confirmed influenza-related pediatric deaths reported during = the=20 2003--04 influenza season, 96 (63%) deaths occurred among children aged = <5=20 years and 61 (40%) among children aged <2 years. Among the 149 = children who=20 died and for whom information on underlying health status was available, = 100=20 (67%) did not have an underlying medical condition that was an = indication for=20 vaccination at that time (68). In California during the 2003--04 = and=20 2004--05 influenza seasons, 51% of children aged <18 years with=20 laboratory-confirmed influenza who died and 40% of those who required = admission=20 to an intensive care unit had no underlying medical conditions = (69).=20 These data indicate that although children with risk factors for = influenza=20 complications are at higher risk for death, the majority of pediatric = deaths=20 occur among children with no known high-risk conditions.

Since 2004, death associated with laboratory-confirmed influenza = virus=20 infection among children (defined as persons aged <18 years) has been = a=20 nationally reportable condition. During 2004--2005, the annual number of = seasonal influenza-associated deaths among children aged <18 years = reported=20 to CDC ranged from 47 during 2004--05 to 88 during 2007--08 (70= ). During=20 April 2009--March 2010, over 300 deaths attributable to = laboratory-confirmed=20 2009 H1N1 influenza among children, the majority of whom had one or more = underlying medical conditions, were reported to CDC in the United = States, and=20 over 1,000 deaths are estimated to have occurred (71; CDC, = unpublished=20 data, 2010).

Deaths among children that have been attributed to co-infection with=20 influenza and Staphylococcus aureus, particularly = methicillin-resistant=20 S. aureus (MRSA), have increased (38,72<= /I>), and=20 illness severity of co-infection is increased compared with influenza = alone=20 (73). The reason for this increase in co-infections has not been=20 established but might reflect an increasing prevalence within the = general=20 population of colonization with MRSA strains, some of which carry = certain=20 virulence factors (74,75= ).

Adults

Among healthy younger adults, illness caused by seasonal influenza is = typically not severe and rarely results in hospitalization, compared = with=20 children aged <5 years, adults aged =E2=89=A565 years, pregnant = women, or persons=20 with chronic medical conditions. However, illness burden among healthy = adults=20 aged 19--49 years is an important cause of outpatient medical visits and = worker=20 absenteeism. The impact of influenza varies considerably by season, = making=20 estimates of the attack rate in healthy younger adults difficult. In = most=20 studies, attack rates have varied from 2% to 10% annually, and influenza = has=20 been estimated to cause 0.6--2.5 workdays lost per illness = (76--80). In=20 one economic analysis, the average annual burden of seasonal influenza = among=20 adults aged 18--49 years who did not have a medical condition that = conferred a=20 higher risk for influenza complications was estimated to include = approximately 5=20 million illnesses, 2.4 million outpatient visits, 32,000 = hospitalizations, and=20 680 deaths (78).

Hospitalization rates during typical influenza seasons are = substantially=20 increased for persons aged =E2=89=A565 years compared with younger age = groups. One=20 retrospective analysis based on data from managed-care organizations = collected=20 during 1996--2000 estimated that the risk during influenza season among = persons=20 aged =E2=89=A565 years with underlying conditions that put them at risk = for=20 influenza-related complications (i.e., one or more of the conditions = listed as=20 indications for vaccination) was approximately 560 influenza-associated=20 hospitalizations per 100,000 persons compared with approximately 190 per = 100,000=20 healthy persons aged =E2=89=A565 years. Persons aged 50--64 years who = have underlying=20 medical conditions also were at substantially increased risk for=20 hospitalizations during influenza season compared with healthy adults = aged=20 50--64 years (44).

Influenza is an important contributor to the annual increase in = deaths=20 attributed to pneumonia and influenza that is observed during the winter = months.=20 During 1976--2001, an estimated yearly average of 32,651 (90%) = influenza-related=20 deaths occurred among adults aged =E2=89=A565 years, with the risk for = an=20 influenza-related death highest in the oldest age groups (6). = Persons=20 aged =E2=89=A585 years were 16 times more likely to die from an = influenza-related=20 illness compared with persons aged 65--69 years (6).

During the 2009 H1N1 pandemic, adults aged <65 years were at = higher risk=20 for influenza-related complications (23,81,82), particularly = those aged=20 50--64 years who had underlying medical conditions, compared with = typical=20 influenza seasons. The distribution of hospitalizations by age group = differed=20 from usual seasonal influenza patterns during 2009--10, with more=20 hospitalizations among younger age groups and fewer among adults aged = =E2=89=A565 years=20 (Fi= gure=20 1). Hospitalization rates exceeded those seen in any recent = influenza season=20 among adults aged =E2=89=A465 years (26). Pneumonia with evidence = of invasive=20 bacterial co-infection has been reported in approximately one third of = fatal=20 cases in autopsy studies (83). In one study of critically ill = adults who=20 required mechanical ventilation, Streptococcus pneumoniae = pneumonia at=20 admission was an independent risk factor for death (84). In = addition,=20 obesity (body-mass index [BMI] =E2=89=A530) and particularly morbid = obesity (BMI =E2=89=A540)=20 appeared to be risk factors for hospitalization and death in some = studies=20 (23,24,81,85,86= ).=20 Additional studies are needed to determine whether obesity is a risk = factor=20 specific to the 2009 H1N1-like influenza viruses or a previously = unrecognized=20 risk factor for influenza-related complications caused by other = influenza=20 viruses. Other epidemiologic features of the 2009 H1N1 pandemic = underscored=20 racial and ethnic disparities in the risk for influenza-related = complications=20 among adults, including higher rates of hospitalization for blacks and a = disproportionate number of deaths among American Indians/Alaska Natives = and=20 indigenous populations in other countries (87--91). These = disparities=20 might be attributable in part to the higher prevalence of underlying = medical=20 conditions or disparities in medical care among these racial/ethnic = groups=20 (92,93).

The duration of influenza symptoms is prolonged and the severity of = influenza=20 illness increased among persons with human immunodeficiency virus (HIV)=20 infection (94--98). A retrospective study of women aged 15--64 = years=20 enrolled in Tennessee's Medicaid program determined that the = attributable risk=20 for cardiopulmonary hospitalizations among women with HIV infection was = higher=20 during influenza seasons than it was either before or after influenza = was=20 circulating. The risk for hospitalization was higher for HIV-infected = women than=20 it was for women with other underlying medical conditions (99). = Another=20 study estimated that the risk for influenza-related death was 94--146 = deaths per=20 100,000 persons with acquired immune deficiency syndrome (AIDS) compared = with=20 0.9--1.0 deaths per 100,000 persons aged 25--54 years and 64--70 deaths = per=20 100,000 persons aged =E2=89=A565 years in the general population = (100).

Influenza-related excess deaths among pregnant women were reported = during the=20 pandemics of 1918--1919, 1957--1958, and 2009--2010 = (48,101--106). Severe=20 infections among postpartum women (those delivered within the previous 2 = weeks)=20 also were observed in the 2009--10 pandemic (48,107,10= 8).=20 Case reports and several epidemiologic studies also indicate that = pregnancy=20 increases the risk for seasonal influenza complications for the mother=20 (109--114). The majority of studies that have attempted to assess = the=20 effect of influenza on pregnant women have measured changes in excess=20 hospitalizations for respiratory illness during influenza season but not = laboratory-confirmed influenza hospitalizations. Pregnant women have an=20 increased number of medical visits for respiratory illnesses during = influenza=20 season compared with nonpregnant women (115). Hospitalized = pregnant women=20 with respiratory illness during influenza season have increased lengths = of stay=20 compared with hospitalized pregnant women without respiratory illness. = Rates of=20 hospitalization for respiratory illness were twice as common during = influenza=20 season (116). A retrospective cohort study of approximately = 134,000=20 pregnant women conducted in Nova Scotia during 1990--2002 compared = medical=20 record data for pregnant women to data from the same women during the = year=20 before pregnancy. Among pregnant women, 0.4% were hospitalized, and 25% = visited=20 a clinician during pregnancy for a respiratory illness. The rate of=20 third-trimester hospital admissions during the influenza season was five = times=20 higher than the rate during the influenza season in the year before = pregnancy=20 and more than twice as high as the rate during the noninfluenza season. = An=20 excess of 1,210 hospital admissions in the third trimester per 100,000 = pregnant=20 women with comorbidities and of 68 admissions per 100,000 women without=20 comorbidities was reported (117). In one study, pregnant women = with=20 hospitalizations for respiratory symptoms did not have an increase in = adverse=20 perinatal outcomes or delivery complications (118); another study = indicated an increase in delivery complications, including fetal = distress,=20 preterm labor, and cesarean delivery. However, infants born to women = with=20 laboratory-confirmed influenza during pregnancy do not have higher rates = of low=20 birth weight, congenital abnormalities, or lower Apgar scores compared = with=20 infants born to uninfected women (109,119).

In a case series conducted during the 2009 H1N1 pandemic, 56 deaths = were=20 reported among 280 women admitted to intensive care units (120). = Among=20 the deaths, 36 (64%) occurred in the third trimester. Pregnant women who = received treatment >4 days after symptom onset were more likely than = those=20 treated within 2 days after symptom onset to be admitted to an = intensive=20 care unit (57% and 9%, respectively; relative risk [RR]: 6.0; 95% CI =3D = 3.5--10.6) (120).

Options for Controlling Influenza

The most effective strategy for preventing influenza is annual = vaccination.=20 Strategies that focus on providing routine vaccination to persons at = higher risk=20 for influenza complications have long been recommended, although = coverage among=20 the majority of these groups remains low. Routine vaccination of certain = persons=20 (e.g., children, contacts of persons at risk for influenza = complications, and=20 health-care personnel [HCP]) who serve as a source of influenza virus=20 transmission might provide additional protection to persons at risk for=20 influenza complications and reduce the overall influenza burden. = However,=20 coverage levels among these persons need to be increased before effects = on=20 transmission can be measured reliably. Antiviral medications can be used = for=20 chemoprophylaxis and have been demonstrated to prevent influenza = illness. When=20 used for treatment, antiviral medications have been demonstrated to = reduce the=20 severity and duration of illness, particularly if used within the first = 48 hours=20 after illness onset. However, antiviral medications are adjuncts to = vaccine in=20 the prevention and control of influenza, and primary prevention through = annual=20 vaccination is the most effective and efficient prevention strategy. = Despite=20 recommendations to use antiviral medications to treat hospitalized = patients with=20 suspected influenza, antiviral drugs are underused (121).

Reductions in detectable influenza A viruses on hands after = handwashing have=20 been demonstrated, and handwashing has been demonstrated to reduce the = overall=20 incidence of respiratory diseases (122--124). Nonpharmacologic=20 interventions (e.g., frequent handwashing and improved respiratory = hygiene) are=20 reasonable and inexpensive. However, the impact of hygiene interventions = such as=20 handwashing on influenza virus transmission is not well understood, and = hygiene=20 measures should not be advocated as a replacement or alternative to = specific=20 prevention measures such as vaccination. Few data are available to = assess the=20 effects of community-level respiratory disease mitigation strategies = (e.g.,=20 closing schools, avoiding mass gatherings, or using respiratory = protection) on=20 reducing influenza virus transmission during typical seasonal influenza=20 epidemics (125--127). An interventional trial among university = students=20 indicated that students living in dormitories who were asked to use = surgical=20 face masks, given an alcohol-based hand sanitizer, and provided with = education=20 about mask use and hand hygiene during influenza season had = substantially lower=20 rates of ILI compared with students in dormitories for whom no = intervention was=20 recommended. However, neither face mask nor hand sanitizer use alone was = associated with statistically significant reduction in ILI (128). = During=20 the 2009 pandemic, one study indicated that having members of households = in=20 which an influenza case was identified discuss ways to avoid = transmission was=20 associated with a significant reduction in the frequency of additional = cases=20 after one household member became ill, suggesting that education = measures might=20 be an effective way to reduce secondary transmission (129). = Limited data=20 suggest that transmission of seasonal influenza or ILI among household = members=20 can be reduced if household contacts use a surgical face mask or = implement hand=20 washing early in the course of an ill index case patient's illness=20 (130,131). However, these interventions might supplement use of = vaccine=20 as a means to reduce influenza transmission or provide some protection = when=20 vaccine is not available (130--132).

Influenza Vaccine Efficacy, Effectiveness, = and=20 Safety

Evaluating Influenza Vaccine Efficacy and Effectiveness Studies

The efficacy (i.e., prevention of illness among vaccinated persons in = controlled trials) and effectiveness (i.e., prevention of illness in = vaccinated=20 populations) of influenza vaccines depend in part on the age and=20 immunocompetence of the vaccine recipient, the degree of similarity = between the=20 viruses in the vaccine and those in circulation (see Effectiveness of = Influenza=20 Vaccination When Circulating Influenza Virus Strains Differ from Vaccine = Strains), and the outcome being measured. Influenza vaccine efficacy and = effectiveness studies have used multiple possible outcome measures, = including=20 the prevention of medically attended acute respiratory illness (MAARI),=20 laboratory-confirmed influenza virus illness, influenza or = pneumonia-associated=20 hospitalizations or deaths, or seroconversion. Efficacy or effectiveness = for=20 more specific outcomes such as laboratory-confirmed influenza typically = will be=20 higher than for less specific outcomes such as MAARI because the causes = of MAARI=20 include infections with other pathogens that influenza vaccination would = not be=20 expected to prevent (133). Observational studies that compare=20 less-specific outcomes among vaccinated populations to those among = unvaccinated=20 populations are subject to biases that are difficult to control for = during=20 analyses. For example, an observational study that determines that = influenza=20 vaccination reduces overall mortality might be biased if healthier = persons in=20 the study are more likely to be vaccinated (134,135). Randomized=20 controlled trials that measure laboratory-confirmed influenza virus = infections=20 as the outcome are the most persuasive evidence of vaccine efficacy, but = such=20 trials cannot be conducted ethically among groups recommended to receive = vaccine=20 annually.

Influenza Vaccine Composition

Both LAIV and TIV contain strains of influenza viruses that are = equivalent=20 antigenically to the annually recommended strains: one influenza A = (H3N2) virus,=20 one influenza A (H1N1) virus, and one influenza B virus. Each year, one = or more=20 virus strains in the vaccine might be changed on the basis of global=20 surveillance for influenza viruses and the emergence and spread of new = strains.=20 The 2010--11 trivalent vaccines will contain A/California/7/2009 = (H1N1)-like,=20 A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens. The=20 A/California/7/2009 (H1N1)-like antigen is derived from a pandemic 2009=20 influenza A (H1N1) virus and is the same vaccine antigen used in the = influenza A=20 (H1N1) 2009 monovalent vaccines. The A/Perth/16/2009 (H3N2)-like antigen = is=20 different from the H3N2-like antigen recommended for the 2009--10 = northern=20 hemisphere seasonal influenza vaccine. The influenza B vaccine strain = will=20 remain B/Brisbane/16/2008 and is not changed compared with the 2009--10 = northern=20 hemisphere seasonal influenza vaccine (136). Viruses for = currently=20 licensed TIV and LAIV preparations are grown in chicken eggs. Either = vaccine is=20 administered annually to provide optimal protection against influenza = virus=20 infection (Ta= ble=20 1). Both TIV and LAIV are widely available in the United States. = Although=20 both types of vaccines are expected to be effective, the vaccines differ = in=20 several respects (Ta= ble=20 1). None of the influenza vaccines licensed in the United States = contains an=20 adjuvant.

Major Differences Between TIV and LAIV

TIV contains inactivated viruses and thus cannot cause influenza. = LAIV=20 contains live attenuated influenza viruses that have the potential to = cause mild=20 signs or symptoms related to vaccine virus infection (e.g., rhinorrhea, = nasal=20 congestion, fever, or sore throat). LAIV is administered intranasally by = sprayer, whereas TIV is administered intramuscularly by injection. LAIV = is=20 licensed for use among nonpregnant persons aged 2--49 years; safety has = not been=20 established in persons with underlying medical conditions that confer a = higher=20 risk for influenza complications. TIV is licensed for use among persons = aged =E2=89=A56=20 months, including those who are healthy and those with chronic medical=20 conditions (Ta= ble=20 1). During the preparation of TIV, the vaccine viruses are made=20 noninfectious (i.e., inactivated or killed) (8). Only subvirion = and=20 purified surface antigen preparations of TIV (often referred to as = "split" and=20 subunit vaccines, respectively) are available in the United States.=20 Standard-dose TIV preparations contain 7.5 mcg HA antigen per vaccine = strain=20 (for children aged <36 months) or 15 mcg of HA antigen (for persons = aged =E2=89=A536=20 months) per vaccine strain (i.e., 22.5 mcg or 45 mcg total HA antigen). = A newly=20 licensed higher dose TIV (60 mcg per vaccine strain or 180 mcg total HA = antigen)=20 was approved recently for persons aged =E2=89=A565 years (Fluzone = High-Dose, Sanofi=20 pasteur).

Correlates of Protection after Vaccination

Immune correlates of protection against influenza infection after = vaccination=20 include serum hemagglutination inhibition antibody and neutralizing = antibody=20 (32,137). Increased levels of antibody induced by vaccination = decrease=20 the risk for illness caused by strains that are similar antigenically to = those=20 strains of the same type or subtype included in the vaccine = (138--141).=20 The majority of healthy children and adults have high titers of antibody = after=20 vaccination (139,142). Although immune correlates such as = achievement of=20 certain antibody titers after vaccination correlate well with immunity = on a=20 population level, the significance of reaching or failing to reach a = certain=20 antibody threshold (typically defined as a hemagglutination titer of = 1:32 or=20 1:40) is not well understood on the individual level. Other immunologic=20 correlates of protection that might best indicate clinical protection = after=20 receipt of an intranasal vaccine such as LAIV (e.g., mucosal antibody) = are more=20 difficult to measure (143,144). Laboratory measurements that = correlate=20 with protective immunity induced by LAIV have been described, including=20 measurement of cell-mediated immunity with ELISPOT assays that measure=20 gamma-interferon (143).

Duration of Immunity

The recommended composition of influenza vaccines changes in most = seasons,=20 with one or more vaccine strains replaced annually to provide better = protection=20 against wild-type viruses that are likely to circulate. However, = evidence from=20 clinical trials suggests that protection against viruses that are = similar=20 antigenically to those contained in the vaccine extends for at least = 6--8=20 months. Three years after vaccination with the A/Hong Kong/68 vaccine, = vaccine=20 effectiveness was 67% for prevention of influenza caused by the A/Hong = Kong/68=20 virus (145). In randomized trials conducted among healthy college = students, immunization with TIV provided 92% and 100% efficacy against = influenza=20 H3N2 and H1N1 illnesses, respectively, during the first year, and a 68%=20 reduction against H1N1 illness during the second year (when the = predominant=20 circulating virus was H1N1) without revaccination (146). In a = similar=20 study of young adults in 1986--1987, TIV reduced influenza A (H1N1) = illness 75%=20 in the first year, H3N2 illness 45% in the second year, and H1N1 illness = 61% in=20 the third year after immunization (146). Serum anti-influenza = antibodies=20 and nasal IgA elicited by vaccination remain detectable in children = vaccinated=20 with LAIV for more than 1 year (147). In one community-based=20 nonrandomized open label trial, continued protection from MAARI during = the=20 2000--01 influenza season was demonstrated in children who received only = a=20 single dose of LAIV during the 1999--2000 season (148).

Adults aged =E2=89=A565 years typically have a diminished immune = response to=20 influenza vaccination compared with young healthy adults, suggesting = that=20 immunity might be of shorter duration (although still extending through = one=20 influenza season) (149,150). However, a review of the published=20 literature concluded that no clear evidence existed that immunity = declined more=20 rapidly in the elderly (151), and additional vaccine doses during = the=20 same season do not increase the antibody response. One study that = measured the=20 proportion of persons who retained seroprotective levels of = anti-influenza=20 antibody declined in all age groups, including those aged =E2=89=A565 = years, within 1=20 year of vaccination. However, the proportion in each age group that = retained=20 seroprotective antibody levels remained above standards typically used = for=20 vaccine licensure for seasonal influenza A (H1N1) and influenza A (H3N2) = in all=20 age groups. In this study, anti-influenza B antibody levels declined = more=20 quickly, but remained elevated well above licensure threshold for at = least 6=20 months in all age groups (152). The frequency of breakthrough = infections=20 is not known to be higher among those who were vaccinated early in the = season.=20 Infections among the vaccinated elderly might be more likely related to = an=20 age-related reduction in ability to respond to vaccination rather than = reduced=20 duration of immunity.

Immunogenicity, Efficacy, and Effectiveness of TIV

Children

Children aged =E2=89=A56 months typically have protective levels of = anti-influenza=20 antibody against specific influenza virus strains after receiving the=20 recommended number of doses of seasonal inactivated influenza vaccine=20 (137,142,153--157). Immunogenicity studies using the influenza A = (H1N1)=20 2009 monovalent vaccine indicated that >90% of children aged = =E2=89=A59 years=20 responded to a single dose with anti-influenza antibody levels that are=20 considered to be protective. Young children had inconsistent responses = to a=20 single dose of the influenza A (H1N1) 2009 monovalent vaccine across = studies,=20 with 20% of children aged 6--35 months responding to a single dose with=20 protective anti-influenza antibody levels. However, in all studies, = 80%--95% of=20 vaccinated infants, children, and adolescents developed protective=20 anti-influenza antibody levels to the 2009 H1N1 influenza virus after 2 = doses=20 (158--160; National Institutes of Health, unpublished data, = 2010).

In most seasons, one or more seasonal vaccine antigens are changed = compared=20 with the previous season. In consecutive years when vaccine antigens = change,=20 children aged <9 years who received only 1 dose of vaccine in their = first=20 year of vaccination are less likely to have protective antibody = responses when=20 administered only a single dose during their second year of vaccination = compared=20 with children who received 2 doses in their first year of vaccination=20 (161--163).

When the vaccine antigens do not change from one season to the next, = priming=20 children aged 6--23 months with a single dose of vaccine in the spring = followed=20 by a dose in the fall engenders similar antibody responses compared with = a=20 regimen of 2 doses in the fall (164). However, one study = conducted during=20 a season when the vaccine antigens did not change compared with the = previous=20 season estimated 62% effectiveness against ILI for healthy children who = had=20 received only 1 dose in the previous influenza season and only 1 dose in = the=20 study season compared with 82% for those who received 2 doses separated = by =E2=89=A54=20 weeks during the study season (165).

The antibody response among children at higher risk for = influenza-related=20 complications (e.g., children with chronic medical conditions) might be = lower=20 than those reported typically among healthy children (166,167). = However,=20 antibody responses among children with asthma are similar to those of = healthy=20 children and are not substantially altered during asthma exacerbations = requiring=20 short-term prednisone treatment (168).

Vaccine effectiveness studies also have indicated that 2 doses are = needed to=20 provide adequate protection during the first season that young children = are=20 vaccinated. Among children aged <5 years who have never received = influenza=20 vaccine previously or who received only 1 dose of influenza vaccine in = their=20 first year of vaccination, vaccine effectiveness is lower compared with = children=20 who received 2 doses in their first year of being vaccinated. Two large=20 retrospective studies of young children who had received only 1 dose of = TIV in=20 their first year of being vaccinated determined that no decrease was = observed in=20 ILI-related office visits compared with unvaccinated children = (165,169).=20 Similar results were reported in a case-control study of children aged = 6--59=20 months in which laboratory-confirmed influenza was the outcome measured=20 (170). These results, along with the immunogenicity data = indicating that=20 antibody responses are substantially higher when young children are = given 2=20 doses, are the basis for the recommendation that all children aged 6 = months--8=20 years who are being vaccinated for the first time should receive 2 = vaccine doses=20 separated by =E2=89=A54 weeks.

Estimates of vaccine efficacy or effectiveness among children aged = =E2=89=A56 months=20 have varied by season and study design. In a randomized trial conducted = during=20 five influenza seasons (1985--1990) in the United States among children = aged=20 1--15 years, annual vaccination reduced laboratory-confirmed influenza A = substantially (77%--91%) (139). A limited 1-year = placebo-controlled study=20 reported vaccine efficacy against laboratory-confirmed influenza illness = of 56%=20 among healthy children aged 3--9 years and 100% among healthy children = and=20 adolescents aged 10--18 years (171). A randomized, double-blind,=20 placebo-controlled trial conducted during two influenza seasons among = children=20 aged 6--24 months indicated that efficacy was 66% against = culture-confirmed=20 influenza illness during the 1999--00 influenza season but did not = reduce=20 culture-confirmed influenza illness substantially during the 2000--01 = influenza=20 season (172).

A case-control study conducted during the 2003--04 season indicated = vaccine=20 effectiveness of 49% against laboratory-confirmed influenza = (170). An=20 observational study among children aged 6--59 months with = laboratory-confirmed=20 influenza compared with children who tested negative for influenza = reported=20 vaccine effectiveness of 44% in the 2003--04 influenza season and 57% = during the=20 2004--05 season (173). Partial vaccination (only 1 dose for = children=20 being vaccinated for the first time) was not effective in either study. = During=20 an influenza season (2003--04) with a suboptimal vaccine match, a = retrospective=20 cohort study conducted among approximately 30,000 children aged 6 = months--8=20 years indicated vaccine effectiveness of 51% against medically attended, = clinically diagnosed pneumonia or influenza (i.e., no laboratory = confirmation of=20 influenza) among fully vaccinated children and 49% among approximately = 5,000=20 children aged 6--23 months (169). Another retrospective cohort = study of=20 similar size conducted during the same influenza season in Denver but = limited to=20 healthy children aged 6--21 months estimated clinical effectiveness of 2 = TIV=20 doses to be 87% against pneumonia or influenza-related office visits=20 (165). Among children, TIV effectiveness might increase with age=20 (139,174). A systematic review of published studies estimated = vaccine=20 effectiveness at 59% for children aged >2 years but concluded that = additional=20 evidence was needed to demonstrate effectiveness among children aged 6 = months--2=20 years (175).

Because of the recognized influenza-related disease burden among = children=20 with other chronic diseases or immunosuppression and the long-standing=20 recommendation for vaccination of these children, randomized = placebo-controlled=20 studies to study efficacy in these children have not been conducted. In = a=20 nonrandomized controlled trial among children aged 2--6 years and 7--14 = years=20 who had asthma, vaccine efficacy was 54% and 78% against = laboratory-confirmed=20 influenza type A infection and 22% and 60% against laboratory-confirmed=20 influenza type B infection, respectively. Vaccinated children aged 2--6 = years=20 with asthma did not have substantially fewer type B influenza virus = infections=20 compared with the control group in this study (176). The = association=20 between vaccination and prevention of asthma exacerbations is unclear.=20 Vaccination was demonstrated to provide protection against asthma = exacerbations=20 in some studies (177,178).

TIV has been demonstrated to reduce acute otitis media in some = studies. Two=20 studies have reported that TIV decreases the risk for influenza-related = otitis=20 media by approximately 30% among children with mean ages of 20 and 27 = months,=20 respectively (179,180). However, a large study conducted among = children=20 with a mean age of 14 months indicated that TIV was not effective = against acute=20 otitis media (172). Influenza vaccine effectiveness against a = nonspecific=20 clinical outcome such as acute otitis media, which is caused by a = variety of=20 pathogens and is not typically diagnosed using influenza virus culture, = would be=20 expected to be relatively low.

Adults Aged <65 Years

One dose of TIV is highly immunogenic in healthy adults aged <65 = years.=20 Limited or no increase in antibody response is reported among adults = when a=20 second dose is administered during the same season (181--183). = The=20 influenza A (H1N1) 2009 monovalent vaccines were also highly = immunogenic;=20 >90% of adults developed levels of anti-influenza antibody considered = to be=20 protective (160,184). When the vaccine and circulating viruses = are=20 antigenically similar, TIV prevents laboratory-confirmed influenza = illness among=20 approximately 70%--90% of healthy adults aged <65 years in randomized = controlled trials (77,80,185--187). Vaccination of healthy adults = also=20 has resulted in decreased work absenteeism and decreased use of = health-care=20 resources, including use of antibiotics, when the vaccine and = circulating=20 viruses are well-matched (77,185,186). Efficacy or effectiveness = against=20 laboratory-confirmed influenza illness was substantially lower in = studies=20 conducted during different influenza seasons when the vaccine strains = were=20 antigenically dissimilar to the majority of circulating strains=20 (77,80,180,182,185,186). However, effectiveness among healthy = adults=20 against influenza-related hospitalization, measured in the most recent = of these=20 studies, was 90% (188).

In certain studies, persons with certain chronic diseases have lower = serum=20 antibody responses after vaccination compared with healthy young adults = and can=20 remain susceptible to influenza virus infection and influenza-related = upper=20 respiratory tract illness (189--191). Vaccine effectiveness among = adults=20 aged <65 years who are at higher risk for influenza complications = typically=20 is lower than that reported for healthy adults. In a case-control study=20 conducted during the 2003--04 influenza season, when the vaccine was a=20 suboptimal antigenic match to many circulating virus strains, = effectiveness for=20 prevention of laboratory-confirmed influenza illness among adults aged = 50--64=20 years with high-risk conditions was 48% compared with 60% for healthy = adults=20 (188). Effectiveness against hospitalization among adults aged = 50--64=20 years with high-risk conditions was 36% compared with 90% effectiveness = among=20 healthy adults in that age range (188). A randomized controlled = trial=20 among adults in Thailand with chronic obstructive pulmonary disease = (median age:=20 68 years) indicated a vaccine effectiveness of 76% in preventing=20 laboratory-confirmed influenza during a season when viruses were = well-matched to=20 vaccine viruses. Effectiveness did not decrease with increasing severity = of=20 underlying lung disease (192).

Few randomized controlled trials have studied the effect of influenza = vaccination on noninfluenza outcomes. A controlled trial conducted in = Argentina=20 among 301 adults hospitalized with myocardial infarction or undergoing=20 angioplasty for cardiovascular disease (56% of whom were aged = =E2=89=A565 years) who=20 were randomized to receive influenza vaccine or no vaccine indicated = that a=20 substantially lower percentage (6%) of cardiovascular deaths occurred = among=20 vaccinated persons at 1 year after vaccination compared with = unvaccinated=20 persons (17%) (193). A randomized, double-blind, = placebo-controlled study=20 conducted in Poland among 658 persons with coronary artery disease = indicated=20 that significantly fewer vaccinated persons had a cardiac ischemic event = during=20 the 9 months of follow up compared with unvaccinated persons (p<0.05) = (194).

Observational studies that have measured clinical endpoints without=20 laboratory confirmation of influenza virus infection typically have = demonstrated=20 substantial reductions in hospitalizations or deaths among adults with = risk=20 factors for influenza complications. For example, in a case-control = study=20 conducted during 1999--2000 in Denmark among adults aged <65 years = with=20 underlying medical conditions, vaccination reduced deaths attributable = to any=20 cause 78% and reduced hospitalizations attributable to respiratory = infections or=20 cardiopulmonary diseases 87% (195). A benefit was reported after = the=20 first vaccination and increased with subsequent vaccinations in = subsequent years=20 (196). Among patients with diabetes mellitus, vaccination was = associated=20 with a 56% reduction in any complication, a 54% reduction in = hospitalizations,=20 and a 58% reduction in deaths (197). Certain experts have noted = that the=20 substantial effects on morbidity and mortality among those who received=20 influenza vaccination in these observational studies should be = interpreted with=20 caution because of the difficulties in ensuring that those who received=20 vaccination had similar baseline health status as those who did not=20 (134,135). One meta-analysis of published studies concluded that = evidence=20 was insufficient to demonstrate that persons with asthma benefit from=20 vaccination (198). However, a meta-analysis that examined = effectiveness=20 among persons with chronic obstructive pulmonary disease identified = evidence of=20 benefit from vaccination (199).

Immunocompromised Persons

TIV produces adequate antibody concentrations against influenza among = vaccinated HIV-infected persons who have no or minimal AIDS-related = symptoms=20 (200--202). Among persons who have advanced HIV disease and low = CD4+=20 T-lymphocyte cell counts, TIV might not induce protective antibody = titers=20 (202,203); a second dose of vaccine does not improve the immune = response=20 in these persons (203,204). A randomized, placebo-controlled = trial=20 determined that TIV was highly effective in preventing symptomatic,=20 laboratory-confirmed influenza virus infection among HIV-infected = persons with a=20 mean of 400 CD4+ T-lymphocyte cells/mm3; however,=20 a limited number of persons with CD4+ T-lymphocyte cell counts of = <200 were=20 included in that study (204). A nonrandomized study of = HIV-infected=20 persons determined that influenza vaccination was most effective among = persons=20 with >100 CD4+ cells and among those with <30,000 viral copies of = HIV=20 type-1/mL (95).

On the basis of certain limited studies, immunogenicity for persons = with=20 solid organ transplants varies according to transplant type. Among = persons with=20 kidney or heart transplants, the proportion who developed seroprotective = antibody concentrations was similar or slightly reduced compared with = healthy=20 persons (205--207). However, a study among persons with liver = transplants=20 indicated reduced immunologic responses to influenza vaccination=20 (208--210), especially if vaccination occurred within the 4 = months after=20 the transplant procedure (208).

Pregnant Women and Neonates

Pregnant women have protective levels of anti-influenza antibodies = after=20 vaccination (211,212). Passive transfer of anti-influenza = antibodies that=20 might provide protection from vaccinated women to neonates has been = reported=20 (211,213--216). One randomized controlled trial conducted in = Bangladesh=20 that provided vaccination to pregnant women during the third trimester=20 demonstrated a 29% reduction in respiratory illness with fever among the = mothers=20 and a 36% reduction in respiratory illness with fever among their = infants during=20 the first 6 months of life. In addition, infants born to vaccinated = women had a=20 63% reduction in laboratory-confirmed influenza illness during the first = 6=20 months of life (217). All women in this trial breastfed their = infants=20 (mean duration: 14 weeks). However, a retrospective study conducted = during=20 1997--2002 that used clinical records data did not indicate a reduction = in ILI=20 among vaccinated pregnant women or their infants (218). In = another study=20 conducted during 1995--2001, medical visits for respiratory illness = among=20 infants were not reduced substantially (219).

Adults Aged =E2=89=A565 Years

One prospective cohort study indicated that immunogenicity among = hospitalized=20 persons who either were aged =E2=89=A565 years or were aged 18--64 years = and had one or=20 more chronic medical conditions was similar compared with outpatients=20 (220). Immunogenicity data from three studies among persons aged = =E2=89=A565=20 years indicate that higher-dose preparations elicit substantially higher = hemagglutinin inhibition (HI) titers compared with the standard dose=20 (221--223). In one study, prespecified criteria for superiority = (defined=20 as when the lower bound of the two-sided confidence interval of a ratio = of=20 geometric mean HI titers is >1.5 and the difference in fourfold rise = of HI=20 titers is >10%) were demonstrated for influenza A (H1N1) and = influenza A=20 (H3N2) antigens among persons aged =E2=89=A565 years who received a TIV = formulation=20 (Fluzone High-Dose, sanofi pasteur) that contains four times the = standard amount=20 of HA antigen (180 mcg [60 mcg of each strain]) of influenza virus = hemagglutinin=20 per dose (222,224). Prespecified criteria for noninferiority to a = standard-dose vaccine (Fluzone, sanofi pasteur) was demonstrated for the = influenza B antigen (222).

The only randomized controlled trial among community-dwelling persons = aged=20 =E2=89=A560 years reported a vaccine efficacy of 58% (95% CI =3D = 26%--77%) against=20 laboratory-confirmed influenza illness during a season when the vaccine = strains=20 were considered to be well-matched to circulating strains (225).=20 Additional information from this trial published separately indicated = that=20 efficacy among those aged =E2=89=A570 years was 57% (95% CI =3D = -36%--87%), similar to=20 younger persons. However, few persons aged >75 years participated in = this=20 study, and the wide confidence interval for the estimate of efficacy = among=20 participants aged =E2=89=A570 years could not exclude no effect (i.e., = included 0)=20 (226). Influenza vaccine effectiveness in preventing MAARI among = the=20 elderly in nursing homes has been estimated at 20%--40% = (227,228), and=20 reported outbreaks among well-vaccinated nursing home populations have = suggested=20 that vaccination might not have any significant effectiveness when = circulating=20 strains are drifted from vaccine strains (229,230). In contrast, = some=20 studies have indicated that vaccination can be up-to-80% effective in = preventing=20 influenza-related death (227,231--233). Among elderly persons not = living=20 in nursing homes or similar long-term--care facilities, influenza = vaccine is=20 27%--70% effective in preventing hospitalization for pneumonia and = influenza=20 (234--236). Influenza vaccination reduces the frequency of = secondary=20 complications and reduces the risk for influenza-related hospitalization = and=20 death among community-dwelling adults aged =E2=89=A565 years with and = without high-risk=20 medical conditions (e.g., heart disease and diabetes) (235--240). = However, studies demonstrating large reductions in hospitalizations and = deaths=20 among the vaccinated elderly have been conducted using medical record = databases=20 and have not measured reductions in laboratory-confirmed influenza = illness.=20 These studies have been challenged because of concerns that they have = not=20 controlled adequately for differences in the propensity for healthier = persons to=20 be more likely than less healthy persons to receive vaccination=20 (134,135,232,241--244).

Immunogenicity of Inactivated 2009 Pandemic H1N1 Vaccines

The 2010--11 seasonal influenza vaccine will contain an influenza A = (H1N1)=20 California/7/2009-like strain, which was also the strain used for the = 2009=20 pandemic H1N1 monovalent vaccines. Clinical studies of the 2009 H1N1 = monovalent=20 vaccines indicate that this vaccine antigen is immunogenic and response = rates=20 are similar to those observed after immunization with influenza A = antigens found=20 in typical seasonal influenza vaccines. Among children aged 6--35 = months,=20 19%--92% responded with an HI titer =E2=89=A540 at =E2=89=A521 days = after 1 dose, and >90%=20 responded with an HI titer =E2=89=A540 after 2 doses separated by = =E2=89=A521 days=20 (159,160; National Institutes of Health, unpublished data, 2010). = Among=20 children aged 3 --9 years, 44%--93% responded with an HI titer = =E2=89=A540 at 21 or more=20 days after 1 dose, and >90% responded with an HI titer =E2=89=A540 = after 2 doses=20 separated by =E2=89=A521 days (158--160; National Institutes of = Health,=20 unpublished data, 2010). Among older children and adults, response rates = after 1=20 dose exceeded 90% (160,184) although geometric mean titers were=20 substantially lower among adults aged =E2=89=A550 years in one study = (184) and=20 among adults aged =E2=89=A565 years (160). Additional data on = 2009 H1N1 pandemic=20 vaccine immunogenicity among persons with chronic medical conditions or = pregnant=20 women are not yet available, but results from studies in other groups = suggest=20 that immunogenicity is likely to be similar to that observed in studies = of=20 seasonal vaccine immunogenicity.

TIV Dosage, Administration, and Storage

The composition of TIV varies according to manufacturer, and package = inserts=20 should be consulted. TIV formulations in multidose vials contain the = vaccine=20 preservative thimerosal; preservative-free, single-dose preparations = also are=20 available. TIV should be stored at 35=C2=B0F--46=C2=B0F (2=C2=B0C--8=C2=B0C) and should not be frozen. TIV that = has been frozen=20 should be discarded. Dosage recommendations and schedules vary according = to age=20 group (Ta= ble=20 2). Vaccine prepared for a previous influenza season should not be=20 administered to provide protection for any subsequent season.

The intramuscular route is recommended for TIV. Adults and older = children=20 should be vaccinated in the deltoid muscle. A needle length of = =E2=89=A51 inch (=E2=89=A525 mm)=20 should be considered for persons in these age groups because needles of = <1=20 inch might be of insufficient length to penetrate muscle tissue in = certain=20 adults and older children (245). When=20 injecting into the deltoid muscle among children with adequate deltoid = muscle=20 mass, a needle length of =E2=85=9E--11/4 inches is recommended (245).

Infants and young children should be vaccinated in the anterolateral = aspect=20 of the thigh. A needle length of =E2=85=9E--1 inch should be used for = children aged=20 <12 months.

Adverse Events After Receipt of TIV

Children

Studies support the safety of annual TIV in children and adolescents. = The=20 largest published postlicensure population-based study assessed TIV = safety in=20 251,600 children aged <18 years (including 8,476 vaccinations in = children=20 aged 6--23 months) who were enrolled in one of five health maintenance=20 organizations within the Vaccine Safety Datalink (VSD) during = 1993--1999. This=20 study indicated no increase in clinically important medically attended = events=20 during the 2 weeks after inactivated influenza vaccination compared with = control=20 periods 3--4 weeks before and after vaccination (246). A = retrospective=20 cohort study using VSD medical records data from 45,356 children aged = 6--23=20 months during 1991--2003 provided additional evidence supporting overall = safety=20 of TIV in this age group. During the 2 weeks after vaccination, TIV was = not=20 associated with statistically significant increases in any clinically = important=20 medically attended events other than gastritis/duodenitis, compared with = 2-week=20 control time periods before and after vaccination. Analysis also = indicated that=20 13 diagnoses, including acute upper respiratory illness, otitis media, = and=20 asthma, were substantially less common during the 2 weeks after = influenza=20 vaccine. On chart review, most children with a diagnosis of = gastritis/duodenitis=20 had acute episodes of vomiting or diarrhea, which usually are = self-limiting=20 symptoms. The positive or negative associations between TIV and any of = these=20 diagnoses do not necessarily indicate a causal relationship = (247). The=20 study identified no increased risk for febrile seizure during the 3 days = after=20 vaccination. Similarly, no increased risk for febrile seizure was = observed=20 during the 14 days after TIV vaccination, after controlling for = simultaneous=20 receipt of measles-mumps-rubella (MMR) vaccine which has a known = association=20 with febrile seizures in the second week after MMR vaccination = (247).=20 Another analysis assessed risk for prespecified adverse events in the = VSD,=20 including seizures and Guillan-Barr=C3=A9 Syndrome (GBS), after TIV = during three=20 influenza seasons (2005--06, 2006--07, and 2007--08). No elevated risk = for=20 adverse events was identified among 1,195,552 TIV doses administered to = children=20 aged <18 years (248).

In a study of 791 healthy children aged 1--15 years, postvaccination = fever=20 was noted among 12% of those aged 1--5 years, 5% among those aged 6--10 = years,=20 and 5% among those aged 11--15 years (139). Fever, malaise, = myalgia, and=20 other systemic symptoms that can occur after vaccination with = inactivated=20 vaccine most often affect persons who have had no previous exposure to = the=20 influenza virus antigens in the vaccine (e.g., young children) = (249).=20 These reactions begin 6--12 hours after vaccination and can persist for = 1--2=20 days (249).

Data about potential adverse events among children after influenza=20 vaccination are available from the Vaccine Adverse Event Reporting = System=20 (VAERS). Because of the limitations of passive reporting systems, = determining=20 causality for specific types of adverse events usually is not possible = using=20 VAERS data alone. Published reviews of VAERS reports submitted after=20 administration of TIV to children aged 6--23 months indicated that the = most=20 frequently reported adverse events were fever, rash, injection-site = reactions,=20 and seizures; the majority of the limited number of reported seizures = appeared=20 to be febrile (250,251). Seizure and fever were the leading = serious=20 adverse events (SAEs) reported to VAERS in these studies = (250,2511);=20 analysis of VSD data did not confirm an association with febrile = seizures and=20 influenza vaccination as observed in VAERS (247).

In April 2010, Australia's Therapeutic Goods Administration reported=20 preliminary data indicating an elevated risk for febrile reactions, = including=20 febrile seizures, among young children in Australia who received the = 2010=20 trivalent vaccine Fluvax Jr., the southern hemisphere inactivated = trivalent=20 vaccine for children manufactured by CSL Biotherapies. The risk for = febrile=20 seizures was estimated to be as high as five to nine cases per 1,000 = vaccinated=20 children aged <5 years, and most seizures occurred among children = aged <3=20 years. Other influenza vaccines, including previous seasonal and = pandemic=20 influenza vaccines manufactured by CSL Biotherapies, have not been = associated=20 with an increased risk for febrile seizures among children in the United = States=20 or Australia. As of July 2010, no cause for the increased frequency of = febrile=20 reactions among young children who received the southern hemisphere CSL=20 Biotherapies vaccine had been identified (252). ACIP will = continue to=20 monitor safety studies being conducted in Australia and might provide = further=20 guidance on use of Afluria, the northern hemisphere trivalent vaccine=20 manufactured by CSL Biotherapies later in 2010. Immunization providers = should=20 consult updated information on use of the CSL vaccine from CDC (http://www.cdc.gov/flu) and FDA (http://www.fda.gov/BiologicsBloodVaccines/SafetyAv= ailability/VaccineSafety/default.htm).

Adults

In placebo-controlled studies among adults, the most frequent side = effect of=20 vaccination was soreness at the vaccination site (affecting 10%--64% of=20 patients) that lasted <2 days (253,254). These local reactions = typically were mild and rarely interfered with the recipients' ability = to=20 conduct usual daily activities. Placebo-controlled trials demonstrated = that=20 among older persons and healthy young adults, administration of TIV is = not=20 associated with higher rates for systemic symptoms (e.g., fever, = malaise,=20 myalgia, and headache) when compared with placebo injections=20 (77,198,253--255). One prospective cohort study indicated that = the rate=20 of adverse events was similar among hospitalized persons who either were = aged=20 =E2=89=A565 years or were aged 18--64 years and had one or more chronic = medical=20 conditions compared with outpatients (220). Among adults = vaccinated in=20 consecutive years, reaction frequencies declined in the second year of=20 vaccination (256). In clinical trials, SAEs were reported to = occur after=20 vaccination with TIV at a rate of <1%. Adverse events in adults aged = =E2=89=A518=20 years reported to VAERS during 1990--2005 were analyzed. The most common = adverse=20 events reported to VAERS in adults included injection-site reactions, = pain,=20 fever, myalgia, and headache. The VAERS review identified no new safety=20 concerns. Fourteen percent of the TIV VAERS reports in adults were = classified as=20 SAEs, similar to proportions seen overall in VAERS. The most common SAE = reported=20 after receipt of TIV in VAERS in adults was GBS (257). The = potential=20 association between TIV and GBS has been an area of ongoing research = (see=20 Guillain-Barr=C3=A9 Syndrome and TIV). No elevated risk for prespecified = events after=20 TIV was identified among 4,773,956 adults in a VSD analysis = (249).

Solicited injection-site reactions and systemic adverse events among = persons=20 aged =E2=89=A565 years were more frequent after vaccination with a = vaccine containing=20 180 mcg of HA antigen (Fluzone High-Dose, sanofi pasteur) compared with = a=20 standard dose (45 mcg) (Fluzone, Sanofi pasteur vaccines) but were = typically=20 mild and transient. In the largest study, 915 (36%) of 2,572 persons who = received Fluzone High-Dose reported injection-site pain, compared with = 306 (24%)=20 of the 1,260 subjects who received Fluzone. The pain was of mild = intensity and=20 resolved within 3 days in the majority of subjects. Among Fluzone High = Dose=20 recipients, 1.1% reported moderate to severe fever; this was = substantially=20 higher than the 0.3% of Fluzone recipients who reported this systemic = adverse=20 event (222). During the 6-month follow-up period, SAEs were = reported in=20 6% of the High-Dose recipients and 7% of the Fluzone recipients=20 (222).

Pregnant Women and Neonates

FDA has classified TIV as a "Pregnancy Category C" medication, = indicating=20 that adequate animal reproduction studies have not been conducted. = Available=20 data do not indicate that influenza vaccine causes fetal harm when = administered=20 to a pregnant woman. One study of approximately 2,000 pregnant women who = received TIV during pregnancy demonstrated no adverse fetal effects and = no=20 adverse effects during infancy or early childhood (258). A = matched=20 case-control study of 252 pregnant women who received TIV within the 6 = months=20 before delivery determined no adverse events after vaccination among = pregnant=20 women and no difference in pregnancy outcomes compared with 826 pregnant = women=20 who were not vaccinated (212). During 2000--2003, an estimated 2 = million=20 pregnant women were vaccinated, and only 20 adverse events among women = who=20 received TIV were reported to VAERS during this time, including nine=20 injection-site reactions and eight systemic reactions (e.g., fever, = headache,=20 and myalgias). In addition, three miscarriages were reported, but these = were not=20 known to be related causally to vaccination (259). Similar = results have=20 been reported in certain smaller studies (211,213,260), and a = recent=20 international review of data on the safety of TIV concluded that no = evidence=20 exists to suggest harm to the fetus (261). The rate of adverse = events=20 associated with TIV was similar to the rate of adverse events among = pregnant=20 women who received pneumococcal polysaccharide vaccine in one small = randomized=20 controlled trial in Bangladesh, and no severe adverse events were = reported in=20 any study group (217).

Persons with Chronic Medical Conditions

In a randomized cross-over study of children and adults with asthma, = no=20 increase in asthma exacerbations was reported for either age group = (262),=20 and two additional studies also have indicated no increase in wheezing = among=20 vaccinated asthmatic children (177) or adults (195). One = study=20 reported that 20%--28% of children aged 9 months--18 years with asthma = had=20 injection-site pain and swelling at the site of influenza vaccination=20 (167), and another study reported that 23% of children aged 6 = months--4=20 years with chronic heart or lung disease had injection-site reactions=20 (153). A blinded, randomized, cross-over study of 1,952 adults = and=20 children with asthma demonstrated that only self-reported "body aches" = were=20 reported more frequently after receipt of TIV (25%) than = placebo-injection (21%)=20 (262). However, a placebo-controlled trial of TIV indicated no = difference=20 in injection-site reactions among 53 children aged 6 months--6 years = with=20 high-risk medical conditions or among 305 healthy children aged 3--12 = years=20 (157).

Among children with high-risk medical conditions, one study of 52 = children=20 aged 6 months--3 years reported fever among 27% and irritability and = insomnia=20 among 25% (153), and a study among 33 children aged 6--18 months = reported=20 that one child had irritability and one had a fever and seizure after=20 vaccination (263). No placebo comparison group was used in these=20 studies.

Immunocompromised Persons

Data demonstrating safety of TIV for HIV-infected persons are = limited, but no=20 evidence exists that vaccination has a clinically important impact on = HIV=20 infection or immunocompetence. One study demonstrated a transient (i.e., = 2--4=20 week) increase in HIV RNA (ribonucleic acid) levels in one HIV-infected = person=20 after influenza virus infection (264). Studies have demonstrated = a=20 transient increase in replication of HIV-1 in the plasma or peripheral = blood=20 mononuclear cells of HIV-infected persons after vaccine administration=20 (202,265). However, more recent and better-designed studies have = not=20 documented a substantial increase in the replication of HIV = (266--269).=20 CD4+ T-lymphocyte cell counts or progression of HIV disease have not = been=20 reduced after influenza vaccination among HIV-infected persons compared = with=20 unvaccinated HIV-infected persons (202,270). Limited information = is=20 available about the effect of antiretroviral therapy on increases in HIV = RNA=20 levels after either natural influenza virus infection or influenza = vaccination=20 (94,271).

Data are similarly limited for persons with other immunocompromising=20 conditions. In small studies, vaccination did not affect allograft = function or=20 cause rejection episodes in recipients of kidney transplants = (205,206),=20 heart transplants (207), or liver transplants (208).

Immediate Hypersensitivity Reactions After Receipt of Influenza=20 Vaccines

Vaccine components rarely can cause allergic reactions, also called = immediate=20 hypersensitivity reactions, among certain recipients. Immediate = hypersensitivity=20 reactions are mediated by preformed immunoglobulin E (IgE) antibodies = against a=20 vaccine component and usually occur within minutes to hours of exposure=20 (272). Symptoms of immediate hypersensitivity range from mild = urticaria=20 (hives) and angioedema to anaphylaxis. Anaphylaxis is a severe = life-threatening=20 reaction that involves multiple organ systems and can progress rapidly. = Symptoms=20 and signs of anaphylaxis can include but are not limited to generalized=20 urticaria, wheezing, swelling of the mouth and throat, difficulty = breathing,=20 vomiting, hypotension, decreased level of consciousness, and shock. = Minor=20 symptoms such as red eyes or hoarse voice also might be present=20 (246,272--275).

Allergic reactions might be caused by the vaccine antigen, residual = animal=20 protein, antimicrobial agents, preservatives, stabilizers, or other = vaccine=20 components (276). Manufacturers use a variety of compounds to = inactivate=20 influenza viruses and add antibiotics to prevent bacterial growth. = Package=20 inserts for specific vaccines of interest should be consulted for = additional=20 information. ACIP has recommended that all vaccine providers should be = familiar=20 with the office emergency plan and be certified in cardiopulmonary = resuscitation=20 (246). The Clinical Immunization Safety Assessment (95% CISA) = network, a=20 collaboration between CDC and six medical research centers with = expertise in=20 vaccination safety, has developed an algorithm to guide evaluation and=20 revaccination decisions for persons with suspected immediate = hypersensitivity=20 after vaccination (272).

Immediate hypersensitivity reaction after receipt of TIV and LAIV are = rare. A=20 VSD study of children aged <18 years in four health maintenance = organizations=20 during 1991--1997 estimated the overall risk for postvaccination = anaphylaxis=20 after childhood vaccine to be approximately 1.5 cases per 1 million = doses=20 administered, and in this study, no cases were identified in TIV = recipients=20 (277). Anaphylaxis occurring after receipt of TIV and LAIV in = adults has=20 been reported rarely to VAERS (257).

Some immediate hypersensitivity reactions after receipt of TIV or = LAIV are=20 caused by the presence of residual egg protein in the vaccines = (278).=20 Although influenza vaccines contain only a limited quantity of egg = protein, this=20 protein can induce immediate hypersensitivity reactions among persons = who have=20 severe egg allergy. Asking persons if they can eat eggs without adverse = effects=20 is a reasonable way to determine who might be at risk for allergic = reactions=20 from receiving influenza vaccines (246). Persons who have had = symptoms=20 such as hives or swelling of the lips or tongue or who have experienced = acute=20 respiratory distress after eating eggs should consult a physician for=20 appropriate evaluation to help determine if future influenza vaccine = should be=20 administered. Persons who have documented IgE-mediated hypersensitivity = to eggs,=20 including those who have had occupational asthma related to egg exposure = or=20 other allergic responses to egg protein, also might be at increased risk = for=20 allergic reactions to influenza vaccine, and consultation with a = physician=20 before vaccination should be considered (279--281). A regimen has = been=20 developed for administering influenza vaccine to asthmatic children with = severe=20 disease and egg hypersensitivity (280).

Hypersensitivity reactions to other vaccine components also can occur = rarely.=20 Although exposure to vaccines containing thimerosal can lead to = delayed-type=20 (Type IV) hypersensitivity (282), the majority of patients do not = have=20 reactions to thimerosal when it is administered as a component of = vaccines, even=20 when patch or intradermal tests for thimerosal indicate hypersensitivity = (283,284). When reported, hypersensitivity to thimerosal = typically has=20 consisted of local delayed hypersensitivity reactions (283).

Ocular and Respiratory Symptoms After Receipt of TIV

Ocular or respiratory symptoms have been reported occasionally within = 24=20 hours after TIV administration, but these symptoms typically are mild = and=20 resolve quickly without specific treatment. In some trials conducted in = the=20 United States, ocular or respiratory symptoms included red eyes = (<1%--6%),=20 cough (1%--7%), wheezing (1%), and chest tightness (1%--3%)=20 (274,275,285--287). However, most of these trials were not=20 placebo-controlled, and causality cannot be determined. In addition, = ocular and=20 respiratory symptoms are features of a variety of respiratory illnesses = and=20 seasonal allergies that would be expected to occur coincidentally among = vaccine=20 recipients unrelated to vaccination. A placebo-controlled vaccine = effectiveness=20 study among young adults indicated that 2% of persons who received the = 2006--07=20 formulation of Fluzone (sanofi pasteur) reported red eyes compared with = none of=20 the controls (p=3D0.03) (288). A similar trial conducted during = the=20 2005--06 influenza season indicated that 3% of Fluzone recipients = reported red=20 eyes compared with 1% of placebo recipients; however the difference was = not=20 statistically significant (289).

Oculorespiratory syndrome (ORS), an acute, self-limited reaction to = TIV with=20 prominent ocular and respiratory symptoms, was first described during = the=20 2000--01 influenza season in Canada. The initial case-definition for ORS = was the=20 onset of one or more of the following within 2--24 hours after receiving = TIV:=20 bilateral red eyes and/or facial edema and/or respiratory symptoms = (coughing,=20 wheezing, chest tightness, difficulty breathing, sore throat, hoarseness = or=20 difficulty swallowing, cough, wheeze, chest tightness, difficulty = breathing,=20 sore throat, or facial swelling) (290). ORS was first described = in Canada=20 and strongly associated with one vaccine preparation (Fluviral S/F, = Shire=20 Biologics, Quebec, Canada) not available in the United States during the = 2000--01 influenza season (291). Subsequent investigations = identified=20 persons with ocular or respiratory symptoms meeting an ORS = case-definition in=20 safety monitoring systems and trials that had been conducted before 2000 = in=20 Canada, the United States, and several European countries = (292--294).

The cause of ORS has not been established; however, studies suggest = that the=20 reaction is not IgE-mediated (295). After changes in the = manufacturing=20 process of the vaccine preparation associated with ORS during 2000--01, = the=20 incidence of ORS in Canada was reduced greatly (293). In one=20 placebo-controlled study, only hoarseness, cough, and itchy or sore eyes = (but=20 not red eyes) were strongly associated with a reformulated Fluviral = preparation.=20 These findings indicated that ORS symptoms following use of the = reformulated=20 vaccine were mild, resolved within 24 hours, and might not typically be = of=20 sufficient concern to cause vaccine recipients to seek medical care=20 (296).

Ocular and respiratory symptoms reported after TIV administration, = including=20 ORS, have some similarities with immediate hypersensitivity reactions. = One study=20 indicated that the risk for ORS recurrence with subsequent vaccination = is low,=20 and persons with ocular or respiratory symptoms (e.g., bilateral red = eyes,=20 cough, sore throat, or hoarseness) after receipt of TIV that did not = involve the=20 lower respiratory tract have been revaccinated without reports of SAEs = after=20 subsequent exposure to TIV (297).

Revaccination in Persons Who Experienced Ocular or Respiratory = Symptoms=20 After Receipt of TIV

When assessing whether a patient who experienced ocular and = respiratory=20 symptoms should be revaccinated, providers should determine if = concerning signs=20 and symptoms of Ig-E mediated immediate hypersensitivity are present = (see=20 Immediate Hypersensitivity after Influenza Vaccines). Health-care = providers who=20 are unsure whether symptoms reported or observed after receipt of TIV = represent=20 an IgE-mediated hypersensitivity immune response should seek advice from = an=20 allergist/immunologist. Persons with symptoms of possible IgE-mediated=20 hypersensitivity after receipt of TIV should not receive influenza = vaccination=20 unless hypersensitivity is ruled out or revaccination is administered = under=20 close medical supervision (272).

Ocular or respiratory symptoms observed after receipt of TIV often = are=20 coincidental and unrelated to TIV administration, as observed among = placebo=20 recipients in some randomized controlled studies. Determining whether = ocular or=20 respiratory symptoms are coincidental or related to possible ORS might = not be=20 possible. Persons who have had red eyes, mild upper facial swelling, or = mild=20 respiratory symptoms (e.g., sore throat, cough, or hoarseness) after = receipt of=20 TIV without other concerning signs or symptoms of hypersensitivity can = receive=20 TIV in subsequent seasons without further evaluation. Two studies = indicated that=20 persons who had symptoms of ORS after receipt of TIV were at a higher = risk for=20 ORS after subsequent TIV administration; however, these events usually = were=20 milder than the first episode (297,298).

Contraindications and Precautions for Use of TIV

TIV is contraindicated and should not be administered to persons = known to=20 have anaphylactic hypersensitivity to eggs or to other components of the = influenza vaccine unless the recipient has been desensitized. = Prophylactic use=20 of antiviral agents is an option for preventing influenza among such = persons.=20 Information about vaccine components is located in package inserts from = each=20 manufacturer. Persons with moderate to severe acute febrile illness = usually=20 should not be vaccinated until their symptoms have abated. Moderate or = severe=20 acute illness with or without fever is a precaution for TIV. GBS within = 6 weeks=20 following a previous dose of influenza vaccine is considered to be a = precaution=20 for use of influenza vaccines.

Guillain-Barr=C3=A9 Syndrome and TIV

The annual incidence of GBS is 10--20 cases per 1 million adults=20 (299). Substantial evidence exists that multiple infectious = illnesses,=20 most notably Campylobacter jejuni gastrointestinal infections and = upper=20 respiratory tract infections, are associated with GBS (300--302). = A=20 recent study identified serologically confirmed influenza virus = infection as a=20 trigger of GBS, with time from onset of influenza illness to GBS of = 3--30 days.=20 The estimated frequency of influenza-related GBS was four to seven times = higher=20 than the frequency that has been estimated for = influenza-vaccine--associated GBS=20 (303).

The 1976 swine influenza vaccine was associated with an increased = frequency=20 of GBS, estimated at one additional case of GBS per 100,000 persons = vaccinated=20 (304,305). The risk for influenza-vaccine--associated GBS was = higher=20 among persons aged =E2=89=A525 years than among persons aged <25 = years (306).=20 However, obtaining epidemiologic evidence for a small increase in risk = for a=20 rare condition with multiple causes is difficult, and no evidence = consistently=20 exists for a causal relation between subsequent vaccines prepared from = other=20 influenza viruses and GBS.

None of the studies conducted using influenza vaccines other than the = 1976=20 swine influenza vaccine has demonstrated an increase in GBS associated = with=20 influenza vaccines on the order of magnitude seen in 1976--77. During = three of=20 four influenza seasons studied during 1977--1991, the overall relative = risk=20 estimates for GBS after influenza vaccination were not statistically = significant=20 in any of these studies (307--309). However, in a study of the = 1992--93=20 and 1993--94 seasons, the overall relative risk for GBS was 1.7 (95% CI = =3D=20 1.0--2.8; p=3D0.04) during the 6 weeks after vaccination, representing=20 approximately one additional case of GBS per 1 million persons = vaccinated; the=20 combined number of GBS cases peaked 2 weeks after vaccination = (305).=20 Results of a study that examined health-care data from Ontario, Canada, = during=20 1992--2004 demonstrated a small but statistically significant temporal=20 association between receiving influenza vaccination and subsequent = hospital=20 admission for GBS. However, no increase in cases of GBS at the = population level=20 was reported after introduction of a mass public influenza vaccination = program=20 in Ontario beginning in 2000 (310). Data from VAERS have = documented=20 decreased reporting of GBS occurring after vaccination across age groups = over=20 time, despite overall increased reporting of other non-GBS conditions = occurring=20 after administration of influenza vaccine (304). Published data = from the=20 United Kingdom's General Practice Research Database (GPRD) indicated = that=20 influenza vaccine was associated with a decreased risk for GBS, although = whether=20 this was associated with protection against influenza or confounding = because of=20 a "healthy vaccinee" effect (e.g., healthier persons might be more = likely to be=20 vaccinated and also be at lower risk for GBS) (311) is unclear. A = separate GPRD analysis identified no association between vaccination and = GBS for=20 a 9-year period; only three cases of GBS occurred within 6 weeks after=20 administration of influenza vaccine (312). A third GPRD analysis=20 indicated that GBS was associated with recent ILI, but not influenza = vaccination=20 (313,314).

The estimated risk for GBS (on the basis of the few studies that have = demonstrated an association between vaccination and GBS) is low (i.e.,=20 approximately one additional case per 1 million persons vaccinated). The = potential benefits of influenza vaccination in preventing serious = illness,=20 hospitalization, and death substantially outweigh these estimates of = risk for=20 vaccine-associated GBS. No evidence indicates that the case-fatality = ratio for=20 GBS differs among vaccinated persons and those not vaccinated. = Preliminary data=20 from the systems monitoring influenza A (H1N1) 2009 monovalent vaccines = suggest=20 that if a risk exists for GBS after receiving inactivated vaccines, it = is not=20 substantially higher than that reported in some seasons for TIV (315);=20 analyses are ongoing to quantify any potential GBS risk = (316).

Use of TIV Among Patients with a History of GBS

The incidence of GBS among the general population is low, but persons = with a=20 history of GBS have a substantially greater likelihood of subsequently=20 experiencing GBS than persons without such a history (299). Thus, = the=20 likelihood of coincidentally experiencing GBS after influenza = vaccination is=20 expected to be greater among persons with a history of GBS than among = persons=20 with no history of this syndrome. Whether influenza vaccination = specifically=20 might increase the risk for recurrence of GBS is unknown. Among 311 = patients=20 with GBS who responded to a survey, 11 (4%) reported some worsening of = symptoms=20 after influenza vaccination; however, some of these patients had = received other=20 vaccines at the same time, and recurring symptoms were generally mild=20 (317). However, as a precaution, persons who are not at high risk = for=20 severe influenza complications and who are known to have experienced GBS = within=20 6 weeks of receipt of an influenza vaccine generally should not be = vaccinated.=20 As an alternative, physicians might consider using influenza antiviral=20 chemoprophylaxis for these persons. Although data are limited, the = established=20 benefits of influenza vaccination might outweigh the risks for many = persons who=20 have a history of GBS and who also are at high risk for severe = complications=20 from influenza.

Vaccine Preservative (Thimerosal) in Multidose Vials of TIV

Thimerosal, a mercury-containing antibacterial compound, has been = used as a=20 preservative in vaccines and other medications since the 1930s (318) and is=20 used in multidose vial preparations of TIV to reduce the likelihood of = bacterial=20 growth. No scientific evidence indicates that thimerosal in vaccines, = including=20 influenza vaccines, is a cause of adverse events other than occasional = local=20 hypersensitivity reactions in vaccine recipients. In addition, no = scientific=20 evidence indicates that thimerosal-containing vaccines are a cause of = adverse=20 events among children born to women who received vaccine during = pregnancy. The=20 weight of accumulating evidence does not suggest an increased risk for=20 neurodevelopment disorders from exposure to thimerosal-containing = vaccines=20 (319--3= 28).=20 The U.S. Public Health Service and other organizations have recommended = that=20 efforts be made to eliminate or reduce the thimerosal content in = vaccines as=20 part of a strategy to reduce mercury exposures from all sources (319,32= 0,329).=20 Also, continuing public concerns about exposure to mercury in vaccines = has been=20 viewed as a potential barrier to achieving higher vaccine coverage = levels and=20 reducing the burden of vaccine-preventable diseases, including = influenza. Since=20 mid-2001, vaccines routinely recommended for infants aged <6 months = in the=20 United States have been manufactured either without or with greatly = reduced=20 (trace) amounts of thimerosal. As a result, a substantial reduction in = the total=20 mercury exposure from vaccines for infants and children already has been = achieved (246). ACIP and other federal agencies and professional = medical=20 organizations continue to support efforts to provide=20 thimerosal-preservative--free vaccine options.

The U.S. vaccine supply for infants and pregnant women is in a period = of=20 transition as manufacturers expand the availability of = thimerosal-reduced or=20 thimerosal-free vaccine to reduce the cumulative exposure of infants to = mercury.=20 Other environmental sources of mercury exposure are more difficult or = impossible=20 to avoid or eliminate (319). The=20 benefits of influenza vaccination for all recommended groups, including = pregnant=20 women and young children, outweigh concerns on the basis of a theoretic = risk=20 from thimerosal exposure through vaccination. The risks for severe = illness from=20 influenza virus infection are elevated among both young children and = pregnant=20 women, and vaccination has been demonstrated to reduce the risk for = severe=20 influenza illness and subsequent medical complications. In contrast, no = harm=20 from exposure to vaccine containing thimerosal preservative has been=20 demonstrated. For these reasons, persons recommended to receive TIV may = receive=20 any age- and risk factor--appropriate vaccine preparation, depending on=20 availability. An analysis of VAERS reports identified no difference in = the=20 safety profile of preservative-containing compared with = preservative-free TIV=20 vaccines in infants aged 6--23 months (251).

Nonetheless, some states have enacted legislation banning the = administration=20 of vaccines containing mercury; the provisions defining mercury content = vary=20 (330). LAIV and many of the single-dose vial or syringe = preparations of=20 TIV are thimerosal-free, and the number of influenza vaccine doses that = do not=20 contain thimerosal as a preservative is expected to increase (Ta= ble=20 2). However, these laws might present a barrier to vaccination = unless=20 influenza vaccines that do not contain thimerosal as a preservative are=20 routinely available in those states.

Dosage, Administration, and Storage of LAIV

Each dose of LAIV contains the same three vaccine antigens used in = TIV.=20 However, the antigens are constituted as live, attenuated, cold-adapted, = temperature-sensitive vaccine viruses. Providers should refer to the = package=20 insert, which contains additional information about the formulation of = this=20 vaccine and other vaccine components. LAIV does not contain thimerosal. = LAIV is=20 made from attenuated viruses that are able to replicate efficiently only = at=20 temperatures present in the nasal mucosa. LAIV recipients might = experience nasal=20 congestion or mild fever, which is probably a result of effects of = intranasal=20 vaccine administration or local viral replication. However, LAIV does = not=20 typically cause the more prominent systemic symptoms of influenza such = as high=20 fever, myalgia, and severe fatigue (331).

LAIV is intended for intranasal administration only and should not be = administered by the intramuscular, intradermal, or intravenous route. = LAIV is=20 not licensed for vaccination of children aged <2 years or adults aged = >49=20 years. LAIV is supplied in a prefilled, single-use sprayer containing = 0.2 mL of=20 vaccine. Approximately 0.1 mL (i.e., half of the total sprayer contents) = is=20 sprayed into the first nostril while the recipient is in the upright = position.=20 An attached dose-divider clip is removed from the sprayer to administer = the=20 second half of the dose into the other nostril. LAIV is shipped at = 35=C2=B0F--46=C2=B0F (2=C2=B0C--8=C2=B0C). LAIV should be=20 stored at 35=C2=B0F--46=C2=B0F (2=C2=B0C--8=C2=B0C) on receipt and can remain at that = temperature until=20 the expiration date is reached (331). Vaccine prepared for a = previous=20 influenza season should not be administered to provide protection for = any=20 subsequent season.

Shedding, Transmission, and Stability of LAIV Viruses

Available data indicate that both children and adults vaccinated with = LAIV=20 can shed vaccine viruses after vaccination, although in lower amounts = than occur=20 typically with shedding of wild-type influenza viruses. In rare = instances, shed=20 vaccine viruses can be transmitted from vaccine recipients to = unvaccinated=20 persons. However, serious illnesses have not been reported among = unvaccinated=20 persons who have been infected inadvertently with vaccine viruses.

One study of 197 children aged 8--36 months in a child care center = assessed=20 transmissibility of vaccine viruses from 98 vaccinated children to the = other 99=20 unvaccinated children; 80% of vaccine recipients shed one or more virus = strains=20 (mean duration: 7.6 days). One influenza type B vaccine strain isolate = was=20 recovered from a placebo recipient and was confirmed to be vaccine-type = virus.=20 The type B isolate retained the cold-adapted, temperature-sensitive, = attenuated=20 phenotype, and it possessed the same genetic sequence as a virus shed = from a=20 vaccine recipient who was in the same play group. The placebo recipient = from=20 whom the influenza type B vaccine strain was isolated had symptoms of a = mild=20 upper respiratory illness but did not experience any serious clinical = events.=20 The estimated probability of acquiring vaccine virus after close contact = with a=20 single LAIV recipient in this child care population was 1%--2% = (332).

Studies assessing whether vaccine viruses are shed have been based on = viral=20 cultures or polymerase chain reaction (PCR) detection of vaccine viruses = in=20 nasal aspirates from persons who have received LAIV. Among 345 subjects = aged=20 5--49 years, 30% had detectable virus in nasal secretions obtained by = nasal=20 swabbing after receiving LAIV. The duration of virus shedding and the = amount of=20 virus shed was correlated inversely with age, and maximal shedding = occurred=20 within 2 days of vaccination. Symptoms reported after vaccination, = including=20 runny nose, headache, and sore throat, did not correlate with virus = shedding=20 (333). Other smaller studies have reported similar findings=20 (334,335). Vaccine strain virus was detected from nasal = secretions in one=20 (2%) of 57 HIV-infected adults who received LAIV, none of 54 = HIV-negative=20 participants (336), and three (13%) of 23 HIV-infected children = compared=20 with seven (28%) of 25 children who were not HIV-infected (337). = No=20 participants in these studies had detectable virus beyond 10 days after = receipt=20 of LAIV. The possibility of person-to-person transmission of vaccine = viruses was=20 not assessed in these studies (334--337).

In clinical trials, viruses isolated from vaccine recipients have = retained=20 attenuated phenotypes. In one study, nasal and throat swab specimens = were=20 collected from 17 study participants for 2 weeks after vaccine receipt=20 (338). Virus isolates were analyzed by multiple genetic = techniques. All=20 isolates retained the LAIV genotype after replication in the human host, = and all=20 retained the cold-adapted and temperature-sensitive phenotypes. A study=20 conducted in a child care setting demonstrated that limited genetic = change=20 occurred in the LAIV strains following replication in the vaccine = recipients=20 (339).

Immunogenicity, Efficacy, and Effectiveness of LAIV

LAIV virus strains replicate primarily in nasopharyngeal epithelial = cells.=20 The protective mechanisms induced by vaccination with LAIV are not = understood=20 completely but appear to involve both serum and nasal secretory = antibodies. The=20 immunogenicity of the approved LAIV has been assessed in multiple = studies=20 conducted among children and adults (147,340--345).

Healthy Children

A randomized, double-blind, placebo-controlled trial among 1,602 = healthy=20 children aged 15--71 months assessed the efficacy of LAIV against=20 culture-confirmed influenza during two seasons (346,347). This = trial=20 included a subset of children aged 60--71 months who received 2 doses in = the=20 first season. During the first season (1996--97), when vaccine and = circulating=20 virus strains were well-matched, efficacy against culture-confirmed = influenza=20 was 94% for participants who received 2 doses of LAIV separated by = =E2=89=A56 weeks, and=20 89% for those who received 1 dose. During the second season (1997--98), = when the=20 A (H3N2) component in the vaccine was not well-matched with circulating = virus=20 strains, efficacy (1 dose) was 86%, for an overall efficacy for two = influenza=20 seasons of 92%. Receipt of LAIV also resulted in 21% fewer febrile = illnesses and=20 a significant decrease in acute otitis media requiring antibiotics=20 (346,348). Other randomized, placebo-controlled trials = demonstrating the=20 efficacy of LAIV in young children against culture-confirmed influenza = include a=20 study conducted among children aged 6--35 months attending child care = centers=20 during consecutive influenza seasons (349) in which 85%--89% = efficacy was=20 observed, and a study conducted among children aged 12--36 months living = in Asia=20 during consecutive influenza seasons in which 64%--70% efficacy was = documented=20 (350). In one community-based, nonrandomized open-label study, = reductions=20 in MAARI were observed among children who received 1 dose of LAIV during = the=20 1990--00 and 2000--01 influenza seasons even though antigenically = drifted=20 influenza A/H1N1 and B viruses were circulating during that season = (148).=20 LAIV efficacy in preventing laboratory-confirmed influenza also has been = demonstrated in studies comparing the efficacy of LAIV with TIV rather = than with=20 a placebo (see Comparisons of LAIV and TIV Efficacy or Effectiveness). = In=20 clinical trials, an increased risk for wheezing postvaccination was = observed in=20 LAIV recipients aged <24 months. An increase in hospitalizations also = was=20 observed in children aged <24 months after vaccination with LAIV=20 (331).

Healthy Adults

A randomized, double-blind, placebo-controlled trial of LAIV = effectiveness=20 among 4,561 healthy working adults aged 18--64 years assessed multiple=20 endpoints, including reductions in self-reported respiratory tract = illness=20 without laboratory confirmation, work loss, health-care visits, and = medication=20 use during influenza outbreak periods. The study was conducted during = the=20 1997--98 influenza season, when the vaccine and circulating A (H3N2) = strains=20 were not well-matched. The frequency of febrile illnesses was not = substantially=20 decreased among LAIV recipients compared with those who received = placebo.=20 However, vaccine recipients had substantially fewer severe febrile = illnesses=20 (19% reduction) and febrile upper respiratory tract illnesses (24% = reduction),=20 and substantial reductions in days of illness, days of work lost, days = with=20 health-care--provider visits, and use of prescription antibiotics and=20 over-the-counter medications (351,352). Efficacy against=20 culture-confirmed influenza in a randomized, placebo-controlled study = among=20 young adults was 57% in the 2004--05 influenza season, 43% in the = 2005--06=20 influenza season, and 51% in the 2007--08 influenza season, although = efficacy in=20 2004--05 and 2005--06 was not demonstrated to be substantially greater = than=20 placebo (187,288,289).

Adverse Events After Receipt of LAIV

Healthy Children Aged 2--18 Years

In a subset of healthy children aged 60--71 months from one clinical = trial,=20 certain signs and symptoms were reported more often after the first dose = among=20 LAIV recipients (n =3D 214) than among placebo recipients (n =3D 95), = including=20 runny nose (48% and 44%, respectively); headache (18% and 12%, = respectively);=20 vomiting (5% and 3%, respectively); and myalgias (6% and 4%, = respectively)=20 (346). However, these differences were not statistically = significant. In=20 other trials, signs and symptoms reported after LAIV administration have = included runny nose or nasal congestion (20%--75%), headache (2%--46%), = fever=20 (0--26%), vomiting (3%--13%), abdominal pain (2%), and myalgias (0--21%) = (340,342,343,349,353--356). These symptoms were associated more = often=20 with the first dose and were self-limited. A placebo-controlled trial in = 9,689=20 children aged 1--17 years assessed prespecified medically attended = outcomes=20 during the 42 days after vaccination (355). Following >1,500=20 statistical analyses in the 42 days after LAIV, elevated risks that were = assessed to be biologically plausible were observed for asthma, upper=20 respiratory infection, musculoskeletal pain, otitis media with effusion, = and=20 adenitis/adenopathy. The increased risk for wheezing events after LAIV = was=20 observed among children aged 18--35 months (RR: 4.06; 90% CI =3D = 1.3--17.9). Of=20 the 16 children with asthma-related events in this study, seven had a = history of=20 asthma on the basis of subsequent medical record review. None required=20 hospitalization, and elevated risks for asthma were not observed in = other age=20 groups (355).In this study, the rate of SAEs was 0.2% in LAIV and = placebo=20 recipients; none of the SAEs was judged to be related to the vaccine by = the=20 study investigators (355).

In a randomized trial, LAIV and TIV were compared among children aged = 6--59=20 months (357). Children with medically diagnosed or treated = wheezing=20 within 42 days before enrollment or with a history of severe asthma were = excluded from this prelicensure study. Among children aged 24--59 months = who=20 received LAIV, the rate of medically significant wheezing, using a = prespecified=20 definition, was not greater compared with those who received TIV = (357).=20 Wheezing was observed more frequently among younger LAIV recipients aged = 6--23=20 months in this study; LAIV is not licensed for this age group.

Another study was conducted among >11,000 children aged 18 = months--18=20 years in which 18,780 doses of vaccine were administered over 4 years. = For=20 children aged 18 months--4 years, no increase was reported in asthma = visits=20 0--15 days after vaccination compared with the prevaccination period. A=20 significant increase in asthma events was reported 15--42 days after=20 vaccination, but only in vaccine year 1 (358). A 4-year, = open-label field=20 trial study assessed LAIV safety of >2,000 doses administered to = children=20 aged 18 months--18 years with a history of intermittent wheeze who were=20 otherwise healthy. Among these children, no increased risk was reported = for=20 medically attended acute respiratory illnesses, including acute asthma=20 exacerbation, during the 0--14 or 0--42 days after LAIV compared with = the pre-=20 and postvaccination reference periods (359).

Initial data from VAERS during 2007--2008 and 2008--2009, following = ACIP's=20 recommendation for use of LAIV in healthy children aged 2--4 years, did = not=20 demonstrate an increased frequency of wheezing after administration of = LAIV.=20 However, data also indicate that uptake of LAIV among children aged 2--4 = years=20 was limited (CDC, unpublished data, 2010). Safety monitoring for = wheezing events=20 after LAIV is ongoing.

Adults Aged <50 Years

Among adults, runny nose or nasal congestion (28%--78%), headache = (16%--44%),=20 and sore throat (15%--27%) have been reported more often among vaccine=20 recipients than placebo recipients (346,360). In one clinical = trial among=20 a subset of healthy adults aged 18--49 years, signs and symptoms = reported=20 significantly more often (p<0.05) among LAIV recipients (n =3D 2,548) = than=20 placebo recipients (n =3D 1,290) within 7 days after each dose included = cough (14%=20 and 11%, respectively), runny nose (45% and 27%, respectively), sore = throat (28%=20 and 17%, respectively), chills (9% and 6%, respectively), and = tiredness/weakness=20 (26% and 22%, respectively) (144). A review of 460 reports to = VAERS after=20 distribution of approximately 2.5 million doses during the 2003--04 and = 2004--05=20 influenza seasons did not indicate any new safety concerns (361). = Few of=20 the LAIV VAERS reports (9%) were SAEs; respiratory events (47%) were the = most=20 common conditions reported (361).

The 2010--11 seasonal live attenuated influenza vaccine will contain = an=20 influenza A (H1N1) California/7/2009-like strain, which was also the = strain used=20 for the 2009 pandemic H1N1 monovalent live attenuated vaccine. (See = Safety=20 Monitoring of Pandemic 2009 H1N1 Monovalent Vaccines for additional = information=20 about 2009 H1N1 monovalent vaccine safety data among children and = adults.)

Persons at Higher Risk for Influenza-Related Complications

Limited data assessing the safety of LAIV use for certain groups at = higher=20 risk for influenza-related complications are available. In one study of = 54=20 HIV-infected persons aged 18--58 years with CD4+ counts =E2=89=A5200 = cells/mm3 who received LAIV, no SAEs were reported = during a=20 1-month follow-up period (336). Similarly, one study demonstrated = no=20 significant difference in the frequency of adverse events or viral = shedding=20 among HIV-infected children aged 1--8 years on effective antiretroviral = therapy=20 who were administered LAIV compared with HIV-uninfected children = receiving LAIV=20 (337). LAIV was well-tolerated among adults aged =E2=89=A565 = years with chronic=20 medical conditions (362). These findings suggest that persons at = risk for=20 influenza complications who have inadvertent exposure to LAIV would not = have=20 significant adverse events or prolonged viral shedding and that persons = who have=20 contact with persons at higher risk for influenza-related complications = may=20 receive LAIV.

Safety Monitoring of Pandemic 2009 H1N1 Monovalent Vaccines

The 2010--11 seasonal influenza vaccine will contain an influenza A = (H1N1)=20 California/7/2009-like strain, which was also the strain used for the = 2009=20 pandemic H1N1 monovalent vaccines. Clinical immunogenicity and safety = studies of=20 the 2009 H1N1 monovalent vaccines indicate that the reactogenicity = profile in=20 children and adults is similar to seasonal influenza vaccines=20 (158--160,184). Ongoing comprehensive safety monitoring of the = pandemic=20 2009 H1N1 vaccine was implemented as part of the pandemic immunization = program=20 (363). A nongovernment working group was established by the = National=20 Vaccine Advisory Committee to provide an=20 independent review of safety data, with members representing other = federal=20 advisory committees as well as experts in internal medicine, pediatrics, = immunology, and vaccine safety (314). Data=20 from the first 2 months of implementation of H1N1 vaccination from VAERS = and VSD=20 suggested a similar safety profile for influenza A (H1N1) 2009 = monovalent=20 vaccines and seasonal influenza vaccines. As of July 2010, analysis and = review=20 of vaccine safety data from numerous systems were underway (314,31= 6).=20

Comparisons of LAIV and TIV Efficacy or Effectiveness

Both TIV and LAIV have been demonstrated to be effective in children = and=20 adults. However, data directly comparing the efficacy or effectiveness = of these=20 two types of influenza vaccines are limited and insufficient to identify = whether=20 one vaccine might offer a clear advantage over the other in certain = settings or=20 populations. Studies comparing the efficacy of TIV to that of LAIV have = been=20 conducted in a variety of settings and populations using several = different=20 outcomes. One randomized, double-blind, placebo-controlled challenge = study that=20 was conducted among 92 healthy adults aged 18--41 years assessed the = efficacy of=20 both LAIV and TIV in preventing influenza infection when challenged with = wild-type strains that were antigenically similar to vaccine strains=20 (364). The overall efficacy in preventing laboratory-documented = influenza=20 from all three influenza strains combined was 85% and 71%, respectively, = when=20 challenged 28 days after vaccination by viruses to which study = participants were=20 susceptible before vaccination. The difference in efficacy between the = two=20 vaccines was not statistically significant in this limited study. No = additional=20 challenges were conducted to assess efficacy at time points later than = 28 days=20 (364). In a randomized, double-blind, placebo-controlled trial = that was=20 conducted among young adults during the 2004--05 influenza season, when = the=20 majority of circulating H3N2 viruses were antigenically drifted from = that=20 season's vaccine viruses, the efficacy of LAIV and TIV against = culture-confirmed=20 influenza was 57% and 77%, respectively. The difference in efficacy was = not=20 statistically significant and was attributable primarily to a difference = in=20 efficacy against influenza B (289). Similar studies conducted = during the=20 2005--06 and 2007--08 influenza seasons identified no significant = difference in=20 vaccine efficacy in 2005--06 (288), but a 50% relative efficacy = or TIV=20 compared with LAIV in the 2007--08 season (187).

A randomized controlled clinical trial conducted among children aged = 6--59=20 months during the 2004--05 influenza season demonstrated a 55% reduction = in=20 cases of culture-confirmed influenza among children who received LAIV = compared=20 with those who received TIV (357). In this study, LAIV efficacy = was=20 higher compared with TIV against antigenically drifted viruses and = well-matched=20 viruses (357). An open-label, nonrandomized, community-based = influenza=20 vaccine trial conducted during an influenza season when circulating H3N2 = strains=20 were poorly matched with strains contained in the vaccine also indicated = that=20 LAIV, but not TIV, was effective against antigenically drifted H3N2 = strains=20 during that influenza season. In this study, children aged 5--18 years = who=20 received LAIV had significant protection against laboratory-confirmed = influenza=20 (37%) and pneumonia and influenza events (50%) (365). An = observational=20 study conducted among military personnel aged 17--49 years over three = influenza=20 seasons indicated that persons who received TIV had a substantially = lower=20 incidence of health-care encounters resulting in diagnostic coding for = pneumonia=20 and influenza compared with those who received LAIV. However, among new = recruits=20 being vaccinated for the first time, the incidence of pneumonia- and=20 influenza-coded health-care encounters among those received LAIV was = similar to=20 those receiving TIV (366).

Although LAIV is not licensed for use in persons with risk factors = for=20 influenza complications, certain studies have compared the efficacy of = LAIV to=20 TIV in these groups. LAIV provided 32% increased protection in = preventing=20 culture-confirmed influenza compared with TIV in one study conducted = among=20 children aged =E2=89=A56 years and adolescents with asthma (367) = and 52%=20 increased protection compared with TIV among children aged 6--71 months = with=20 recurrent respiratory tract infections (368).

Effectiveness of Vaccination for Decreasing Transmission to = Contacts

Decreasing transmission of influenza from caregivers and household = contacts=20 to persons at high risk might reduce ILI and complications among persons = at high=20 risk. Influenza virus infection and ILI are common among HCP = (369--371).=20 Influenza outbreaks have been attributed to low vaccination rates among = HCP in=20 hospitals and long-term--care facilities (372--374). One = serosurvey=20 demonstrated that 23% of HCP had serologic evidence of influenza virus = infection=20 during a single influenza season; the majority had mild illness or = subclinical=20 infection (369). Observational studies have demonstrated that = vaccination=20 of HCP is associated with decreased deaths among nursing home patients=20 (375,376). In one cluster-randomized controlled trial that = included 2,604=20 residents of 44 nursing homes, significant decreases in mortality, ILI, = and=20 medical visits for ILI care were demonstrated among residents in nursing = homes=20 in which staff were offered influenza vaccination (coverage rate: 48%) = compared=20 with nursing homes in which staff were not provided with vaccination = (coverage=20 rate: 6%) (377). Another trial demonstrated substantially lower = rates of=20 ILI among residents and staff absences in nursing homes where staff were = specifically targeted for vaccination (coverage rate: 70%) compared with = nursing=20 homes where no intervention was attempted (coverage rate: 32%) = (378). A=20 review concluded that vaccination of HCP in settings in which patients = also were=20 vaccinated provided significant reductions in deaths among elderly = patients from=20 all causes and deaths from pneumonia (379).

Epidemiologic studies of community outbreaks of influenza demonstrate = that=20 school-aged children typically have the highest influenza illness attack = rates,=20 suggesting routine universal vaccination of children might reduce = transmission=20 to their household contacts and possibly others in the community. = Results from=20 certain studies have indicated that the benefits of vaccinating children = might=20 extend to protection of their adult contacts and to persons at risk for=20 influenza complications in the community. However, these data are = limited, and=20 most studies have not used laboratory-confirmed influenza as an outcome = measure.=20 A single-blinded, randomized controlled study conducted as part of a = 1996--1997=20 vaccine effectiveness study demonstrated that vaccinating preschool-aged = children with TIV reduced influenza-related morbidity among some = household=20 contacts (380). A randomized, placebo-controlled trial among = children=20 with recurrent respiratory tract infections demonstrated that members of = families with children who had received a live attenuated virosomal = vaccine=20 formulation (not currently available in the United States) were = substantially=20 less likely to have respiratory tract infections and reported = substantially=20 fewer workdays lost compared with families with children who received = placebo=20 (381). One cluster randomized trial conducted among rural = Hutterite=20 communities in Canada compared laboratory confirmed influenza among = unvaccinated=20 persons in communities where children were administered influenza = vaccine=20 (coverage: 83%) among children aged 3--15 years with communities where = children=20 received hepatitis A vaccine. Influenza vaccine effectiveness for = prevention of=20 influenza among unvaccinated persons was 61% (95% CI =3D 8%--81%) = (382)

In nonrandomized community-based studies, administration of LAIV has = been=20 demonstrated to reduce MAARI (383,384) and ILI-related economic = and=20 medical consequences (e.g., workdays lost and number of health-care = provider=20 visits) among contacts of vaccine recipients (384). Households = with=20 children attending schools in which school-based LAIV vaccination = programs had=20 been established reported less ILI and fewer physician visits during = peak=20 influenza season compared with households with children in schools in = which no=20 LAIV vaccination had been offered. However a decrease in the overall = rate of=20 school absenteeism was not reported in communities in which LAIV = vaccination was=20 offered (384). During an influenza outbreak during the 2005--06 = influenza=20 season, countywide school-based influenza vaccination was associated = with=20 reduced absenteeism among elementary and high school students in one = county that=20 implemented a school-based vaccination program compared with another = county=20 without such a program (385). These community-based studies have = not used=20 laboratory-confirmed influenza as an outcome.

Some studies also have documented reductions in influenza illness = among=20 persons living in communities where focused programs for vaccinating = children=20 have been conducted. A community-based observational study conducted = during the=20 1968 pandemic using a univalent inactivated vaccine reported that a = vaccination=20 program targeting school-aged children (coverage rate: 86%) in one = community=20 reduced influenza rates within the community among all age groups = compared with=20 another community in which aggressive vaccination was not conducted = among=20 school-aged children (386). An observational study conducted in = Russia=20 demonstrated reductions in ILI among the community-dwelling elderly = after=20 implementation of a vaccination program using TIV for children aged 3--6 = years=20 (57% coverage achieved) and children and adolescents aged 7--17 years = (72%=20 coverage achieved) (387). In a nonrandomized community-based = study=20 conducted over three influenza seasons, 8%--18% reductions in the = incidence of=20 MAARI during the influenza season among adults aged =E2=89=A535 years = were observed in=20 communities in which LAIV was offered to all children aged =E2=89=A518 = months (estimated=20 coverage rate: 20%--25%) compared with communities that did not provide = routine=20 influenza vaccination programs for all children (383). In a = subsequent=20 influenza season, the same investigators documented a 9% reduction in = MAARI=20 rates during the influenza season among persons aged 35--44 years in=20 intervention communities, where coverage was estimated at 31% among = school=20 children. However, MAARI rates among persons aged =E2=89=A545 years were = lower in the=20 intervention communities regardless of the presence of influenza in the=20 community, suggesting that lower rates could not be attributed to = vaccination of=20 school children against influenza (365).

The largest study to examine the community effects of increasing = overall=20 vaccine coverage was an ecologic study that described the experience in = Ontario,=20 Canada, which is the only province to implement a universal influenza=20 vaccination program beginning in 2000. On the basis of models developed = from=20 administrative and viral surveillance data, influenza-related mortality, = hospitalizations, ED use, and physicians' office visits decreased = substantially=20 more in Ontario after program introduction than in other provinces, with = the=20 largest reductions observed in younger age groups (388). In = addition,=20 influenza-associated antibiotic prescriptions were substantially reduced = compared with other provinces (389).

Efficacy and Effectiveness of Influenza Vaccination When Circulating = Influenza Virus Strains Differ from Vaccine Strains

Vaccination can provide reduced but substantial cross-protection = against=20 drifted strains in some seasons, including reductions in severe outcomes = such as=20 hospitalization. Usually one or more circulating viruses with antigenic = changes=20 compared with the vaccine strains are identified in each influenza = season. In=20 addition, two distinct lineages of influenza B viruses have = co-circulated in=20 recent years, and limited cross-protection is observed against the = lineage not=20 represented in the vaccine (70= ).=20 However, assessment of the clinical effectiveness of influenza vaccines = cannot=20 be determined solely by laboratory evaluation of the degree of antigenic = match=20 between vaccine and circulating strains. In some influenza seasons, = circulating=20 influenza viruses with significant antigenic differences predominate, = and=20 reductions in vaccine effectiveness sometimes are observed compared with = seasons=20 when vaccine and circulating strains are well-matched=20 (77,170,188,239,289,390). However, even during years when vaccine = strains=20 were not antigenically well-matched to circulating strains (the result = of=20 antigenic drift), substantial protection has been observed against = severe=20 outcomes, presumably because of vaccine-induced cross-reacting = antibodies=20 (77,188,289,352). For example, in one study conducted during the = 2003--04=20 influenza season, when the predominant circulating strain was an = influenza A=20 (H3N2) virus that was antigenically different from that season's vaccine = strain,=20 effectiveness against laboratory-confirmed influenza illness among = persons aged=20 50--64 years was 60% among healthy persons and 48% among persons with = medical=20 conditions that increased the risk for influenza complications = (188). An=20 interim, within-season analysis during the 2007--08 influenza season = indicated=20 that vaccine effectiveness was 44% overall, 54% among healthy persons = aged 5--49=20 years, and 58% against influenza A, despite the finding that viruses = circulating=20 in the study area were predominately a drifted influenza A (H3N2) and an = influenza B strain from a different lineage compared with vaccine = strains (391). Among=20 children, both TIV and LAIV provide protection against infection even in = seasons=20 when vaccines and circulating strains are not well-matched. Vaccine=20 effectiveness against ILI was 49%--69% in two observational studies, and = 49%=20 against medically attended, laboratory-confirmed influenza in a = case-control=20 study conducted among young children during the 2003--04 influenza = season, when=20 a drifted influenza A (H3N2) strain predominated, based on viral = surveillance=20 data (165,169). However, the 2009--10 seasonal influenza vaccines = provided no protection against medically attended illness caused by the = pandemic=20 2009 influenza A (H1N1) virus, because of substantial changes in key = viral=20 antigens compared with recently circulating strains (392).

Continued improvements in collecting representative circulating = viruses and=20 use of surveillance data to forecast antigenic drift are needed. = Manufacturing=20 trivalent influenza virus vaccines is a challenging process that takes = 6--8=20 months to complete. Shortening manufacturing time to increase the time = to=20 identify good vaccine candidate strains from among the most recent = circulating=20 strains also is important. Data from multiple seasons that are collected = in a=20 consistent manner are needed to better understand vaccine effectiveness = during=20 seasons when circulating and vaccine virus strains are not = well-matched.

Cost-Effectiveness of Influenza Vaccination

Economic studies of influenza vaccination are difficult to compare = because=20 they have used different measures of both costs and benefits (e.g., = cost-only,=20 cost-effectiveness, cost-benefit, or cost-utility measures). However, = most=20 studies indicate that vaccination reduces or minimizes health care, = societal,=20 and individual costs and the productivity losses and absenteeism = associated with=20 influenza illness. One national study estimated the annual economic = burden of=20 seasonal influenza in the United States (using 2003 population and = dollars) to=20 be $87.1 billion, including $10.4 billion in direct medical costs=20 (78).

Studies of influenza vaccination in the United States among persons = aged =E2=89=A565=20 years have estimated substantial reductions in hospitalizations and = deaths and=20 overall societal cost savings (234,235). A study of a larger = population=20 comparing persons aged 50--64 years with those aged =E2=89=A565 years = estimated the=20 cost-effectiveness of influenza vaccination to be $28,000 per QALY saved = (in=20 2000 dollars) in persons aged 50--64 years compared with $980 per QALY = saved=20 among persons aged =E2=89=A565 years (393).

Economic analyses among adults aged <65 years have reported mixed = results=20 regarding influenza vaccination. Two studies in the United States = indicated that=20 vaccination can reduce both direct medical costs and indirect costs from = work=20 absenteeism and reduced productivity (79,394). However, another = U.S.=20 study indicated no productivity and absentee savings in a strategy to = vaccinate=20 healthy working adults, although vaccination still was estimated to be=20 cost-effective (395). In Ontario, Canada, where a universal = influenza=20 vaccination program was implemented beginning in 2000, costs were = estimated to=20 be approximately twice as much as a targeted vaccination program; = however, the=20 number of cases of influenza was reduced 61%, and influenza-related = mortality=20 declined 28%, saving an estimated 1,134 QALYs per season overall from a=20 health-care payer perspective. Most cost savings were attributed to the=20 avoidance of hospitalizations. The incremental cost-effectiveness ratio = was=20 estimated to be $10,797 Canadian per QALY gained (396).

Cost analyses have documented the considerable financial burden of = illness=20 among children. In a study of 727 children conducted at a medical center = during=20 2000--2004, the mean total cost of hospitalization for influenza-related = illness=20 was $13,159 ($39,792 for patients admitted to an intensive care unit and = $7,030=20 for patients cared for exclusively in the general wards) (397). A = strategy that focuses on vaccinating children with medical conditions = that=20 confer a higher risk for influenza complications are more cost-effective = than a=20 strategy of vaccinating all children (395). An analysis that = compared the=20 costs of vaccinating children of varying ages with TIV and LAIV = indicated that=20 costs per QALY saved increased with age for both vaccines. In 2003 = dollars per=20 QALY saved, costs for routine vaccination using TIV were $12,000 for = healthy=20 children aged 6--23 months and $119,000 for healthy adolescents aged = 12--17=20 years compared with $9,000 and $109,000, respectively, using LAIV = (398).=20 Economic evaluations of vaccinating children have demonstrated a wide = range of=20 cost estimates, but have generally found this strategy to be either cost = saving=20 or cost beneficial (399--402).

Economic analyses most influenced by the vaccination venue, with = vaccination=20 in medical-care settings incurring higher projected costs. In a = published model,=20 the mean cost (year 2004 values) of vaccination was lower in mass = vaccination=20 ($17.04) and pharmacy ($11.57) settings than in scheduled doctor's = office visits=20 ($28.67) (403). Vaccination in nonmedical settings was projected = to be=20 cost saving for healthy adults aged =E2=89=A550 years and for high-risk = adults of all=20 ages. For healthy adults aged 18--49 years, preventing an episode of = influenza=20 would cost $90 if vaccination were delivered in a pharmacy setting, $210 = in a=20 mass vaccination setting, and $870 during a scheduled doctor's office = visit=20 (403). Medicare and Vaccines for Children program reimbursement = rates in=20 recent years have been less than the costs associated with providing = vaccination=20 in a medical practice (404,405).

Vaccination Coverage Levels

Continued annual monitoring is needed to determine the effects on = vaccination=20 coverage of vaccine supply delays and shortages, changes in influenza=20 vaccination recommendations and target groups for vaccination, = reimbursement=20 rates for vaccine and vaccine administration, and other factors. One of = the=20 Healthy People 2010 objectives (objective no. 14-29a) includes = achieving=20 an influenza vaccination coverage level of 90% for persons aged = =E2=89=A565 years and=20 among nursing home residents (406,407); new strategies to improve = coverage are needed to achieve this objective (408,40= 9).=20

On the basis of 2009 final data and 2010 early release data from the = National=20 Health Interview Survey (NHIS), estimated national influenza vaccine = coverage=20 during the 2007--08 and 2008--09 influenza seasons did not increase=20 substantially among persons aged =E2=89=A565 years and those aged 50--64 = years (Ta= ble=20 3) and are only slightly higher than coverage levels observed before = the=20 2004--05 vaccine shortage year (410--412). In the 2007--08 and = 2008--09=20 influenza seasons, estimated vaccination coverage levels (based on NHIS = data)=20 among adults with high-risk conditions aged 18--49 years were 30.4% and = 33%,=20 respectively, substantially lower than the Healthy People 2000 = and=20 Healthy People 2010 objectives of 60% (Ta= ble=20 3) (406,407). Among adults with asthma aged 18--49 years and = 50--64=20 years, estimated coverage during the 2006--07 influenza season was 24% = and 55%=20 respectively; the national objective for coverage among adults with = asthma is=20 60% (413). Epidemiologic studies conducted during the 2009 = pandemic=20 indicated that more hospitalizations and deaths were occurring among = adults aged=20 <65 years with high-risk conditions than among any other group, and = these=20 adults were among the initial target groups to receive the 2009 H1N1 = vaccination=20 while vaccine supply was limited (414).=20 However, coverage among adults aged <65 years with medical conditions = that=20 confer a higher risk for influenza complications was <40% for the = 2009 H1N1=20 monovalent vaccine (415).

During the 2009 influenza A (H1N1) pandemic, state-level estimates of = seasonal vaccine coverage data for both seasonal influenza and the = monovalent=20 2009 H1N1 vaccines were obtained via telephone surveys conducted by the=20 Behavioral Risk Factor Surveillance System (BRFSS) and the National 2009 = H1N1=20 Flu Survey. By January 31, 2010 estimated state seasonal influenza = vaccination=20 coverage among persons aged =E2=89=A56 months ranged from 30.3% to 54.5% = (median:=20 40.6%). Median coverage was 41.2% for children aged 6 months--17 years, = 38.3%=20 for adults aged 18--49 years with high-risk conditions, 28.8% for adults = aged=20 18--49 years without high-risk conditions, 45.5% for adults aged 50--64 = years,=20 and 69.3% for adults aged =E2=89=A565 years. These results, compared = with the previous=20 season, suggest large increases in coverage for children and a moderate = increase=20 for adults aged 18--49 years without high-risk compared with seasonal = influenza=20 vaccine coverage estimates in previous seasons (415,416).=20 However, vaccine coverage estimates using BRFSS data typically have been = higher=20 than estimates derived from NHIS data (416).

Studies conducted among children and adults indicate that = opportunities to=20 vaccinate persons at risk for influenza complications (e.g., during=20 hospitalizations for other causes) often are missed. In one study, 23% = of=20 children hospitalized with influenza and a comorbidity had a previous=20 hospitalization during the preceding influenza vaccination season = (417).=20 In a study of hospitalized Medicare patients, only 31.6% were vaccinated = before=20 admission, 1.9% during admission, and 10.6% after admission = (418). A=20 study in New York City conducted during 2001--2005 among 7,063 children = aged=20 6--23 months indicated that 2-dose vaccine coverage increased from 1.6% = to 23.7%=20 over time; however, although the average number of medical visits during = which=20 an opportunity to be vaccinated decreased during the course of the study = from=20 2.9 to 2.0 per child, 55% of all visits during the final year of the = study still=20 represented a missed vaccination opportunity (419). Using = standing orders=20 in hospitals increases vaccination rates among hospitalized persons=20 (420), and vaccination of hospitalized patients is safe and = stimulates an=20 appropriate immune response (220). In one survey, the strongest = predictor=20 of receiving vaccination was the survey respondent's belief that he or = she was=20 in a high-risk group, based on data from one survey; however, many = persons in=20 high-risk groups did not know that they were in a group recommended for=20 vaccination (421,422). In one study, over half of adults who did = not=20 receive influenza vaccination reported that they would have received = vaccine if=20 this had been recommended by their health-care provider = (422).

Reducing racial/ethnic health disparities, including disparities in = influenza=20 vaccination coverage, is an overarching national goal that is not being = met=20 (407). Estimated vaccination coverage levels in 2008 among = persons aged=20 =E2=89=A565 years were 70% for non-Hispanic whites, 52% for non-Hispanic = blacks, and 52%=20 for Hispanics (423). Among Medicare beneficiaries, other key = factors that=20 contribute to disparities in coverage include variations in the = propensity of=20 patients to actively seek vaccination and variations in the likelihood = that=20 providers recommend vaccination (424,425). One study estimated = that=20 eliminating these disparities in vaccination coverage would have an = impact on=20 mortality similar to the impact of eliminating deaths attributable to = kidney=20 disease among blacks or liver disease among Hispanics (426). = Differences=20 in coverage by race or ethnicity might be partly attributable to = differences in=20 beliefs about vaccine effectiveness and safety (422). Among = nursing home=20 patients, fewer blacks and Hispanics are offered vaccine or receive it = compared=20 with whites, and blacks refuse vaccination more frequently (427). = Disparities in seasonal influenza vaccine coverage among adult whites = (43%),=20 blacks (31%), and Hispanics (31%) also were observed during 2009--2010 = (416).

Reported vaccination levels are low among children at increased risk = for=20 influenza complications. Coverage among children aged 2--17 years with = asthma=20 was estimated to be 29% for the 2004--05 influenza season (428).=20 During the 2007--08 influenza season, the fourth season for which ACIP=20 recommended that all children aged 6--23 months receive vaccination, = National=20 Immunization Survey data demonstrated that 41% of children aged 6--23 = months=20 received at least 1 dose of influenza vaccine, and 23% were fully = vaccinated=20 (i.e., received 1 or 2 doses depending on previous vaccination history); = however, results varied substantially among states (429). Data=20 from the eight Immunization Information System sentinel sites during = 2008--09=20 indicated that 48% of children aged 6--23 months had received at least 1 = dose,=20 and 29% were fully vaccinated (430).=20 Coverage levels in these sites for older children were lower and = declined with=20 increasing age, ranging from 22% fully vaccinated among children aged = 2--4 years=20 to 9% among children aged 13--18 years (430). As=20 has been reported for older adults, a physician recommendation for = vaccination=20 and the perception that having a child be vaccinated "is a smart idea" = were=20 associated positively with likelihood of vaccination of children aged = 6--23=20 months (431). Similarly, children with asthma were more likely to = be=20 vaccinated if their parents recalled a physician recommendation to be = vaccinated=20 or believed that the vaccine worked well (432). Implementation of = a=20 reminder/recall system in a pediatric clinic increased the percentage of = children with asthma receiving vaccination from 5% to 32% (433).=20 Reminder/recall systems might be particularly useful when limited = vaccine=20 availability requires targeted vaccination of children with high-risk = conditions=20 (434).

Although annual vaccination is recommended for HCP and is a high = priority for=20 reducing morbidity associated with influenza in health-care settings and = for=20 expanding influenza vaccine use (435--437), NHIS data = demonstrated a=20 vaccination coverage level of only 44.4% among HCP during the 2006--07 = season,=20 and 49% during the 2007--08 season (Ta= ble=20 3). Coverage levels during the 2009 pandemic were higher for = seasonal=20 vaccine, but remained low for the 2009 pandemic vaccine. By mid-January = 2010,=20 estimated vaccination coverage among HCP was 37% for 2009 pandemic = influenza A=20 (H1N1) and 62% for seasonal influenza, based on a RAND = Corporation--conducted=20 telephone survey that used a somewhat different methodology than NHIS = (438).=20 Overall, 64% received either of these influenza vaccines, higher = coverage than=20 any previous season, but only 35% of HCP reported receiving both = vaccines (438).=20 Vaccination of HCP has been associated with reduced work absenteeism=20 (370) and with fewer deaths among nursing home patients = (375,377)=20 and elderly hospitalized patients (379). Factors associated with = a higher=20 rate of influenza vaccination among HCP include older age, being a = hospital=20 employee, having employer-provided health-care insurance, having had=20 pneumococcal or hepatitis B vaccination in the past, or having visited a = health-care professional during the preceding year. HCP who decline = vaccination=20 frequently express doubts about the risk for influenza and the need for=20 vaccination, are concerned about vaccine effectiveness and side effects, = and=20 dislike injections (439).

Vaccine coverage among pregnant women increased during the 2007--08 = influenza=20 season, with 24% of pregnant women reporting vaccination, excluding = pregnant=20 women who reported diabetes, heart disease, lung disease, and other = selected=20 high-risk conditions; seasonal vaccine coverage estimates for 2008--09 = were only=20 11%, however, which is closer to pre-2007 estimates and likely reflects=20 variation in estimates caused by the small sample size rather than = significant=20 fluctuations in coverage (Ta= ble=20 3). The causes of persistent low coverage among pregnant women are = not fully=20 determined. However, in a study of influenza vaccination acceptance by = pregnant=20 women, 71% of those who were offered the vaccine chose to be vaccinated=20 (440). However, a 1999 survey of obstetricians and gynecologists=20 determined that only 39% administered influenza vaccine to obstetric = patients in=20 their practices, although 86% agreed that pregnant women's risk for=20 influenza-related morbidity and mortality increases during the last two=20 trimesters (441). Pregnancy was an important risk factor during = the 2009=20 H1N1 pandemic (106,120), and because the 2009 H1N1 influenza = virus is=20 expected to continue circulation during 2010--11, improved vaccination = coverage=20 among pregnant women is needed.

Influenza vaccination coverage in all groups recommended for = vaccination=20 remains suboptimal. Despite the timing of the peak of influenza disease, = administration of vaccine decreases substantially after November. = According to=20 results from NHIS, for the three most recent influenza seasons for which = these=20 data are available, approximately 84% of all influenza vaccinations were = administered during September--November. Among persons aged =E2=89=A565 = years, the=20 percentage of September--November vaccinations was 92% (442).=20 Because many persons recommended for vaccination remain unvaccinated at = the end=20 of November, CDC encourages public health partners and health-care = providers to=20 conduct vaccination clinics and other activities that promote seasonal = influenza=20 vaccination annually during National Influenza Vaccination Week = (December=20 6--12, 2010) and throughout the remainder of the influenza = season.

Self-report of influenza vaccination among adults compared with = determining=20 vaccination status from the medical record, is a sensitive and specific = source=20 of information (443). Patient self-reports should be accepted as = evidence=20 of influenza vaccination in clinical practice (443). However, = information=20 on the validity of parents' reports of pediatric influenza vaccination = is not=20 yet available.

Vaccination coverage estimates for the influenza A (H1N1) 2009 = monovalent=20 vaccines indicate that most doses were administered to the initial = target=20 groups, and that, by January 2, 2010 (approximately 90 days after = vaccine first=20 became available), an estimated 20% of the U.S. population (61 million = persons)=20 had been vaccinated, including 28% of persons in the initial target = groups. An=20 estimated 30% of U.S. children aged 6 months--18 years had been = vaccinated,=20 including 33% of children aged 6 months--4 years. Estimated coverage for = specific initial target groups was 38% for pregnant women, 22% for HCP, = and 12%=20 for adults aged 25--64 years with medical conditions that confer a = higher risk=20 for influenza complications. Estimates of 2009 H1N1 vaccination coverage = levels=20 generally were higher among non-Hispanic whites than among non-Hispanic = blacks=20 (438). These=20 coverage estimates were in the same approximate range as estimates for = seasonal=20 vaccination coverage, suggesting that concerns about the pandemic were = not=20 sufficient to overcome some barriers to influenza vaccination among = persons at=20 higher risk for influenza complications.

Recommendations for Using TIV and LAIV = During the=20 2010--11 Influenza Season

Routine vaccination of all persons aged =E2=89=A56 months is = recommended. During the=20 2009--10 influenza season, an estimated 85% of the U.S. population = already had=20 an indication for vaccination (444). A=20 universal vaccination recommendation for all persons aged =E2=89=A56 = months eliminates=20 the need to determine whether each person has an indication for = vaccination and=20 emphasizes the importance of preventing influenza among person of all = ages. The=20 expansion of recommendations for annual vaccination to include all = adults is=20 supported by evidence that influenza vaccines are safe and effective. In = addition, morbidity and mortality among adults aged <50 years, = including=20 adults who were previously healthy, occurs in every influenza season. = Although=20 most adults in this age group who develop influenza-related = complications have=20 medical risk factors, some have no previously identified risk factors = for=20 influenza complications, or have risk factors but are unaware that they = should=20 be vaccinated. Expansion of vaccination recommendations to all adults = reflects=20 the need to remove potential barriers to receipt of influenza vaccine, = including=20 lack of awareness about vaccine indications among persons at higher risk = for=20 influenza complications and their close contacts. Although the capacity = now=20 exists to produce sufficient influenza vaccines to meet the predicted = increase=20 in demand, the annual supply of influenza vaccine and timing of its = distribution=20 cannot be guaranteed in any year.

Further support for expansion of recommendations to include all = adults is=20 based on data from the 2009 pandemic experience. Data from epidemiologic = studies=20 conducted during the 2009 influenza A (H1N1) pandemic indicates that the = risk=20 for influenza complications among adults aged <50 years who had 2009 = pandemic=20 influenza A (H1N1) is greater than is typically seen for seasonal = influenza=20 (12). Explosive outbreaks of 2009 H1N1 influenza among young = adults in=20 settings such as college campuses (445) were part of the basis = for=20 prioritizing vaccination of all persons aged 6 months--24 years during = the 2009=20 pandemic influenza response. Pandemic 2009 influenza A (H1N1)-like = viruses are=20 expected to continue to circulate during the 2010--11 influenza season, = and a=20 substantial proportion of young adults do not yet have immunity as a = result of=20 natural infection with this virus (446). In addition, severe = infections=20 were observed more frequently in some younger adults who did not have = previously=20 recognized risk factors for influenza-related complications, including = obese=20 persons, persons in certain racial and ethnic minority groups, and = postpartum=20 women (24,48,85,86,90,447).

Both TIV and LAIV prepared for the 2010--11 season will include=20 A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like, and=20 B/Brisbane/60/2008-like antigens. The influenza B virus component of the = 2010--11 vaccine is from the Victoria lineage (448). These = viruses will=20 be used because they are representative of influenza viruses that are = predicted=20 to be circulating in the United States during the 2010--11 influenza = season and=20 have favorable growth properties in eggs. The H1N1 strain recommended = for the=20 2010--11 trivalent influenza vaccine is the same as the vaccine strain = in the=20 2009 H1N1 monovalent vaccines given during the pandemic. The 2009 = pandemic=20 influenza virus-derived vaccine strain has replaced the seasonal = influenza H1N1=20 vaccine strains that were present in the vaccine since 1977.

Healthy nonpregnant persons aged 2--49 years can choose to receive = either TIV=20 or LAIV. Some TIV formulations are FDA-licensed for use in persons as = young as=20 age 6 months (see Recommended Vaccines for Different Age Groups). = Persons aged=20 =E2=89=A565 years can be administered either standard-dose TIV 15 mcg = per vaccine=20 strain) or the newly licensed TIV containing 60 mcg HA antigen per = vaccine=20 strain (Sanofi pasteur). TIV is licensed for use in persons with = high-risk=20 conditions (Ta= ble=20 2). LAIV is FDA-licensed for use only for persons aged 2--49 years. = In=20 addition, FDA has indicated that the safety of LAIV has not been = established in=20 persons with underlying medical conditions that confer a higher risk for = influenza complications.

All children aged 6 months--8 years who have not been vaccinated = previously=20 at any time with at least 1 dose of either LAIV (if appropriate) or TIV = should=20 receive 2 doses of age-appropriate vaccine in the same season, with a = single=20 dose during subsequent seasons. Persons who received a 2009 H1N1 = monovalent=20 vaccine should still be vaccinated with the 2010--11 formulation of TIV = or LAIV=20 to provide protection against influenza A (H3N2) and influenza B strains = that=20 are expected to circulate during the 2010--11 influenza season. In = addition, the=20 duration of protection after receipt of the 2009 H1N1 monovalent = influenza=20 vaccines is unknown and likely declines over time.

In addition, emphasis on providing routine vaccination annually to = certain=20 groups at higher risk for influenza infection or complications is = advised,=20 including all children aged 6 months--18 years, all persons aged = =E2=89=A550 years, and=20 other persons at risk for medical complications from influenza. These = persons,=20 their household and close contacts, and all HCP should continue to be a = focus of=20 vaccination efforts as providers and programs transition to routinely=20 vaccinating all persons aged =E2=89=A56 months (Box). Despite a = recommendation for=20 vaccination for approximately 85% of the U.S. population over the past = two=20 seasons, <50% of the U.S. population received a seasonal influenza=20 vaccination in 2008--09 or 2009--10. Estimated vaccine coverage for the = 2009=20 H1N1 monovalent vaccine coverage was <40% (438).

Rationale for Vaccination of Specific = Populations

Children Aged 6 Months--18 Years

Annual vaccination for all children aged 6 months--18 years is = recommended.=20 Healthy children aged 2--18 years can receive either LAIV or TIV. = Children aged=20 6--23 months, and those aged 2--4 years who have evidence of asthma, = wheezing,=20 or who have medical conditions that put them at higher risk for = influenza=20 complications should receive TIV (see Considerations When Using LAIV). =

Recommendations to provide routine influenza vaccination to all = children and=20 adolescents aged 6 months--18 years are made on the basis of 1) = accumulated=20 evidence that influenza vaccine is effective and safe for children (see=20 Influenza Vaccine Efficacy, Effectiveness, and Safety); 2) increased = evidence=20 that influenza has substantial adverse impacts among children and their = contacts=20 (e.g., school absenteeism, increased antibiotic use, medical care = visits, and=20 parental work loss) (see Health-Care Use, Hospitalizations, and Deaths=20 Attributed to Influenza); and 3) an expectation that a simplified = age-based=20 influenza vaccine recommendation for all children and adolescents will = improve=20 vaccine coverage levels among children who already have a risk- or = contact-based=20 indication for annual influenza vaccination.

Children typically have the highest attack rates during community = outbreaks=20 of influenza and serve as a major source of transmission within = communities=20 (1,2). If sufficient vaccination coverage among children can be = achieved,=20 potential benefits include the indirect effect of reducing influenza = among=20 persons who have close contact with children and reducing overall = transmission=20 within communities (449). Achieving and sustaining = community-level=20 reductions in influenza will require mobilization of community resources = and=20 development of sustainable annual vaccination campaigns to assist = health-care=20 providers and vaccination programs in providing influenza vaccination = services=20 to children of all ages. In many areas, innovative community-based = efforts,=20 which might include mass vaccination programs in school or other = community=20 settings, will be needed to supplement vaccination services provided in=20 health-care providers' offices or public health clinics. In = nonrandomized=20 community-based controlled trials, reductions in ILI-related symptoms = and=20 medical visits among household contacts have been demonstrated in = communities=20 where vaccination programs among school-aged children were established = compared=20 with communities without such vaccination programs (365,386,387). =

All children aged 6 months--8 years who receive a seasonal influenza = vaccine=20 for the first time should be administered 2 doses. Children aged 6 = months--8=20 years who received a seasonal vaccine for the first time during = 2009--2010 but=20 who received only 1 dose should receive 2 doses, rather than 1, during=20 2010--2011. In addition, for the 2010--11 influenza season, children = aged 6=20 months--8 years who did not receive at least 1 dose of an influenza A = (H1N1)=20 2009 monovalent vaccine should receive 2 doses of a 2010--11 seasonal = influenza=20 vaccine, regardless of previous influenza vaccination history (Fi= gure=20 3). Children aged 6 months--8 years for whom the previous 2009--10 = seasonal=20 or influenza A (H1N1) 2009 monovalent vaccine history cannot be = determined=20 should receive 2 doses of a 2010--11 seasonal influenza vaccine. For all = children, the second dose of a recommended 2-dose series should be = administered=20 =E2=89=A54 weeks after the initial dose.

The recommendation to administer 2 doses to children who did not = receive an=20 influenza A (H1N1) 2009 monovalent vaccine, regardless of previous = seasonal=20 influenza vaccine history, is new. This change in recommendations is = made on the=20 basis of data from several immunogenicity studies indicating that = children aged=20 <9 years have lower antibody levels and lower rates of protective = response=20 after receiving a single dose of vaccines containing the 2009 pandemic = H1N1=20 antigen compared with older children and adults. However, >80% of = infants and=20 children aged <3 years and >90% of older children who receive 2 = doses of a=20 vaccine that contains the 2009 H1N1 antigen develop protective antibody = levels=20 (158,160; National Institutes of Health, unpublished data, 2010). = Therefore, current immunogonicity data indicate that at least 2 doses of = the=20 2009 H1N1 vaccine antigen are needed to produce protective antibody = levels for=20 the majority of young children. This recommendation includes children = who have=20 received at least 2 doses of a seasonal influenza vaccine in a previous = season=20 and who would normally be scheduled to only receive 1 seasonal vaccine = dose in=20 the 2010--11 season.

A second dose is not necessary for children being vaccinated for the = first=20 time who were aged 8 years at the time of the first dose but who are = seen again=20 after they have reached age 9 years. Children aged 6 months--8 years who = had=20 never received a seasonal influenza vaccine previously and who received = only the=20 2009 H1N1 monovalent vaccine should receive 2 doses of the 2010--11 = seasonal=20 influenza vaccine, to provide adequate protection against influenza A = (H3N2) and=20 influenza B. If possible, children recommended for 2 doses of seasonal = influenza=20 vaccine should receive them both before onset of influenza season. = However,=20 vaccination, including the second dose, is recommended even after = influenza=20 virus begins to circulate in a community.

Children who had a laboratory-confirmed 2009 pandemic influenza A = (H1N1)=20 virus infection (e.g., reverse transcription--PCR or virus culture = specific for=20 2009 pandemic influenza A (H1N1) virus) are likely to be immune to this = virus.=20 There is no known harm in providing 2 doses of 2010--11 seasonal = influenza=20 vaccine to a child who has been infected previously with the 2009 = pandemic=20 influenza A (H1N1) virus. However, at immunization provider discretion, = these=20 children can receive the appropriate number of seasonal vaccine doses (1 = or 2)=20 without regard to previous receipt of the influenza A (H1N1) 2009 = monovalent=20 vaccine. However, most children did not receive specific diagnostic = testing=20 (i.e., were untested or received a rapid antigen test), and for others, = evidence=20 of laboratory confirmation using a diagnostic test specific for the 2009 = H1N1=20 antigen is unavailable to immunization providers. If no test results are = available and no influenza A (H1N1) 2009 monovalent vaccine had been=20 administered, children who had a febrile respiratory illness during = 2009--2010=20 cannot be assumed to have had influenza A (H1N1) virus infection, and = these=20 children should receive 2 doses of the 2010--11 seasonal vaccine. = Providers who=20 are determining the number of vaccine doses recommended for children = with=20 laboratory-confirmed 2009 pandemic influenza A (H1N1) virus infection = (Fi= gure=20 3) should also determine whether 2 doses are indicated on the basis = of=20 seasonal vaccine history.

Persons at Risk for Medical Complications

Vaccination to prevent influenza is particularly important for = persons who=20 are at increased risk for severe complications from influenza or at = higher risk=20 for influenza-related outpatient, ED, or hospital visits. When vaccine = supply is=20 limited, vaccination efforts should focus on delivering vaccination to = the=20 following persons:

all children aged 6 months--4 years (59 months);

all persons aged =E2=89=A550 years;

adults and children who have chronic pulmonary = (including=20 asthma) or cardiovascular (except isolated hypertension), renal, = hepatic,=20 neurological, hematologic, or metabolic disorders (including diabetes=20 mellitus);

persons who have immunosuppression (including=20 immunosuppression caused by medications or by HIV);

women who are or will be pregnant during the = influenza=20 season;

children and adolescents (aged 6 months--18 years) = who are=20 receiving long-term aspirin therapy and who might be at risk for = experiencing=20 Reye syndrome after influenza virus infection;

residents of nursing homes and other long-term--care = facilities;

American Indians/Alaska Natives;

persons who are morbidly obese (BMI =E2=89=A540); =

HCP;

household contacts and caregivers of children aged = <5 years=20 and adults aged =E2=89=A550 years, with particular emphasis on = vaccinating contacts of=20 children aged <6 months; and

household contacts and caregivers of persons with = medical=20 conditions that put them at higher risk for severe complications from=20 influenza.

For children, the risk for severe complications from influenza is = highest=20 among those aged <2 years, who have much higher rates of = hospitalization for=20 influenza-related complications compared with older children = (7,54,61).=20 Medical care and ED visits attributable to influenza are increased among = children aged <5 years compared with older children (54). = Chronic=20 neurologic conditions are thought to place persons at higher risk for = influenza=20 complications on the basis of the potential for compromised respiratory = function=20 or the handling of respiratory secretions, both of which can increase = the risk=20 for aspiration; such conditions include cognitive dysfunction, spinal = cord=20 injuries, seizure disorders, or neuromuscular disorders (46). =

An observational study conducted during the 2009 H1N1 pandemic = indicated that=20 morbid obesity, and possibly obesity, might be a new or previously = unrecognized=20 risk factor for influenza-related complications (85). In another = study,=20 American Indians/Alaska Natives were demonstrated to have a higher risk = for=20 death from 2009 H1N1 influenza (90= ). These=20 medical and race/ethnicity risk factors might reflect a higher = prevalence of=20 underlying chronic medical conditions, including conditions that are not = known=20 by the patient or provider. Other minority groups, including blacks, = have been=20 demonstrated to have higher incidence of hospitalizations as a result of = laboratory-confirmed influenza compared with whites (CDC, unpublished = data,=20 2010); additional study is needed to determine the reasons. Persons who = have=20 chronic medical conditions, who are pregnant, or who are at higher risk = for 2009=20 H1N1 influenza-related complications should be encouraged to begin = receiving a=20 routine annual influenza vaccination as programs and practitioners = transition to=20 providing vaccination for all persons aged =E2=89=A56 months (Box).

Persons Who Live With or Care for Persons at Higher Risk for=20 Influenza-Related Complications

All persons aged =E2=89=A56 months should be vaccinated annually. As = providers and=20 programs transition to providing annual vaccination to all persons, = continued=20 emphasis should be placed on vaccination of persons who live with or = care for=20 persons at higher risk for influenza-relate complications. When vaccine = supply=20 is limited, vaccination efforts should focus on delivering vaccination = to=20 persons at higher risk for influenza-related complications as well as = these=20 persons:

HCP;

household contacts (including children) and = caregivers of=20 children aged =E2=89=A459 months (i.e., aged <5 years) and adults = aged =E2=89=A550 years;=20 and

household contacts (including children) and = caregivers of=20 persons with medical conditions that put them at higher risk for = severe=20 complications from influenza.

Healthy persons who are infected with influenza virus, including = those with=20 subclinical infection, can transmit influenza virus to persons at higher = risk=20 for complications from influenza. In addition to HCP, groups that can = transmit=20 influenza to high-risk persons include:

employees of assisted living and other residences = for persons=20 in groups at high risk;

persons who provide home care to persons in groups = at high=20 risk; and

household contacts of persons in groups at high = risk,=20 including contacts such as children or mothers of = newborns.

In addition, because children aged <5 years are at increased risk = for=20 influenza-related hospitalization (7,47,61,450,451) compared with = older=20 children, vaccination is recommended for their household contacts and=20 out-of-home caregivers. Because influenza vaccines have not been = licensed by FDA=20 for use among children aged <6 months, emphasis should be placed on=20 vaccinating contacts of these children.

Healthy HCP and persons aged 2--49 years who are contacts of persons = in these=20 groups and who are not contacts of severely immunocompromised persons = living in=20 a protected environment (see Close Contacts of Immunocompromised = Persons) should=20 receive either LAIV or TIV when indicated or requested. All other = persons,=20 including pregnant women, should receive TIV.

All HCP and persons in training for health-care professions should be = vaccinated annually against influenza. Persons working in health-care = settings=20 who should be vaccinated include physicians, nurses, and other workers = in both=20 hospital and outpatient-care settings, medical emergency--response = workers=20 (e.g., paramedics and emergency medical technicians), employees of = nursing home=20 and long-term--care facilities who have contact with patients or = residents, and=20 students in these professions who will have contact with patients=20 (436,437,452).

Facilities that employ HCP should provide vaccine to workers by using = approaches that have been demonstrated to be effective in increasing = vaccination=20 coverage. The HCP influenza coverage goal should be vaccination of 100% = of=20 employees who do not have medical contraindications. Health-care = administrators=20 should consider the level of vaccination coverage among HCP to be one = measure of=20 a patient safety quality program and consider obtaining signed = declinations from=20 personnel who decline influenza vaccination for reasons other than = medical=20 contraindications (437,453,454). Influenza vaccination rates = among HCP=20 within facilities should be measured regularly and reported, and ward-, = unit-,=20 and specialty-specific coverage rates should be provided to staff and=20 administration (437).

Policies that work best to achieve this coverage goal might vary = among=20 facilities. Studies have demonstrated that organized campaigns can = attain higher=20 rates of vaccination among HCP with moderate effort and by using = strategies that=20 increase vaccine acceptance (435,437,455,45= 6). A=20 mandatory influenza vaccination policy for HCP, exempting only those = with a=20 medical contraindication, has been demonstrated to be a highly effective = approach to achieving high vaccine coverage among HCP (456--458). = Hospitals and health-care systems that have mandated vaccination of HCP = often=20 have achieved coverage rates of >90%, and persons refusing = vaccination who do=20 not have a medical contraindication have been required to wear a = surgical mask=20 during influenza season in some programs (458). Efforts to = increase=20 vaccination coverage among HCP using mandatory vaccination policies are=20 supported by various national accrediting and professional = organizations,=20 including the Infectious Diseases Society of America, and in certain = states by=20 statute (457,459,460). Worker objections, including legal = challenges, are=20 an important consideration for facilities considering mandates = (459,461).=20 Studies to assess the impact of mandatory HCP vaccination on patient = outcomes=20 are needed.

The Joint Commission on Accreditation of Health-Care Organizations = has=20 approved an infection-control standard that requires accredited = organizations to=20 offer influenza vaccinations to staff, including volunteers and licensed = independent practitioners with close patient contact. The standard = became an=20 accreditation requirement beginning January 1, 2007 (462). Some = states=20 have regulations regarding vaccination of HCP in long-term--care = facilities=20 (463), require that health-care facilities offer influenza = vaccination to=20 HCP, or require that HCP either receive influenza vaccination or = indicate a=20 religious, medical, or philosophic reason for not being vaccinated=20 (464,465).

Children aged <6 months are not recommended for vaccination, and=20 antivirals are not licensed for use among infants. Protection of young = infants,=20 who have hospitalization rates similar to those observed among the = elderly,=20 depends on vaccination of the infants' close contacts. A recent study = conducted=20 in Bangladesh demonstrated that infants born to vaccinated women have=20 significant protection from laboratory-confirmed influenza, either = through=20 transfer of influenza-specific maternal antibodies or by reducing the = risk for=20 exposure to influenza that might occur through vaccination of the mother = (217). All household contacts, health-care and day care = providers, and=20 other close contacts of young infants should be vaccinated.

Immunocompromised persons are at risk for influenza complications but = might=20 have inadequate protection after vaccination. Vaccination of close = contacts of=20 immunocompromised persons, including HCP, might reduce the risk for = influenza=20 transmission. In 2006, a joint recommendation from ACIP and the Hospital = Infection Control Practices Advisory Committee (HICPAC) recommended that = TIV be=20 used for vaccinating household members, HCP, and others who have close = contact=20 with severely immunosuppressed persons (e.g., patients with = hematopoietic stem=20 cell transplants) during those periods in which the immunosuppressed = person=20 requires care in a protective environment (typically defined as a = specialized=20 patient-care area with a positive airflow relative to the corridor,=20 high-efficiency particulate air filtration, and frequent air changes) = (437,466). To=20 reduce the theoretic risk for vaccine virus transmission, ACIP/HICPAC=20 recommended that HCP who receive LAIV should avoid providing care for = severely=20 immunosuppressed patients requiring a protected environment for 7 days = after=20 vaccination, and hospital visitors who have received LAIV should avoid = contact=20 with severely immunosuppressed persons in protected environments for 7 = days=20 after vaccination but should not be restricted from visiting less = severely=20 immunosuppressed patients. Healthy nonpregnant persons aged 2--49 years, = including HCP, who have close contact with persons with lesser degrees = of=20 immunosuppression (e.g., persons with chronic immunocompromising = conditions such=20 as HIV infection, corticosteroid or chemotherapeutic medication use, or = who are=20 cared for in other hospital areas such as neonatal intensive care units) = can=20 receive TIV or LAIV.

The rationale for avoiding use of LAIV among HCP or other close = contacts of=20 severely immunocompromised patients is the theoretic risk that a live = attenuated=20 vaccine virus could be transmitted to the severely immunosuppressed = person.=20 However, instances of LAIV transmission from a recently vaccinated = person to an=20 immunocompromised contact in health-care settings have not been = reported. In=20 addition, the temperature-sensitive and attenuated viruses present in = LAIV do=20 not cause illness when administered to immunocompromised persons with = HIV=20 infection (336), children undergoing cancer treatment = (467), or=20 immunocompromised ferrets given dexamethasone and cytarabine = (468).=20 Concerns about the theoretic risk posed by transmission of live = attenuated=20 vaccine viruses contained in LAIV to patients should not be used to = justify=20 preferential use of TIV in health-care settings other than inpatient = units that=20 house severely immunocompromised patients requiring protected = environments. Some=20 health-care facilities might choose to not restrict use of LAIV in close = contacts of severely immunocompromised persons, based on the lack of = evidence=20 for transmission in health-care settings since licensure in 2004.

Pregnant and Postpartum Women

Vaccination of pregnant women protects women and newborns. The = American=20 College of Obstetricians and Gynecologists and the American Academy of = Family=20 Physicians also have previously recommended routine vaccination of all = pregnant=20 women (469). Women=20 who are postpartum are also at risk for influenza complications and = should be=20 vaccinated (108). No preference is indicated for use of TIV that = does not=20 contain thimerosal as a preservative (see Vaccine Preservative = [Thimerosal] in=20 Multidose Vials of TIV) for any group recommended for vaccination, = including=20 pregnant and postpartum women. LAIV is not licensed for use in pregnant = women,=20 but postpartum women can receive LAIV or TIV. Pregnant and postpartum = women do=20 not need to avoid contact with persons recently vaccinated with = LAIV.

Breastfeeding Mothers

Breastfeeding does not affect the immune response adversely and is = not a=20 contraindication for vaccination (246). Unless contraindicated = because of=20 other medical conditions, women who are breastfeeding can receive either = TIV or=20 LAIV. In one randomized controlled trial conducted in Bangladesh, = infants born=20 to women vaccinated during pregnancy had a lower risk for = laboratory-confirmed=20 influenza. However, the contribution to protection from influenza of=20 breastfeeding compared with passive transfer of maternal antibodies = during=20 pregnancy was not determined (217).

Travelers

The risk for exposure to influenza during travel depends on the time = of year=20 and destination. In the temperate regions of the Southern Hemisphere, = influenza=20 activity occurs typically during April--September. In temperate climate = zones of=20 the Northern and Southern Hemispheres, travelers also can be exposed to=20 influenza during the summer, especially when traveling as part of large = tourist=20 groups (e.g., on cruise ships) that include persons from areas of the = world in=20 which influenza viruses are circulating (470,471). In the = tropics,=20 influenza occurs throughout the year. In a study among Swiss travelers = to=20 tropical and subtropical countries, influenza was the most frequently = acquired=20 vaccine-preventable disease (472).

Any traveler who wants to reduce the risk for influenza infection = should=20 consider influenza vaccination, preferably at least 2 weeks before = departure. In=20 particular, persons at high risk for complications of influenza and who = were not=20 vaccinated with influenza vaccine during the preceding fall or winter = should=20 consider receiving influenza vaccine before travel if they plan to = travel:

to the tropics,

with organized tourist groups at any time of year, = or

to the Southern Hemisphere during=20 April--September.

No information is available about the benefits of revaccinating = persons=20 before summer travel who already were vaccinated during the preceding = fall, and=20 revaccination is not recommended. Persons at high risk who receive the = previous=20 season's vaccine before travel should be receive the current vaccine the = following fall or winter. Persons at higher risk for influenza = complications=20 should consult with their health-care practitioner to discuss the risk = for=20 influenza or other travel-related diseases before embarking on travel = during the=20 summer.

Recommended Vaccines for Different Age Groups

Each season, vaccination providers should check the latest = information on FDA=20 approval of the 2010--11 seasonal influenza vaccines and CDC = recommendations for=20 use of these vaccines to determine which vaccines are licensed for use = in any=20 particular age. Immunization providers should consult updated = information on use=20 of influenza vaccines from CDC (available at http://www.cdc.gov/flu) and FDA = (available at=20 http://www.fda.gov/BiologicsBloodVaccines/SafetyAv= ailability/vaccinesafety/default.htm).=20 The following information is based on approvals for the 2009--10 = seasonal=20 influenza vaccines.

When vaccinating children aged 6--35 months with TIV, health-care = providers=20 should use TIV that has been licensed by FDA for this age group (i.e., = TIV=20 manufactured by sanofi pasteur [FluZone] or CSL Biotherapies (Afluria)=20 (286). TIV from Novartis (Fluvirin) is FDA-approved in the United = States=20 for use among persons aged =E2=89=A54 years (287). One TIV = preparation from=20 GlaxoSmithKline (Fluarix) is licensed for use in children aged = =E2=89=A53 years, and=20 another preparation (FluLaval) is labeled for use in persons aged = =E2=89=A518 years=20 (274,275,285). LAIV from MedImmune (FluMist) is recommended for = use by=20 healthy nonpregnant persons aged 2--49 years (Ta= ble=20 2) (360). If a pediatric vaccine dose (0.25mL) is = administered=20 inadvertently to an adult, an additional pediatric dose (0.25 mL) should = be=20 given to provide a full adult dose (0.5mL). If the error is discovered = later=20 (after the patient has left the vaccination setting), an adult dose = should be=20 administered as soon as the patient can return. Vaccination with a = formulation=20 approved for adult use should be counted as a dose if inadvertently = administered=20 to a child.

An inactivated trivalent influenza vaccine (Fluzone High-Dose, sanofi = pasteur.) that contains an increased amount of influenza virus antigen = compared=20 with other inactivated influenza vaccines was licensed in 2009. Fluzone=20 High-Dose is available as single dose prefilled syringe formulation=20 distinguished from Fluzone by a gray syringe plunger rod (224). = As with=20 other 2010--11 influenza vaccines, Fluzone High-Dose will contain the = three=20 recommended virus strains (A/California/7/2009 (H1N1)-like, = A/Perth/16/2009=20 (H3N2)-like, and B/Brisbane/60/2008-like antigens) (136). ACIP = recommends=20 that all persons aged =E2=89=A565 years receive an inactivated 2010--11 = seasonal=20 influenza vaccination but has not expressed a preference for Fluzone = High-Dose=20 or any other inactivated influenza vaccine for use in persons aged = =E2=89=A565 years=20 (473).=20 Whether or not the higher postvaccination immune responses observed = among=20 Fluzone High-Dose vaccine recipients (221--223) will result in = greater=20 protection against influenza illness is not known. High-dose vaccine = should not=20 be administered to persons aged <65 years. Several other new vaccine=20 formulations are being evaluated in immunogenicity and efficacy trials; = when=20 licensed, these new products will increase the influenza vaccine supply = and=20 provide additional vaccine choices for practitioners and their patients. = Providers should review the formulation and packaging before = administering=20 influenza vaccine to ensure the product used is appropriate for the age = of the=20 patient.

Influenza Vaccines and Use of Influenza Antiviral Medications

Administration of TIV to persons receiving influenza antivirals for = treatment=20 or chemoprophylaxis is acceptable. The effect on safety and = effectiveness of=20 LAIV coadministration with influenza antiviral medications has not been = studied.=20 However, because influenza antivirals reduce replication of influenza = viruses,=20 LAIV should not be administered until 48 hours after cessation of = influenza=20 antiviral therapy. If influenza antiviral medications are administered = within 2=20 weeks after receipt of LAIV, the vaccine dose should be repeated 48 or = more=20 hours after the last dose of antiviral medication. Persons receiving = antivirals=20 within the period 2 days before to 14 days after vaccination with LAIV = should be=20 revaccinated at a later date with any approved vaccine formulation=20 (246,331).

Considerations When Using LAIV

LAIV is an option for vaccination of healthy nonpregnant persons aged = 2--49=20 years without contraindications, including HCP and other close contacts = of=20 high-risk persons (excepting severely immunocompromised hospitalized = persons who=20 require care in a protected environment). The precaution regarding use = of LAIV=20 in protected environments is based upon a theoretic concern that the = live=20 attenuated vaccine virus could be transmitted to severely = immunocompromised=20 persons. However, no transmission of LAIV in health-care settings ever = has been=20 reported, and because these viruses are also cold-adapted (and cannot=20 effectively replicate at normal body temperature) the risk for = transmitting a=20 vaccine virus to a severely immunocompromised person and causing severe=20 infection appears to be extremely low. HCP working in environments such = as=20 neonatal intensive care, oncology, or labor and delivery units can = receive LAIV=20 without any restrictions.

No preference is indicated for LAIV or TIV when considering = vaccination of=20 healthy nonpregnant persons aged 2--49 years. Possible advantages of = LAIV=20 include its potential to induce a broad mucosal and systemic immune = response in=20 children, its ease of administration, and the possibly increased = acceptability=20 of an intranasal rather than intramuscular route of administration.

If the vaccine recipient sneezes immediately after administration, = the dose=20 should not be repeated. However, if nasal congestion is present that = might=20 impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of = administration should be considered until resolution of the illness, or = TIV=20 should be administered instead. No data exist about concomitant use of = nasal=20 corticosteroids or other intranasal medications (331).

Although FDA licensure of LAIV excludes children aged 2--4 years with = a=20 history of asthma or recurrent wheezing, the precise risk, if any, of = wheezing=20 caused by LAIV among these children is unknown because experience with = LAIV=20 among these young children is limited. Young children might not have a = history=20 of recurrent wheezing if their exposure to respiratory viruses has been = limited=20 because of their age. Certain children might have a history of wheezing = with=20 respiratory illnesses but have not had asthma diagnosed.

Clinicians and vaccination programs should screen for asthma or = wheezing=20 illness (or history of wheezing illness) when considering use of LAIV = for=20 children aged 2--4 years, and should avoid use of this vaccine in = children with=20 asthma or a wheezing episode within the previous 12 months. Health-care=20 providers should consult the medical record, when available, to identify = children aged 2--4 years with asthma or recurrent wheezing that might = indicate=20 asthma. In addition, to identify children who might be at greater risk = for=20 asthma and possibly at increased risk for wheezing after receiving LAIV, = parents=20 or caregivers of children aged 2--4 years should be asked: "In the past = 12=20 months, has a health-care provider ever told you that your child had = wheezing or=20 asthma?" Children whose parents or caregivers answer "yes" to this = question and=20 children who have asthma or who had a wheezing episode noted in the = medical=20 record during the preceding 12 months should not receive LAIV. TIV is = available=20 for use in children with asthma or wheezing (474). LAIV=20 can be administered to persons with minor acute illnesses (e.g., = diarrhea or=20 mild upper respiratory tract infection with or without fever). However, = if nasal=20 congestion is present that might impede delivery of the vaccine to the=20 nasopharyngeal mucosa, use of TIV, or deferral of administration should = be=20 considered until resolution of the illness, is recommended.LAIV is = approved for=20 use in persons aged 2--49 years. However, the effectiveness or safety of = LAIV is=20 not known or is of potential concern for certain persons, and LAIV is = not=20 recommended for these persons. Do not administer LAIV to the following = groups:=20

persons with a history of hypersensitivity, = including=20 anaphylaxis, to any of the components of LAIV or to eggs;

children aged <2 years, because of an increased = risk for=20 hospitalization and wheezing observed in clinical trials;

children aged 2--4 years whose parents or caregivers = report=20 that a health-care provider has told them during the preceding 12 = months that=20 their child had wheezing or asthma or whose medical record indicates a = wheezing episode has occurred during the preceding 12 months;

persons with asthma;

persons aged =E2=89=A550 years;

adults and children who have chronic pulmonary, = cardiovascular=20 (except isolated hypertension), renal, hepatic, = neurologic/neuromuscular,=20 hematologic, or metabolic disorders;

adults and children who have immunosuppression = (including=20 immunosuppression caused by medications or by HIV);

children or adolescents aged 6 months--18 years = receiving=20 aspirin or other salicylates (because of the association of Reye = syndrome with=20 wild-type influenza virus infection); or

pregnant women.

A moderate or severe illness with or without fever is a precaution = for use of=20 LAIV. Development of GBS within 6 weeks following a previous dose of = influenza=20 vaccine is considered to be a precaution for use of influenza vaccines. = LAIV=20 should not be administered to close contacts of immunosuppressed persons = who=20 require a protected environment.

Personnel Who Can Administer LAIV

Low-level introduction of vaccine viruses into the environment = probably is=20 unavoidable when administering LAIV, but no instances have been reported = of=20 illness or attenuated vaccine virus infections among inadvertently = exposed HCP=20 or immunocompromised patients. The risk for acquiring vaccine viruses = from the=20 environment is unknown but is probably low; in addition, vaccine viruses = are=20 cold-adapted and attenuated, and unlikely to cause symptomatic = influenza.=20 Severely immunosuppressed persons should not administer LAIV. However, = other=20 persons at higher risk for influenza complications can administer LAIV. = These=20 include persons with underlying medical conditions placing them at = higher risk=20 or who are likely to be at risk, including pregnant women, persons with = asthma,=20 and persons aged =E2=89=A550 years.

Concurrent Administration of Influenza Vaccine With Other = Vaccines

Use of LAIV concurrently with measles, mumps, rubella (MMR) alone and = MMR and=20 varicella vaccine among children aged 12--15 months has been studied, = and no=20 interference with the immunogenicity to antigens in any of the vaccines = was=20 observed (331,475). Among adults aged =E2=89=A550 years, the = safety and=20 immunogenicity of zoster vaccine and TIV was similar whether = administered=20 simultaneously or spaced 4 weeks apart (476). In the absence of = specific=20 data indicating interference, following ACIP's general recommendations = for=20 vaccination is prudent (246). Inactivated vaccines do not = interfere with=20 the immune response to other inactivated vaccines or to live vaccines.=20 Inactivated or live vaccines can be administered simultaneously with = LAIV.=20 However, after administration of a live vaccine, at least 4 weeks should = pass=20 before another live vaccine is administered.

Recommendations for Vaccination = Administration and=20 Vaccination Programs

Influenza vaccination levels increased substantially over the past 20 = years,=20 and a record proportion of children received seasonal or pandemic = influenza A=20 (H1N1) vaccines in 2009--10. However, a majority of persons in most = groups=20 recommended for vaccination do not receive an annual vaccine. Strategies = to=20 improve vaccination levels, including using reminder/recall systems and = standing=20 orders programs (408,40= 9,423),=20 should be implemented whenever feasible. Vaccination efforts should = begin as=20 soon as vaccine is available and continue through the influenza season, = which=20 typically extends through April. Vaccination coverage can be increased = by=20 administering vaccine before and during the influenza season to persons = during=20 hospitalizations or routine health-care visits. Vaccinations can be = provided in=20 alternative settings (e.g., schools, pharmacies, grocery stores, = workplaces, or=20 other locations in the community), thereby making special visits to = physicians'=20 offices or clinics unnecessary. Coordinated campaigns such as the = National=20 Influenza Vaccination Week (December 6--12, 2010) provide opportunities = to=20 refocus public attention on the benefits, safety, and availability of = influenza=20 vaccination throughout the influenza season. The 2009 pandemic provided=20 opportunities for innovative programs to administer vaccine in a variety = of=20 settings, and lessons learned from this experience should be applied = when=20 developing routine influenza immunization programs.

Discussing Risk for Adverse Events after Vaccination

Concern about vaccine safety is often cited by persons who refuse=20 vaccination, including health-care workers. When educating patients = about=20 adverse events, clinicians should provide Vaccine Information Statements = (available at http://www.cdc.gov/vaccines= /pubs/vis),=20 and emphasize the risks and benefits of vaccination. Providers should = inform=20 patients or parents that 1) TIV contains noninfectious killed viruses = and cannot=20 cause influenza; 2) LAIV contains weakened influenza viruses that cannot = replicate outside the upper respiratory tract and are unlikely to infect = others;=20 3) many patients will experience no side effects and most known side = effects are=20 mild, transient, and manageable, such as injection-site pain after = receipt of=20 TIV or rhinorrhea after LAIV; and 4) concomitant symptoms or respiratory = disease=20 unrelated to vaccination with either TIV or LAIV can occur after = vaccination.=20

Patients concerned about more severe adverse events might be = reassured by=20 discussing the many safety studies available, the safety monitoring = systems=20 currently in use, and the immunization provider or program's previous = experience=20 with influenza vaccines. Providers concerned about the risk for severe = adverse=20 events or who observe or report a severe adverse event after vaccination = should=20 keep in mind that relatively common events will occur by chance after=20 vaccination. For example, one study used the background rate of = spontaneous=20 abortion to estimate that 397 per 1 million vaccinated pregnant women = would be=20 predicted to have a spontaneous abortion within 1 day of vaccination=20 (477). Even rare events will be observed by chance after = vaccination if=20 large numbers of persons are vaccinated, as occurs with annual influenza = immunization campaigns. For example, if a cohort of 10 million = individuals was=20 vaccinated, approximately 22 cases of GBS and six cases of sudden death = would be=20 expected to occur within 6 weeks of vaccination as coincident background = cases=20 unrelated to vaccination (477).

Information About the Vaccines for Children Program

The Vaccines for Children (VFC) program supplies vaccine to all = states,=20 territories, and the District of Columbia for use by participating = providers.=20 These vaccines are to be provided to eligible children without vaccine = cost to=20 the patient or the provider. Although the provider might charge a = vaccine=20 administration fee, vaccination will not be denied to parents who cannot = pay an=20 administration fee. All routine childhood vaccines recommended by ACIP = are=20 available through this program, including influenza vaccines. The = program saves=20 parents and providers out-of-pocket expenses for vaccine purchases and = provides=20 cost savings to states through CDC's vaccine contracts. The program = results in=20 lower vaccine prices and ensures that all states pay the same contract = prices.=20 Detailed information about the VFC program is available at http://www.= cdc.gov/vaccines/programs/vfc/default.htm.

Influenza Vaccine Supply Considerations

The annual supply of influenza vaccine and the timing of its = distribution=20 cannot be guaranteed in any year. During the 2009--10 influenza season, = 114=20 million doses of seasonal influenza vaccine were distributed in the = United=20 States. However, influenza vaccine distribution delays or vaccine = shortages=20 remain possible. One factor that affects production is the inherent = critical=20 time constraints in manufacturing the vaccine given the annual updating = of the=20 influenza vaccine strains. Multiple manufacturing and regulatory issues = also=20 might affect the production schedule.

If supplies of seasonal influenza vaccine are not adequate, = vaccination=20 should be carried out in accordance with local circumstances of supply = and=20 demand based on the judgment of state and local health officials and = health-care=20 providers. National guidance for tiered use of influenza vaccine during=20 prolonged distribution delays or supply shortfalls will be based = primarily on=20 epidemiologic studies indicating that certain persons are at higher risk = for=20 influenza infection or influenza-related complications, as well as which = vaccine=20 formulations have limited supplies. When epidemiologic studies or other = data=20 that would guide tiered use are unavailable, persons previously = demonstrated to=20 be at higher risk for influenza or influenza-related complications = should be=20 among those targeted by immunization programs for receipt of limited = supplies.=20 Even if vaccine use is not restricted to certain persons known to be at = higher=20 risk for influenza complications, strategies employed by immunization = programs=20 and providers during periods of limited vaccine availability should = emphasize=20 outreach to persons at higher risk for influenza or influenza-related=20 complications (Box), or who are part of populations that have limited = access to=20 medical care. During shortages of TIV, LAIV should be used = preferentially when=20 feasible for all healthy nonpregnant persons aged 2--49 years (including = HCP)=20 who desire or are recommended for vaccination to increase the = availability of=20 inactivated vaccine for persons at high risk.

Timing of Vaccination

Vaccination efforts should be structured to ensure the vaccination of = as many=20 persons as possible over the course of several months, with emphasis on=20 vaccinating before influenza activity in the community begins. Even if = vaccine=20 distribution begins before October, distribution probably will not be = completed=20 until December or January. The following recommendations reflect this = phased=20 distribution of vaccine.

In any given year, the optimal time to vaccinate patients cannot be=20 determined precisely because influenza seasons vary in their timing and=20 duration, and more than one outbreak might occur in a single community = in a=20 single year. In the United States, localized outbreaks that indicate the = start=20 of seasonal influenza activity can occur as early as October. However, = in=20 >80% of influenza seasons since 1976, peak influenza activity (which = often is=20 close to the midpoint of influenza activity for the season) has not = occurred=20 until January or later, and in >60% of seasons, the peak was in = February or=20 later. In general, health-care providers should begin offering = vaccination soon=20 after vaccine becomes available and if possible by October. To avoid = missed=20 opportunities for vaccination, providers should offer vaccination during = routine=20 health-care visits or during hospitalizations whenever vaccine is = available.=20

Vaccination efforts should continue throughout the season, because = the=20 duration of the influenza season varies and influenza might not appear = in=20 certain communities until February or March. Providers should offer = influenza=20 vaccine routinely, and organized vaccination campaigns should continue=20 throughout the influenza season, including after influenza activity has = begun in=20 the community. Vaccine administered in December or later, even if = influenza=20 activity has already begun, is likely to be beneficial in the majority = of=20 influenza seasons. The majority of adults have antibody protection = against=20 influenza virus infection within 2 weeks after vaccination = (478,479).

All children aged 6 months--8 years who are recommended for 2 doses = should=20 receive their first dose as soon after vaccine becomes available as is = feasible=20 and should receive the second dose =E2=89=A54 weeks later. This practice = increases the=20 opportunity for both doses to be administered before or shortly after = the onset=20 of influenza activity.

Planners are encouraged to develop the capacity and flexibility to = schedule=20 at least one vaccination clinic in December. Guidelines for planning = large-scale=20 vaccination clinics, including school-based clinics, are available at = http://www.cdc.gov/flu/professionals/vaccination/vax_clinic.htm,=20 http://www.cdc.gov/h1n1flu/vaccination/statelocal/settingupclinics= .htm,=20 and http://www.cdc.gov/h1= n1flu/vaccination/slv.

During a vaccine shortage or delay, substantial proportions of TIV or = LAIV=20 doses might not be released and distributed until November and December = or=20 later. When the vaccines are substantially delayed or disease activity = has not=20 subsided, providers should consider offering vaccination clinics into = January=20 and beyond as long as vaccine supplies are available.

Strategies for Implementing Vaccination Recommendations

The expansion of the recommendations to all persons aged =E2=89=A56 = months highlights=20 the importance of making influenza vaccine readily accessible in a = variety of=20 settings. Many of the persons at highest risk for complications will = likely=20 continue to be vaccinated in health-care settings. However, vaccination = in=20 health-care settings must increasingly be complemented by vaccination in = nonmedical settings that increase convenience and access. During the = 2009--2010=20 H1N1 Vaccination Program, substantial efforts were made at the state and = local=20 level to direct vaccine to locations such as schools, pharmacies, = workplaces,=20 and health departments.

Health-Care Settings

Health-care settings remain a central component of an overall = influenza=20 vaccination strategy. Studies consistently show that provider = recommendation is=20 the strongest predictor of vaccination (425,480,481). While = nonmedical=20 settings play an important role for those motivated to seek vaccination, = health-care settings are critical for facilitating vaccination of all = those who=20 come into contact with the setting, including those who might not seek = out=20 vaccination.

Successful vaccination programs combine publicity and education for = HCP and=20 other potential vaccine recipients, use of reminder/recall systems, = assessment=20 of practice-level vaccination rates with feedback to staff, and efforts = to=20 remove administrative and financial barriers that prevent persons from = receiving=20 the vaccine, including use of standing orders programs = (409,482,483). The=20 use of standing orders programs by long-term--care facilities (e.g., = nursing=20 homes and skilled nursing facilities), hospitals, and home health = agencies=20 ensures that vaccination is offered. Standing orders programs for = influenza=20 vaccination should be conducted under the supervision of a licensed = practitioner=20 according to a physician-approved facility or agency policy by HCP = trained to=20 screen patients for contraindications to vaccination, administer = vaccine, and=20 monitor and report adverse events. The Centers for Medicare and Medicaid = Services (CMS) has removed the physician signature requirement for the=20 administration of influenza and pneumococcal vaccines to Medicare and = Medicaid=20 patients in hospitals, long-term--care facilities, and home health = agencies=20 (484). To the extent allowed by local and state law, these = facilities and=20 agencies can implement standing orders for influenza and pneumococcal=20 vaccination of Medicare- and Medicaid-eligible patients. Payment for = influenza=20 vaccine under Medicare Part B is available (485,486). Other = settings=20 (e.g., outpatient facilities, managed-care organizations, assisted = living=20 facilities, correctional facilities, pharmacies, and adult workplaces) = are=20 encouraged to introduce standing orders programs (487). In=20 addition, physician reminders (e.g., flagging charts) and patient = reminders are=20 recognized strategies for increasing rates of influenza vaccination=20 (483).

Outpatient Facilities Providing Ongoing Care

Staff in facilities providing ongoing medical care (e.g., physicians' = offices, public health clinics, employee health clinics, hemodialysis = centers,=20 hospital specialty-care clinics, and outpatient rehabilitation programs) = should=20 offer vaccine to all patients during visits throughout the influenza = season. The=20 offer of vaccination and its receipt or refusal should be documented in = the=20 medical record or immunization information system. Patients who do not = have=20 regularly scheduled visits during the fall should be reminded by mail,=20 telephone, or other means of the need for vaccination.

Outpatient Facilities Providing Episodic or Acute Care

Acute health-care facilities (e.g., EDs and walk-in clinics) should = offer=20 vaccinations throughout the influenza season or provide written = information=20 regarding why, where, and how to obtain the vaccine. This written = information=20 should be provided in languages at literacy levels appropriate for the=20 populations served by the facility.

Acute-Care Hospitals

Hospitals should serve as a key setting for identifying persons at = increased=20 risk for influenza complications. Unvaccinated persons without = contraindications=20 who are hospitalized at any time during the period when vaccine is = available=20 should be offered and strongly encouraged to receive influenza vaccine = before=20 they are discharged. Standing orders to offer influenza vaccination to = all=20 hospitalized persons should be considered.

Nursing Homes and Other Long-Term--Care Facilities

Vaccination should be provided routinely to all residents of = long-term--care=20 facilities. If possible, all residents should be vaccinated before = influenza=20 season. In the majority of seasons, TIV will become available to = long-term--care=20 facilities in October or November, and vaccination should commence as = soon as=20 vaccine is available. As soon as possible after admission to the = facility, the=20 benefits and risks of vaccination should be discussed and education = materials=20 provided (488). Informed consent is required, but this does not=20 necessarily mean a signed consent must be present in order to implement = a=20 standing order for vaccination (489). Residents admitted after = completion=20 of the vaccination program at the facility should be vaccinated at the = time of=20 admission.

Lower rates of severe illness among older persons were observed = during the=20 2009 pandemic, but outbreaks among residents of nursing homes and other=20 long-term--care facilities still occurred (490).=20 Although the influenza viruses that will circulate during the 2010--11 = season=20 are unknown, multiple influenza types and subtypes that often infect and = cause=20 severe infections among older adults (e.g., H3N2) circulate each winter=20 influenza season. The 2010--11 influenza vaccine formulation should be=20 administered to all residents and staff.

Since October 2005, CMS has required nursing homes participating in = the=20 Medicare and Medicaid programs to offer all residents influenza and = pneumococcal=20 vaccines and to document the results. According to the requirements, = each=20 resident is to be vaccinated unless contraindicated medically, the = resident or a=20 legal representative refuses vaccination, or the vaccine is not = available=20 because of shortage. This information is to be reported as part of the = CMS=20 Minimum Data Set, which tracks nursing home health parameters=20 (486,491).

Vaccination Provided by Visiting Nurses and Others Providing Home = Care to=20 Persons at High Risk

Vaccine should be administered in the home if necessary as soon as = influenza=20 vaccine is available and throughout the influenza season. Caregivers and = other=20 persons in the household (including children) should be referred for=20 vaccination.

Vaccination for Health-Care Personnel

Health-care facilities should offer influenza vaccinations to all = HCP,=20 including night, weekend, and temporary staff. Particular emphasis = should be=20 placed on providing vaccinations to workers who provide direct care for = persons=20 at high risk for influenza complications. Efforts should be made to = educate HCP=20 regarding the benefits of vaccination and the potential health = consequences of=20 influenza illness for their patients, themselves, and their family = members. All=20 HCP should be provided convenient access to influenza vaccine at the = work site,=20 free of charge, as part of employee health programs (437,455,46= 2).

Other Settings

Influenza vaccination has increasingly become available in nonmedical = settings. In the 2009--2010 vaccination season, 33% of seasonal = influenza=20 vaccinations occurred in health departments, pharmacies or drug stores,=20 workplaces, schools, or other nonmedical locations (CDC, unpublished = data,=20 2009). The proportion of 2009 H1N1 vaccine administered in these = settings was=20 45% (CDC, unpublished data, 2010). Availability of vaccine in a range of = settings such as pharmacies and the workplace is especially important = for=20 persons who do not regularly accesss the health-care system. In = addition, with=20 the recent expansion of the influenza recommendations to include all = persons=20 aged =E2=89=A56 months, implementation of strategies that are = sustainable beyond=20 vaccination in provider offices are necessary. School-located = vaccination=20 provides an opportunity to address the challenges associated with large = numbers=20 of children to vaccinate, a short window of time for vaccination, and = the need=20 for annual revaccination. A number of states and immunization programs = have=20 effectively conducted school-located vaccination both for seasonal = vaccination=20 (492,493) and 2009 H1N1 vaccination (494). School-located=20 vaccination does, however, present challenges from a resource = perspective both=20 for vaccine costs and program costs (493), because reimbursement=20 practices might be different compared with those used in medical = settings. In=20 addition, documentation of vaccination must be provided to the = vaccinated=20 person's primary care provider and where appropriate state or local = vaccine=20 registries.

Nonmedical settings that should be considered to reach the elderly = include=20 assisted living housing, retirement communities, and recreation centers. = Such=20 facilities should offer unvaccinated residents, attendees, and staff = annual=20 on-site vaccination before the start of the influenza season. Continuing = to=20 offer vaccination throughout the fall and winter months is appropriate. = Efforts=20 to vaccinate newly admitted patients or new employees also should be = continued,=20 both to prevent illness and to avoid having these persons serve as a = source of=20 new influenza infections. Staff education should emphasize the benefits = for=20 self, staff and patients of protection from influenza through = vaccination.

Future Directions for Research and = Recommendations=20 Related to Influenza Vaccine

Although available influenza vaccines are effective and safe, = additional=20 research is needed to improve prevention efforts. Most severe morbidity = and=20 mortality during typical influenza seasons occurs among persons aged = =E2=89=A565 years=20 of those who have chronic medical conditions (6,7,24). More = immunogenic=20 influenza vaccines are needed for persons at higher risk for = influenza-related=20 complications. Additional research also is needed to understand = potential biases=20 in estimating the benefits of vaccination among older adults in reducing = hospitalizations and deaths (134,241,495). Additional = studies of=20 the relative cost-effectiveness and cost utility of influenza = vaccination among=20 children and adults, especially those aged <65 years, are needed and = should=20 be designed to account for year-to-year variations in influenza attack = rates,=20 illness severity, hospitalization costs and rates, and vaccine = effectiveness=20 when evaluating the long-term costs and benefits of annual vaccination=20 (496). Additional data on indirect effects of vaccination also = are needed=20 to quantify the benefits of influenza vaccination of HCP in protecting = their=20 patients (379) and the impact of a universal vaccination = recommendation=20 on influenza epidemiology, particularly the impact on persons at higher = risk for=20 influenza complications. In addition, a better understanding is needed = of how to=20 motivate persons, particularly those at risk for influenza-related = complications=20 and their close contacts, to seek or accept annual influenza = vaccination.

The expansion of annual vaccination recommendations to include all = persons=20 aged =E2=89=A56 months will require a substantial increase in resources = for=20 epidemiologic research to develop long-term studies capable of assessing = the=20 possible effects on community-level transmission. In Canada, a universal = vaccination recommendation implemented in Ontario in 2000 has been = compared with=20 typical practice in other Canadian provinces. These studies have been=20 challenging to conduct, but have indicated that a universal = recommendation for=20 annual vaccination is associated with overall reductions in = influenza-related=20 mortality, hospitalizations, ED use, physicians' office visits, and = antibiotic=20 use (388,389,396). However, differences between health-care = systems in=20 Canada and the United States limit the ability to generalize the = findings in=20 Ontario to the United States, and measures of the impact of a universal=20 recommendation in the United States will likely require many years to = evaluate.=20 Additional planning to improve surveillance systems capable of = monitoring=20 effectiveness, safety and vaccine coverage, and further development of=20 implementation strategies will be necessary. Vaccination programs = capable of=20 delivering annual influenza vaccination to a broad range of the = population could=20 potentially serve as a resilient and sustainable platform for delivering = vaccines and monitoring outcomes for other urgently required public = health=20 interventions (e.g., vaccines for future influenza pandemics or medical=20 countermeasures to prevent or treat illnesses caused by acts of = terrorism).

Seasonal Influenza Vaccine and Influenza = Viruses of=20 Animal Origin

Human infection with novel or nonhuman influenza A virus strains, = including=20 influenza A viruses of animal origin, is a nationally notifiable disease = in the=20 United States (497). Human infections with nonhuman or novel = human=20 influenza A virus should be identified quickly and investigated to = determine=20 possible sources of exposure, identify additional cases, and evaluate = the=20 possibility of human-to-human transmission because transmission patterns = could=20 change over time with variations in these influenza A viruses.

Sporadic severe and fatal human cases of infection with highly = pathogenic=20 avian influenza A (H5N1) virus have been identified in Asia, Africa, = Europe, and=20 the Middle East, primarily among persons who have had direct or close=20 unprotected contact with sick or dead birds associated with the ongoing = H5N1=20 panzootic among birds (498--506). Severe lower respiratory = illness with=20 multiorgan failure has been reported in fatal H5N1 cases, and = asymptomatic=20 infection and clinically mild cases also have been reported = (507--510).=20 Limited, nonsustained human-to-human transmission of H5N1 virus has = likely=20 occurred in some case clusters (508,511). To date, there is no = evidence=20 of genetic reassortment between human influenza A and H5N1 viruses. = However,=20 influenza viruses derived from strains circulating among poultry (e.g., = the H5N1=20 virus, which has caused outbreaks of avian influenza and occasionally = have=20 infected humans) have the potential to recombine with human influenza A = viruses=20 (512,513). To date, highly pathogenic H5N1 virus has not been = identified=20 in wild or domestic birds or in humans in the United States. Guidance = for=20 testing suspected cases of H5N1 virus infection among persons in the = United=20 States and follow-up of contacts is available (514,515). Human = H5N1 cases=20 have continued to occur in 2009 and 2010, including in the Middle East = and=20 Southeast Asia (516).

Human illness from infection with different avian influenza A subtype = viruses=20 also has been documented, including infections with low pathogenic and = highly=20 pathogenic viruses. A range of clinical illness has been reported for = human=20 infection with low pathogenic avian influenza viruses, including = conjunctivitis=20 with influenza A (H7N7) virus in the United Kingdom, lower respiratory = tract=20 disease and conjunctivitis with influenza A (H7N2) virus in the United = Kingdom,=20 and uncomplicated ILI with influenza A (H9N2) virus in Hong Kong and = China=20 (517--523). Two human cases of infection with low pathogenic = influenza A=20 (H7N2) have been reported in the United States (520).=20 Although human infections with highly pathogenic A (H7N7) virus = infections=20 typically have ILI or conjunctivitis, severe infections, including one = fatal=20 case in the Netherlands, have been reported following exposure to = poultry=20 (524--526). Conjunctivitis also has been reported because of = human=20 infection with highly pathogenic influenza A (H7N3) virus in Canada and = low=20 pathogenic A (H7N3) in the United Kingdom (517,525). In contrast, = sporadic infections with highly pathogenic avian influenza A (H5N1) = virus have=20 caused severe illness in many countries, with an overall case-fatality=20 proportion of approximately 60% (508,526).

Swine influenza A (H1N1), A (H1N2), and A (H3N2) viruses, including=20 reassortant viruses, are endemic among pig populations in the United = States=20 (527). Two clusters of influenza A (H2N3) virus infections among = pigs=20 have been reported recently (528). Outbreaks among pigs normally = occur in=20 colder weather months (late fall and winter) and sometimes with the = introduction=20 of new pigs into susceptible herds. An estimated 30% of the pig = population in=20 the United States has serologic evidence of having had swine influenza A = (H1N1)=20 virus infection. Sporadic human infections with a variety of swine = influenza A=20 viruses occur in the United States, but the incidence of these human = infections=20 is unknown (529--534). Persons infected with swine influenza A = viruses=20 typically report direct contact with ill pigs or places where pigs have = been=20 present (e.g., agricultural fairs or farms) and have symptoms that are=20 clinically indistinguishable from infection with other respiratory = viruses=20 (531,532,535,53= 6).=20 Swine influenza virus infection has not been associated with household = exposure=20 to pork products or consumption of pork. Clinicians should consider = swine=20 influenza A virus infection in the differential diagnosis of patients = with ILI=20 who have had recent contact with pigs. Sporadic cases among persons = whose=20 infections were linked to swine exposure have not resulted in sustained=20 human-to-human transmission of swine influenza A viruses or community = outbreaks=20 (9,536). The 2009 pandemic influenza A (H1N1) virus contains some = genes=20 previously found in viruses currently circulating among swine, but the = origin of=20 the pandemic has not been definitively linked to swine exposures among = humans.=20 Although immunity to swine influenza A viruses appears to be low = (<2%) in the=20 overall human population, 10%--20% of persons with occupational exposure = to pigs=20 (e.g., pig farmers or pig veterinarians) have been documented in certain = studies=20 to have antibody evidence of prior swine influenza A (H1N1) virus = infection=20 (529,537).

Current seasonal influenza vaccines are not expected to provide = protection=20 against human infection with avian influenza A viruses, including = influenza A=20 (H5N1) viruses, or to provide protection against influenza A viruses = currently=20 circulating exclusively in swine (318,44= 8).=20 However, reducing seasonal influenza risk through influenza vaccination = of=20 persons who might be exposed to nonhuman influenza viruses (e.g., H5N1 = virus)=20 might reduce the theoretic risk for recombination of influenza A viruses = of=20 animal origin and human influenza A viruses by preventing seasonal = influenza A=20 virus infection within a human host.

CDC has recommended that persons who are charged with responding to = avian=20 influenza outbreaks among poultry receive seasonal influenza vaccination = (538,539). As part of preparedness activities, the Occupational = Safety=20 and Health Administration (OSHA) has issued an advisory notice regarding = poultry=20 worker safety that is intended for implementation in the event of a = suspected or=20 confirmed avian influenza outbreak at a poultry facility in the United = States.=20 OSHA guidelines recommend that poultry workers in an involved facility = receive=20 vaccination against seasonal influenza; OSHA also has recommended that = HCP=20 involved in the care of patients with documented or suspected avian = influenza=20 should be vaccinated with the most recent seasonal human influenza = vaccine to=20 reduce the risk for co-infection with human influenza A viruses=20 (539).

Recommendations for Using Antiviral Agents =

Annual vaccination is the primary strategy for preventing = complications of=20 influenza virus infections. Antiviral medications with activity against=20 influenza viruses are useful adjuncts in the prevention of influenza, = and=20 effective when used early in the course of illness for treatment. Four = influenza=20 antiviral agents are licensed in the United States: amantadine, = rimantadine,=20 zanamivir, and oseltamivir. Investigational antiviral medications, such = as=20 peramivir and intravenous formulations of zanamivir, might be available = under=20 investigational new drug protocols (540).

During the 2007--08 influenza season, influenza A (H1N1) viruses with = a=20 mutation that confers resistance to oseltamivir became more common in = the United=20 States and other countries (541--543). As of June 2010, in the = United=20 States, approximately 99% of seasonal influenza A (H1N1) viruses (i.e., = H1N1=20 viruses not associated with the 2009 pandemic) tested have been = resistant to=20 oseltamivir. None of the influenza A (H3N2) or influenza B viruses = tested were=20 resistant to oseltamivir. However, few seasonal influenza viruses = isolated after=20 May 2009 are available for testing. As of June 2010, with few = exceptions, 2009=20 pandemic influenza A (H1N1) virus strains that began circulating in = April 2009=20 remained sensitive to oseltamivir, and all were sensitive to zanamivir=20 (16). Sporadic cases of 2009 pandemic influenza A (H1N1) virus = infection=20 with an H275Y mutation in neuraminidase associated with oseltamivir = resistance=20 have been reported worldwide, but as of June 2010, no sustained = community-wide=20 transmission has been identified (544). Such = oseltamivir-resistant virus=20 infections have been identified in severely immunosuppressed patients, = persons=20 receiving oseltamivir chemoprophylaxis, and in some persons without = oseltamivir=20 exposure, including some influenza illness clusters (544--549). = CDC's=20 recommendations for use of influenza antiviral medications should be = consulted=20 for guidance on antiviral use (15). New guidance on clinical = management=20 of influenza, including use of antivirals, also is available from the = Infectious=20 Diseases Society of America and the World Health Organization = (550--552).=20 ACIP recommendations for antiviral use will be published separately = later in=20 2010.

Sources of Information Regarding Influenza = and its=20 Surveillance

Information regarding influenza surveillance, prevention, detection, = and=20 control is available at http://www.cdc.gov/flu. During = October--May,=20 surveillance information is updated weekly. In addition, periodic = updates=20 regarding influenza are published in MMWR (http://www.cdc.gov/mmwr). = Additional=20 information regarding influenza vaccine can be obtained by calling=20 1-800-CDC-INFO (1-800-232-4636). State and local health departments = should be=20 consulted about availability of influenza vaccine, access to vaccination = programs, information related to state or local influenza activity, = reporting of=20 influenza outbreaks and influenza-related pediatric deaths, and advice=20 concerning outbreak control.

Vaccine Adverse Event Reporting System = (VAERS)

Clinically significant adverse events that follow vaccination should = be=20 reported to the Vaccine Adverse Event Reporting System (VAERS) at http://vaers.hhs.gov/esub/index<= /A>.=20 Reports can be filed securely online, by mail, or by fax. A VAERS form = can be=20 downloaded from the VAERS website or requested by sending an e-mail = message to=20 info@vaers.org, by calling = telephone=20 1-800-822-7967, or by sending a faxed request to 1-877-721-0366. = Additional=20 information on VAERS or vaccine safety is available at http://vaers.hhs.gov/about/inde= x or=20 by calling telephone 1-800-822-7967.

Reporting of Adverse Events that Occur After = Administering Antiviral Medications (MedWatch)

Health-care professionals should report all serious adverse events = (SAEs)=20 after antiviral medication use promptly to MedWatch, FDA's adverse event = reporting program for medications. SAEs are defined as medical events = that=20 involve hospitalization, death, life-threatening illness, disability, or = certain=20 other medically important conditions. SAEs that follow administration of = medications should be reported at http://www.fda.gov/me= dwatch/report/hcp.htm.

National Vaccine Injury Compensation = Program

The National Vaccine Injury Compensation Program (VICP), established = by the=20 National Childhood Vaccine Injury Act of 1986, as amended, provides a = mechanism=20 through which compensation can be paid on behalf of a person determined = to have=20 been injured or to have died as a result of receiving a vaccine covered = by VICP.=20 The Vaccine Injury Table lists the vaccines covered by VICP and the = injuries and=20 conditions (including death) for which compensation might be paid. = If the=20 injury or condition is not on the Table, or does not occur within the = specified=20 time period on the Table, persons must prove that the vaccine caused the = injury=20 or condition.

For a person to be eligible for compensation, the general filing = deadlines=20 for injuries require claims to be filed within 3 years after the first = symptom=20 of the vaccine injury; for a death, claims must be filed within 2 years = of the=20 vaccine-related death and not more than 4 years after the start of the = first=20 symptom of the vaccine-related injury from which the death occurred. = When a new=20 vaccine is covered by VICP or when a new injury/condition is added to = the Table,=20 claims that do not meet the general filing deadlines must be filed = within 2=20 years from the date the vaccine or injury/condition is added to the = Table for=20 injuries or deaths that occurred up to 8 years before the Table change. = Persons=20 of all ages who receive a VICP-covered vaccine might be eligible to file = a=20 claim. Both the intranasal (LAIV) and injectable (TIV) trivalent = influenza=20 vaccines are covered under VICP. Additional information about VICP is = available=20 at http//www.hrsa.gov/vacci= necompensation=20 or by calling 1-800-338-2382.

Additional Information Regarding Influenza = Virus=20 Infection Control Among Specific Populations

Each year, ACIP provides general, annually updated information = regarding=20 control and prevention of influenza. Other reports related to = controlling and=20 preventing influenza among specific populations (e.g., immunocompromised = persons, HCP, hospital patients, pregnant women, children, and = travelers) also=20 are available in the following publications:

CDC. = General=20 recommendations on immunization: recommendations of the Advisory = Committee on=20 Immunization Practices (ACIP) and the American Academy of Family = Physicians=20 (AAFP). MMWR 2006;55(No. RR-15).

CDC. = Influenza=20 vaccination of health-care personnel: recommendations of the = Healthcare=20 Infection Control Practices Advisory Committee (HICPAC) and the = Advisory=20 Committee on Immunization Practices (ACIP). MMWR 2006;55(No. = RR-2).

CDC. = Recommended=20 immunization schedules for persons aged 0 through 18 years---United = States,=20 2010. MMWR 2010;58:Q1--4.

CDC. = Guidelines=20 for preventing health-care--associated pneumonia, 2003: = recommendations of CDC=20 and the Healthcare Infection Control Practices Advisory Committee. = MMWR=20 2004;53(No. RR-3).

CDC. Respiratory hygiene/cough etiquette in = health-care=20 settings. Atlanta, GA: US Department of Health and Human Services, = CDC; 2003.=20 Available at http://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.h= tm.

CDC. Prevention and control of vaccine-preventable = diseases in=20 long-term--care facilities. Atlanta, GA: US Department of Health and = Human=20 Services, CDC; 2006. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/longtermcare= .htm.

CDC. Vaccine safety. Atlanta, GA: US Department of = Health and=20 Human Services, CDC; 2009. Available at http://www.cdc.gov/va= ccinesafety/index.htm.

American College of Obstetricians and Gynecologists. = Influenza=20 vaccination and treatment during pregnancy. ACOG committee opinion no. = 305.=20 Obstet Gynecol 2004;104:1125--6.

American Academy of Pediatrics. 2009 red book: = report of the=20 Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: = American=20 Academy of Pediatrics;2009.

Bodnar UR, Maloney SA, Fielding KL, et al. = Preliminary=20 guidelines for the prevention and control of ILI among passengers and = crew=20 members on cruise ships. Atlanta, GA: US Department of Health and = Human=20 Services, CDC;1999. Available at http://wwwn.cdc.gov/travel/files/pre-guidelines-flu-cruise-ship= s1999.ashx.

CDC. Infection control guidance for the prevention = and control=20 of influenza in acute-care facilities. Atlanta, GA: US Department of = Health=20 and Human Services, CDC;2007. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/hea= lth-carefacilities.htm.

Food and Drug Administration. FDA pandemic influenza = preparedness strategic plan. Washington, DC: Food and Drug = Administration;=20 2007. Available at=20 http://www.fda.gov/oc/op/pandemic/strategicplan03_07.html.

World Health Organization. Recommendations for = influenza=20 vaccines. Geneva, Switzerland: World Health Organization;2007. = Available at http://www.who.int/csr/disease/influenza/vaccinerecommendat= ions/en/index.html.

American Heart Association and American College of = Cardiology.=20 Influenza vaccination as secondary prevention for cardiovascular = disease.=20 Circulation 2006;114:1549--53. Available at http://= circ.ahajournals.org/cgi/content/full/114/14/1549.=20

Acknowledgments

Assistance in the preparation of this report was provided by Carolyn = Bridges,=20 MD, Sandra dos santos Chaves, MD, Larisa Gubareva, MD, PhD, Amanda = Zongrone,=20 Influenza Division; Peng-jun Lu, PhD, Jeanne Santoli, MD, Abigail = Shefer, MD,=20 Immunization Services Division; Penina Haber, PhD, Barbara Slade, MD,=20 Immunization Safety Office, National Center for Preparedness, Detection, = and=20 Control of Infectious Diseases, CDC. Neal Halsey, MD, The Johns Hopkins = School=20 of Public Health, and David Hrncir, MD, Southwest = Allergy=20 & Asthma Center, San Antonio, Texas, contributed to = the=20 hypersensitivity section of this report.

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* A list of the members appears on = page 62 of=20 this report.

=E2=80=A0 = ILI is defined=20 as fever (temperature of =E2=89=A5100=C2=B0F [=E2=89=A537.8=C2=B0C) and a cough and/or a sore throat in = the absence of=20 a known cause other than influenza.

FIGURE 1. Cumulative rate of = hospitalizations=20 during three influenza seasons, by age group --- Emerging Infections = Program,=20 United States, 2007--2010

* 2009 Pandemic Influenza A(H1N1)=20 hospitalization data from September 1, 2009--January 21, 2010.

=E2=80=A0 Per 10,000=20 population.

Alternate Text: The figure shows the cumulative rate of=20 hospitalizations per 10,000 population by age group during three = influenza=20 seasons: 2007-08, 2008-09, and pandemic influenza A(H1N1) for September = 1,=20 2009-January 21, 2010.

FIGURE 2. Percentage of visits = for=20 influenza-like Illness (ILI)* reported by the U.S. Outpatient = Influenza-like=20 Illness Surveillance Network (ILINet),=E2=80=A0 by=20 surveillance week --- United States, October 1, 2006--May 1, = 2010

100=C2=B0F [>37.8=C2=B0C) = and a cough and/or a sore throat in the absence of a known cause other = than influenza. ILINet consists of approximately 2,400 health-care = providers in 50 states reporting approximately 16 million patient visits = each year."=20 src=3D"http://www.cdc.gov/mmwr/preview/mmwrhtml/figures/r59e0729a1f2.gif"= =20 width=3D626 height=3D295>

* ILI is defined as fever = (temperature of=20 =E2=89=A5100=C2=B0F [=E2=89=A537.8=C2=B0C) and a cough and/or a sore = throat in the absence of a known=20 cause other than influenza.

=E2=80=A0 ILINet=20 consists of approximately 2,400 health-care providers in 50 states = reporting=20 approximately 16 million patient visits each year.

=C2=A7 The mean=20 percentage of visits for ILI during noninfluenza weeks for the previous = three=20 seasons plus two standard deviations. A noninfluenza week is a week = during which=20 <10% of specimens tested positive for influenza.

Alternate text: The figure shows the percentage of visits for=20 influenza-like Illness (ILI) reported by the U.S. Outpatient = Influenza-like=20 Illness Surveillance Network (ILINet) for the period October 1, 2006-May = 1,=20 2010. ILI is defined as fever (temperature of >100=C2=B0F = [>37.8=C2=B0C) and a cough=20 and/or a sore throat in the absence of a known cause other than = influenza.=20 ILINet consists of approximately 2,400 health-care providers in 50 = states=20 reporting approximately 16 million patient visits each year.=20

BOX. Summary of influenza = vaccination=20 recommendations, 2010

=E2=80=A2 All persons aged =E2=89=A56 months = should be vaccinated=20 annually.

=E2=80=A2 Protection of persons at higher risk = for=20 influenza-related complications should continue to be a focus of=20 vaccination efforts as providers and programs transition to = routine=20 vaccination of all persons aged =E2=89=A56 months.

=E2=80=A2 When vaccine supply is limited, = vaccination efforts=20 should focus on delivering vaccination to persons who:

-- are aged 6 months--4 years (59 months);

-- are aged =E2=89=A550 years;

-- have chronic pulmonary (including asthma),=20 cardiovascular (except hypertension), renal, hepatic, neurologic,=20 hematologic, or metabolic disorders (including diabetes = mellitus);

-- are immunosuppressed (including = immunosuppression=20 caused by medications or by human immunodeficiency virus);

-- are or will be pregnant during the = influenza=20 season;

-- are aged 6 months--18 years and receiving = long-term=20 aspirin therapy and who therefore might be at risk for = experiencing Reye=20 syndrome after influenza virus infection;

-- are residents of nursing homes and other = chronic-care=20 facilities;

-- are American Indians/Alaska Natives;

-- are morbidly obese (body-mass index = =E2=89=A540);

-- are health-care personnel;

-- are household contacts and caregivers of = children=20 aged <5 years and adults aged =E2=89=A550 years, with = particular emphasis on=20 vaccinating contacts of children aged <6 months; and

-- are household contacts and caregivers of = persons with=20 medical conditions that put them at higher risk for severe = complications=20 from influenza.

TABLE 1. Live, attenuated = influenza=20 vaccine (LAIV) compared with inactivated influenza vaccine (TIV) = for=20 seasonal influenza, U.S. formulations

Factor

LAIV

TIV

Route of administration

Intranasal spray

Intramuscular injection

Type of vaccine

Live virus

Killed virus

No. of included virus strains

3 (2 influenza A, 1 influenza B) =

3 (2 influenza A, 1 influenza = B)

Vaccine virus strains updated

Annually

Annually

Frequency of administration

Annually*

Annually*

Approved age

Persons aged 2--49 yrs=E2=80=A0

Persons aged =E2=89=A56 mos=C2=A7

Interval between 2 doses recommended for = children=20 aged =E2=89=A56 mos--8 yrs who are receiving influenza vaccine for = the first=20 time

=E2=89=A54 wks

=E2=89=A54 wks

Can be given to persons with medical = risk factors=20 for influenza-related complications=E2=80=A0

No

Yes

Can be given to children with asthma or = children=20 aged 2--4 yrs with wheezing in the past yr=C2=B6

No

Yes

Can be administered to family members or = close=20 contacts of immunosuppressed persons not requiring a protected=20 environment

Yes

Yes

Can be administered to family members or = close=20 contacts of immunosuppressed persons requiring a protected = environment=20 (e.g., hematopoietic stem cell transplant recipient)

No

Yes

Can be administered to family members or = close=20 contacts of persons at higher risk including pregnant women, but = not=20 severely immunosuppressed

Yes

Yes

Can be administered simultaneously with = other=20 vaccines

Yes**

Yes=E2=80=A0=E2=80=A0

If not administered simultaneously, can = be=20 administered within 4 weeks of another live vaccine

Prudent to space =E2=89=A54 wks = apart

Yes

If not administered simultaneously, can = be=20 administered within 4 wks of an inactivated vaccine

Yes

Yes

* Children aged =E2=89=A56 = months--8 years who=20 have never received a seasonal influenza vaccine before or who did = not=20 receive at least 1 dose of an influenza A (H1N1) 2009 monovalent = vaccine=20 should receive 2 doses, spaced =E2=89=A54 weeks apart. Those = children aged 6=20 months--8 years who were vaccinated for the first time in the = 2009--10=20 season with the seasonal 2009--10 vaccine but who received only 1 = dose of=20 seasonal influenza vaccine should receive 2 doses in the following = year,=20 spaced =E2=89=A54 wks apart.

=E2=80=A0=20 Persons at higher risk for complications of influenza infection = because of=20 underlying medical conditions should not receive LAIV. Such = persons=20 include those who have chronic pulmonary (including asthma),=20 cardiovascular (except hypertension), renal, hepatic, neurologic,=20 hematologic, or metabolic (including diabetes mellitus) disorders; = those=20 who are immunosuppressed (including immunosuppression caused by=20 medications or by human immunodeficiency virus); those who are or = will be=20 pregnant during the influenza season; those aged 6 months--18 = years and=20 receiving long-term aspirin therapy and who therefore might be at = risk for=20 experiencing Reye syndrome after influenza virus infection; and = residents=20 of nursing homes and other chronic-care facilities.

=C2=A7=20 Approval varies by formulation. Fluzone (sanofi pasteur) = and=20 Afluria (CSL Biotherapies) have been approved previously for use = in=20 children as young as age 6 months. Fluzone High-Dose is approved = for use=20 in persons aged =E2=89=A565 years. Immunization providers should = check Food and=20 Drug Administration--approved prescribing information for 2010--11 = influenza vaccines for the most updated information.

=C2=B6=20 Clinicians and vaccination programs should screen for = possible=20 reactive airways diseases when considering use of LAIV for = children aged=20 2--4 years and should avoid use of this vaccine in children with = asthma or=20 a recent wheezing episode. Health-care providers should consult = the=20 medical record, when available, to identify children aged 2--4 = years with=20 asthma or recurrent wheezing that might indicate asthma. In = addition, to=20 identify children who might be at greater risk for asthma and = possibly at=20 increased risk for wheezing after receiving LAIV, parents or = caregivers of=20 children aged 2--4 years should be asked: "In the past 12 months, = has a=20 health-care provider ever told you that your child had wheezing or = asthma?" Children whose parents or caregivers answer "yes" to this = question and children who have asthma or who had a wheezing = episode noted=20 in the medical record within the preceding 12 months, should not = receive=20 LAIV.

** LAIV coadministration has = been=20 evaluated systematically only among children aged 12--15 months = who=20 received with measles, mumps and rubella vaccine or varicella = vaccine.

=E2=80=A0=E2=80=A0=20 Inactivated influenza vaccine coadministration has been = evaluated=20 systematically only among adults who received pneumococcal = polysaccharide=20 or zoster vaccine.

TABLE 2. Influenza vaccines = for=20 different age groups --- United States, 2010--11 season* =

Vaccine

Trade = name

Manufacturer

Presentation

Mercury content = (mcg Hg/0.5=20 mL dose)

Age = group

No. of = doses

Route

TIV=E2=80=A0

Fluzone

sanofi pasteur

0.25 mL prefilled syringe

0.0

6--35 mos

1 or 2=C2=A7

Intramuscular=C2=B6

0.5 mL prefilled syringe

0.0

=E2=89=A536 mos

1 or 2=C2=A7

Intramuscular

0.5 mL vial

0.0

=E2=89=A536 mos

1 or 2=C2=A7

Intramuscular

5.0 mL multidose vial

25.0

=E2=89=A56 mos

1 or 2=C2=A7

Intramuscular

TIV

Fluvirin

Novartis Vaccine

5.0 mL multidose vial

24.5

=E2=89=A54 yrs

1 or 2=C2=A7

Intramuscular

0.5 mL prefilled syringe

<1.0

TIV

Fluarix

Glaxo SmithKline

0.5 mL prefilled syringe

0.0

=E2=89=A53 yrs

1

Intramuscular

TIV

FluLaval

Glaxo SmithKline

5.0 mL multidose vial

25.0

=E2=89=A518 yrs

1

Intramuscular

TIV

Afluria

CSL Biotherapies

0.5 mL prefilled syringe

0.0

=E2=89=A56 mos

1

Intramuscular

5.0 mL multidose vial

25.0

TIV High Dose**

Fluzone High-Dose

sanofi pasteur

0.5 mL prefilled syringe

0.0

=E2=89=A565 yrs

1

Intramuscular

LAIV=E2=80=A0=E2=80=A0

FluMist=C2=A7=C2=A7

MedImmune

0.2 mL sprayer, divided dose

0.0

2--49 yrs

1 or 2=C2=A7

Intranasal

* Immunization providers = should check=20 Food and Drug Administration--approved prescribing information for = 2010--11 influenza vaccines for the most updated information.

=E2=80=A0=20 Trivalent inactivated vaccine.

=C2=A7=20 Children aged 6 months--8 years who have never received a = seasonal=20 TIV before or who did not receive at least 1 dose of an influenza = A (H1N1)=20 2009 monovalent vaccine should receive 2 doses, spaced =E2=89=A54 = weeks apart.=20 Those children aged 6 months--8 years who were vaccinated for the = first=20 time in the 2009--10 season with the seasonal 2009--10 seasonal = vaccine=20 but who received only 1 dose should receive 2 doses of the = 2010--11=20 influenza vaccine formula, spaced =E2=89=A54 weeks apart.

=C2=B6 For=20 adults and older children, the recommended site of vaccination is = the=20 deltoid muscle. The preferred site for infants and young children = is the=20 anterolateral aspect of the thigh.

** Trivalent inactivated vaccine high = dose. A 0.5-mL=20 dose contains 60 mcg each of A/California/7/2009 (H1N1)-like,=20 A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like = antigens.

=E2=80=A0=E2=80=A0 Live=20 attenuated influenza vaccine.

=C2=A7=C2=A7=20 FluMist is shipped refrigerated and stored in the = refrigerator at=20 36=C2=B0F--46=C2=B0F=20 (2=C2=B0C--8=C2=B0C)=20 after arrival in the vaccination clinic. The dose is 0.2 mL = divided=20 equally between each nostril. Health-care providers should consult = the=20 medical record, when available, to identify children aged 2--4 = years with=20 asthma or recurrent wheezing that might indicate asthma. In = addition, to=20 identify children who might be at greater risk for asthma and = possibly at=20 increased risk for wheezing after receiving LAIV, parents or = caregivers of=20 children aged 2--4 years should be asked: "In the past 12 months, = has a=20 health-care provider ever told you that your child had wheezing or = asthma?" Children whose parents or caregivers answer "yes" to this = question and children who have asthma or who had a wheezing = episode noted=20 in the medical record within the past 12 months should not receive = FluMist.

TABLE 3. Influenza = vaccination*=20 coverage levels for the 2006--07, 2007--08, and 2008--09 influenza = seasons, among population groups --- National Health Interview = Survey=20 (NHIS), United States, 2007--2009, and National Immunization = Survey (NIS),=20 2006--2008.

2006--07 = season

2007--08 = season

2008--09 = season

Crude sample = size=E2=80=A0

Influenza = vaccination=20 level

Crude sample = size

Influenza = vaccination=20 level

Crude sample = size

Influenza = vaccination=20 level

Population = Group

%

(95% CI=C2=A7)

%

(95% = CI)

%

(95% = CI)

Persons with an age = indication

Aged 6--23 mos (NIS=C2=B6)

9,710

31.8

(30.2--33.4)

11964

40.7

(39.1--42.2)

NA**

NA

NA

Aged 2--4 yrs

853

37.9

(34.2--41.7)

674

40.3

(35.8--45.0)

652

41.8)

(36.5--47.4)

Aged 50--64 yrs

3,746

36.0

(34.0--38.0)

3,258

38.4

(36.4--40.4)

3,136

40.1

(37.9--42.3)

Aged =E2=89=A565 yrs

3,086

65.6

(63.3--67.9)

2,658

66.3

(64.2--68.3)

2,455

65.5

(63.2--67.8)

Persons with high-risk = conditions=E2=80=A0=E2=80=A0

Aged 5--17 yrs

387

33.0

(26.2--40.7)

262

36.2

(29.3--43.6)

273

34.7

(27.8--42.3)

Aged 18--49 yrs

1,186

25.5

(22.4--28.9)

1,049

30.4

(27.1--34.0)

1,087

33.0

(29.7--36.4)

Aged 50--64 yrs

1,117

46.1

(42.8--49.4)

1,001

48.4

(44.7--52.2)

1,048

51.3

(47.2--55.3)

Aged 18--64 yrs

2,303

35.3

(33.0--37.7)

2,050

38.8

(36.2--41.4)

2,135

42.0

(39.3--44.6)

Persons without high--risk = conditions

Aged 5--17 yrs

3,307

17.5

(15.9--19.2)

2,925

21.1

(19.3--23.1)

2,906

24.6

(22.4--26.9)

Aged 18--49 yrs

7,905

15.3

(14.2--16.4)

6,467

17.0

(15.7--18.3)

6,083

19.3

(18.1--20.7)

Aged 50--64 yrs

2,619

31.8

(29.5--34.1)

2,248

34.1

(31.7-36.6)

2,083

34.3

(31.8--36.9)

Pregnant women=C2=A7=C2=A7

177

13.4

(8.5--20.5)

113

24.2

(15.1--36.6)

177

11.3

(6.4--19.0)

Health-care workers=C2=B6=C2=B6

850

44.4

(40.2--48.7)

1,037

49.0

(45.1--52.8)

NA

NA

NA

Household contacts of persons at high = risk,=20 including children aged <5 years***

Aged 5--17 yrs

741

26.0

(21.5--31.1)

968

24.8

(21.4--28.6)

997

26.0

(23.6--30.3)

Aged 18--49 yrs

1,349

17.0

(15.0--19.4)

1,753

19.5

(17.1--22.1)

1,775

23.7

(21.4--26.2)

* Answered yes to this = question,=20 "During the past 12 months, have you had a flu shot (flu spray)," = and=20 answered the follow-up question "What was the month and year of = your most=20 recent shot (spray), which were asked during a face-to-face = interview=20 conducted any day during March through August.

=E2=80=A0=20 Population sizes by subgroups are available at http://www.cdc.gov/flu/professionals/vaccin= ation/pdf/influenza_vaccine_target_populations.pdf.

=C2=A7 95%=20 confidence interval.

=C2=B6 NIS=20 uses provider-verified vaccination status to improve the accuracy = of the=20 estimate. The NIS estimate for the 2008--09 season will be = available=20 summer or fall 2010.

** Data not yet available. =

=E2=80=A0=E2=80=A0=20 Adults categorized as being at high risk for = influenza-related=20 complications self-reported one or more of the following: 1) ever = being=20 told by a physician they had diabetes, emphysema, coronary heart = disease,=20 angina, heart attack, or other heart condition; 2) having a = diagnosis of=20 cancer during the preaceding 12 months (excluding nonmelanoma skin = cancer)=20 or ever being told by a physician they have lymphoma, leukemia, or = blood=20 cancer during the previous 12 months (postcoding for a cancer = diagnosis=20 was not yet completed at the time of this publication so this = diagnosis=20 was not included in the 2006--07 season data.); 3) being told by a = physician they have chronic bronchitis or weak or failing kidneys; = or 4)=20 reporting an asthma episode or attack during the preceding 12 = months. For=20 children aged <18 years, high-risk conditions included ever = having been=20 told by a physician of having diabetes, cystic fibrosis, sickle = cell=20 anemia, congenital heart disease, other heart disease, or = neuromuscular=20 conditions (seizures, cerebral palsy, and muscular dystrophy), or = having=20 an asthma episode or attack during the preceding 12 months.

=C2=A7=C2=A7 Aged=20 18--44 years, pregnant at the time of the survey, and without = high-risk=20 conditions.

=C2=B6=C2=B6=20 Adults were classified as health-care workers if they were = currently=20 employed in a health-care occupation or in a health-care--industry = setting, on the basis of standard occupation and industry = categories=20 recoded in groups by CDC's National Center for Health Statistics. =

*** Interviewed sample child = or adult=20 in each household containing at least one of the following: a = child aged=20 <5 years, an adult aged =E2=89=A565 years, or any person aged = 5--17 years at=20 high risk (as defined in previous footnote for adults at high = risk). To=20 obtain information on household composition and high-risk status = of=20 household members, the sampled adult, child, and person files from = NHIS=20 were merged. Interviewed adults who were health-care workers or = who had=20 high-risk conditions were excluded. Information could not be = assessed=20 regarding high-risk status of other adults aged 18--64 years in = the=20 household; therefore, certain adults aged 18--64 years who live = with an=20 adult aged 18--64 years at high risk were not included in the = analysis.=20 Also note that although the recommendation for children aged 2--4 = years=20 was not in place during the 2005--06 season, children aged 2--4 = years were=20 included in these calculations as if the recommendation already = was in=20 place to facilitate comparison of coverage data for subsequent=20 years.

FIGURE 3. Number of 2010--2011 = seasonal=20 influenza vaccine doses recommended for children

* Figure developed by CDC with the = American=20 Academy of Pediatrics, Committee on Infectious Diseases.

=E2=80=A0 Children who=20 had a laboratory-confirmed 2009 pandemic H1N1 virus infection (e.g., = reverse=20 transcription--polymerase chain reaction or virus culture specific for = 2009=20 pandemic influenza A(H1N1) virus) are likely to be immune to this virus. = At=20 provider discretion, these children can have a "Yes" entered at this = box, and=20 proceed down the path to the next box to determine whether two doses are = indicated based on seasonal vaccine history. However, if no test result = is=20 available and no influenza A(H1N1) 2009 monovalent vaccine was = administered,=20 enter "no" here.

=C2=A7 Interval=20 between 2 doses is =E2=89=A54 weeks.

Alternate text: The figure shows an algorithm that health-care = providers can use to determine whether to administer 1 or 2 doses of = seasonal=20 influenza vaccine to children aged 6 months-8 years.

Advisory Committee on Immunization = Practices

Membership List, June 2010

Chair: Carol Baker, MD, Baylor College of Medicine, = Houston,=20 Texas.

Executive Secretary: Larry Pickering, MD, National = Center for=20 Immunization and Respiratory Diseases, CDC, Atlanta, = Georgia.

Members: Lance Chilton, MD, University of New Mexico,=20 Albuquerque, New Mexico; Paul Cieslak, MD, Oregon Public Health = Division,=20 Portland, Oregon; Kristen Ehresmann, MPH, Minnesota Department of = Health, St.=20 Paul, Minnesota; Janet Englund, MD, University of Washington and = Children's=20 Hospital and Regional Medical Center, Seattle, Washington; Franklyn = Judson, MD,=20 University of Colorado Health Sciences Center, Denver, Colorado; Wendy = Keitel,=20 MD, Baylor College of Medicine, Houston, Texas; Susan Lett, MD, = Massachusetts=20 Department of Public Health, Boston, Massachusetts; Michael Marcy, MD, = UCLA=20 Center for Vaccine Research, Torrance, California; Cody Meissner, MD, = Tufts=20 Medical Center, Boston, Massachusetts; Kathleen Neuzil, MD, University = of=20 Washington, Seattle, Washington; Sara Rosenbaum, JD, Georgetown = University,=20 Washington, DC; Mark Sawyer, MD, University of California - San Diego,=20 California; Ciro Valent Sumaya, MD, Texas A&M Health Science Center, = College=20 Station, Texas; Jonathan Temte, MD, University of Wisconsin School of = Medicine=20 and Public Health, Madison, Wisconsin.

Ex Officio Members: James E. Cheek, MD, Indian Health = Service,=20 Albuquerque, New Mexico; Wayne Hachey, DO, Department of Defense, Falls = Church,=20 Virginia; Ted Cieslak, MD, Department of Defense, Atlanta, Georgia; = Geoffrey S.=20 Evans, MD, Health Resources and Services Administration, Rockville, = Maryland;=20 Bruce Gellin, MD, National Vaccine Program Office, District of Columbia; = Linda=20 Murphy, Centers for Medicare and Medicaid Services, Baltimore, Maryland; = George=20 T. Curlin, MD, National Institutes of Health, Bethesda, Maryland; Norman = Baylor,=20 PhD, Food and Drug Administration, Bethesda, Maryland; Linda Kinsinger, = MD,=20 Department of Veterans Affairs, Durham, North Carolina.

Liaison Representatives: American Academy of Family = Physicians,=20 Doug Campos-Outcalt, MD, Phoenix, Arizona; American Academy of = Pediatrics,=20 Joseph Bocchini, MD, Shreveport, Louisiana, David Kimberlin, MD, = Birmingham,=20 Alabama; American College Health Association, James C. Turner, MD,=20 Charlottesville, Virginia; American College of Obstetricians and = Gynecologists,=20 Stanley Gall, MD, Louisville, Kentucky; American College of Physicians, = Gregory=20 Poland, MD, Rochester, Minnesota; American Geriatrics Society, Kenneth = Schmader,=20 MD, Durham, North Carolina; America's Health Insurance Plans, Mark = Netoskie, MD,=20 MBA, Houston, Texas; American Medical Association, Litjen Tan, PhD, = Chicago,=20 Illinois; American Osteopathic Association, Stanley Grogg, DO, Tulsa, = Oklahoma;=20 American Pharmacists Association, Stephan L. Foster, PharmD, Memphis, = Tennessee;=20 Association for Prevention Teaching and Research, W. Paul McKinney, MD,=20 Louisville, Kentucky; Biotechnology Industry Organization, Clement = Lewin, PhD,=20 Cambridge, Massachusetts; Canadian National Advisory Committee on = Immunization,=20 Joanne Langley, MD, Halifax, Nova Scotia, Canada; Council of State and=20 Territorial Epidemiologists, Christine Hahn, MD, Boise, Idaho; = Department of=20 Health, United Kingdom David M. Salisbury, MD, London, United Kingdom;=20 Healthcare Infection Control Practices Advisory Committee, Alexis = Elward, MD, St=20 Louis, Missouri; Infectious Diseases Society of America, Samuel L. Katz, = MD,=20 Durham, North Carolina; National Association of County and City Health=20 Officials, Jeff Duchin, MD, Seattle, Washington; National Association of = Pediatric Nurse Practitioners, Patricia Stinchfield, MPH, St Paul, = Minnesota;=20 National Foundation for Infectious Diseases, William Schaffner, MD, = Nashville,=20 Tennessee; National Immunization Council and Child Health Program, = Mexico, Vesta=20 Richardson, MD, Mexico City, Mexico; National Medical Association, = Patricia=20 Whitley-Williams, MD, New Brunswick, New Jersey; National Vaccine = Advisory=20 Committee, Guthrie Birkhead, MD, Albany, New York; Pharmaceutical = Research and=20 Manufacturers of America, Damian A. Braga, Swiftwater, Pennsylvania, = Peter=20 Paradiso, PhD, Collegeville, Pennsylvania; Society for Adolescent = Medicine, Amy=20 Middleman, MD, Houston, Texas; Society for Healthcare Epidemiology of = America,=20 Harry Keyserling, MD, Atlanta, Georgia.

ACIP Influenza Work Group

Chair: Kathleen Neuzil, MD, Seattle, = Washington.

Members: Terry Adirim, MD, District of Columbia; = William=20 Atkinson, MD, Atlanta, Georgia; Carol Baker, MD, Houston, Texas; Beth = Bell, MD,=20 Atlanta, Georgia, Nancy Bennett, MD, Rochester, New York; Henry = Bernstein, DO,=20 Lebanon, New Hampshire; Joseph Bresee, MD, Atlanta, Georgia; Carolyn = Bridges,=20 MD, Atlanta, Georgia; Karen Broder, MD, Atlanta, Georgia; Doug = Campos-Outcalt,=20 MD, Phoenix, Arizona; Fred Cassels, MD, Rockville, Maryland; Lance = Chilton, MD,=20 Albuquerque, New Mexico; David Cho, MD, District of Columbia; Nancy Cox, = PhD,=20 Atlanta, Georgia; Therese Cvetkovich, MD, Rockville, Maryland; Sandra = Dos Santos=20 Chaves, MD, Atlanta, Georgia; Jeff Duchin, MD, Seattle, Washington; = Janet=20 Englund, MD, Seattle, Washington; Anthony Fiore, MD, Atlanta, Georgia; = Sandra=20 Fryhofer, MD, Atlanta, Georgia; Stanley Gall, MD, Louisville, Kentucky; = Paul=20 Gargiullo, PhD, Atlanta, Georgia; Steven Gordon, MD, Cleveland, Ohio; = Wayne=20 Hachey, DO, Falls Church, Virginia; John Iskander, MD, Atlanta GA; Wendy = Keitel,=20 MD, Houston, Texas; Elyse Olshen Kharbanda, MD, New York, NY; David = Lakey, MD,=20 Austin, Texas; Susan Lett, MD, Boston, Massachusetts; Tamara Lewis, MD, = Salt=20 Lake City, Utah; Cynthia Nolletti, MD, Rockville, Maryland; Gregory = Poland, MD,=20 Rochester, Minnesota; William Schaffner, MD, Nashville, Tennessee; = Robert=20 Schechter, MD, Sacramento, California; Kenneth Schmader, MD, Durham, NC; = David=20 Shay, MD, Atlanta, Georgia; Nadine Sicard, MD, Ottawa, Canada; Danuta=20 Skowronski, MD, Vancouver, British Columbia, Canada; Patricia = Stinchfield, St.=20 Paul, Minnesota; Ray Strikas, MD, District of Columbia; Litjen Tan, PhD, = Chicago, Illinois; Mary Vernon-Smiley, MD Atlanta, Georgia; Timothy = Uyeki, MD,=20 Atlanta, Georgia; Amanda Zongrone, Atlanta, = Georgia.

Use of trade names and commercial sources is for = identification=20 only and does not imply endorsement by the U.S. Department of = Health and=20 Human Services.

References to non-CDC sites on the = Internet are=20 provided as a service to MMWR readers and do not constitute = or=20 imply endorsement of these organizations or their programs by CDC = or the=20 U.S. Department of Health and Human Services. CDC is not = responsible for=20 the content of pages found at these sites. URL addresses listed in = MMWR were current as of the date of=20 publication.

All MMWR HTML versions of articles are electronic = conversions=20 from typeset documents. This conversion might result in character = translation or=20 format errors in the HTML version. Users are referred to the electronic = PDF=20 version (http://www.cdc.gov/mmwr) and/or the original MMWR paper = copy for=20 printable versions of official text, figures, and tables. An original = paper copy=20 of this issue can be obtained from the Superintendent of Documents, U.S. = Government Printing Office (GPO), Washington, DC 20402-9371; telephone: = (202)=20 512-1800. Contact GPO for current prices.

**Questions or = messages=20 regarding errors in formatting should be addressed to mmwrq@cdc.gov.

TABLE 1. Live, attenuated = influenza=20 vaccine (LAIV) compared with inactivated influenza vaccine (TIV) = for=20 seasonal influenza, U.S. formulations
Factor	LAIV	TIV
Route of administration	Intranasal spray	Intramuscular injection
Type of vaccine	Live virus	Killed virus
No. of included virus strains	3 (2 influenza A, 1 influenza B) =	3 (2 influenza A, 1 influenza = B)
Vaccine virus strains updated	Annually	Annually
Frequency of administration	Annually*	Annually*
Approved age	Persons aged 2--49 yrs=E2=80=A0	Persons aged =E2=89=A56 mos=C2=A7
Interval between 2 doses recommended for = children=20 aged =E2=89=A56 mos--8 yrs who are receiving influenza vaccine for = the first=20 time	=E2=89=A54 wks	=E2=89=A54 wks
Can be given to persons with medical = risk factors=20 for influenza-related complications=E2=80=A0	No	Yes
Can be given to children with asthma or = children=20 aged 2--4 yrs with wheezing in the past yr=C2=B6	No	Yes
Can be administered to family members or = close=20 contacts of immunosuppressed persons not requiring a protected=20 environment	Yes	Yes
Can be administered to family members or = close=20 contacts of immunosuppressed persons requiring a protected = environment=20 (e.g., hematopoietic stem cell transplant recipient)	No	Yes
Can be administered to family members or = close=20 contacts of persons at higher risk including pregnant women, but = not=20 severely immunosuppressed	Yes	Yes
Can be administered simultaneously with = other=20 vaccines	Yes**	Yes=E2=80=A0=E2=80=A0
If not administered simultaneously, can = be=20 administered within 4 weeks of another live vaccine	Prudent to space =E2=89=A54 wks = apart	Yes
If not administered simultaneously, can = be=20 administered within 4 wks of an inactivated vaccine	Yes	Yes
* Children aged =E2=89=A56 = months--8 years who=20 have never received a seasonal influenza vaccine before or who did = not=20 receive at least 1 dose of an influenza A (H1N1) 2009 monovalent = vaccine=20 should receive 2 doses, spaced =E2=89=A54 weeks apart. Those = children aged 6=20 months--8 years who were vaccinated for the first time in the = 2009--10=20 season with the seasonal 2009--10 vaccine but who received only 1 = dose of=20 seasonal influenza vaccine should receive 2 doses in the following = year,=20 spaced =E2=89=A54 wks apart. =E2=80=A0=20 Persons at higher risk for complications of influenza infection = because of=20 underlying medical conditions should not receive LAIV. Such = persons=20 include those who have chronic pulmonary (including asthma),=20 cardiovascular (except hypertension), renal, hepatic, neurologic,=20 hematologic, or metabolic (including diabetes mellitus) disorders; = those=20 who are immunosuppressed (including immunosuppression caused by=20 medications or by human immunodeficiency virus); those who are or = will be=20 pregnant during the influenza season; those aged 6 months--18 = years and=20 receiving long-term aspirin therapy and who therefore might be at = risk for=20 experiencing Reye syndrome after influenza virus infection; and = residents=20 of nursing homes and other chronic-care facilities. =C2=A7=20 Approval varies by formulation. Fluzone (sanofi pasteur) = and=20 Afluria (CSL Biotherapies) have been approved previously for use = in=20 children as young as age 6 months. Fluzone High-Dose is approved = for use=20 in persons aged =E2=89=A565 years. Immunization providers should = check Food and=20 Drug Administration--approved prescribing information for 2010--11 = influenza vaccines for the most updated information. =C2=B6=20 Clinicians and vaccination programs should screen for = possible=20 reactive airways diseases when considering use of LAIV for = children aged=20 2--4 years and should avoid use of this vaccine in children with = asthma or=20 a recent wheezing episode. Health-care providers should consult = the=20 medical record, when available, to identify children aged 2--4 = years with=20 asthma or recurrent wheezing that might indicate asthma. In = addition, to=20 identify children who might be at greater risk for asthma and = possibly at=20 increased risk for wheezing after receiving LAIV, parents or = caregivers of=20 children aged 2--4 years should be asked: "In the past 12 months, = has a=20 health-care provider ever told you that your child had wheezing or = asthma?" Children whose parents or caregivers answer "yes" to this = question and children who have asthma or who had a wheezing = episode noted=20 in the medical record within the preceding 12 months, should not = receive=20 LAIV. ** LAIV coadministration has = been=20 evaluated systematically only among children aged 12--15 months = who=20 received with measles, mumps and rubella vaccine or varicella = vaccine. =E2=80=A0=E2=80=A0=20 Inactivated influenza vaccine coadministration has been = evaluated=20 systematically only among adults who received pneumococcal = polysaccharide=20 or zoster vaccine.

*TABLE 2. Influenza vaccines = for=20 different age groups --- United States, 2010--11 season =**
Vaccine	Trade = name	Manufacturer	Presentation	Mercury content = (mcg Hg/0.5=20 mL dose)	Age = group	No. of = doses	Route
TIV=E2=80=A0	Fluzone	sanofi pasteur	0.25 mL prefilled syringe	0.0	6--35 mos	1 or 2=C2=A7	Intramuscular=C2=B6
0.5 mL prefilled syringe	0.0	=E2=89=A536 mos	1 or 2=C2=A7	Intramuscular
0.5 mL vial	0.0	=E2=89=A536 mos	1 or 2=C2=A7	Intramuscular
5.0 mL multidose vial	25.0	=E2=89=A56 mos	1 or 2=C2=A7	Intramuscular
TIV	Fluvirin	Novartis Vaccine	5.0 mL multidose vial	24.5	=E2=89=A54 yrs	1 or 2=C2=A7	Intramuscular
0.5 mL prefilled syringe	<1.0
TIV	Fluarix	Glaxo SmithKline	0.5 mL prefilled syringe	0.0	=E2=89=A53 yrs	1	Intramuscular
TIV	FluLaval	Glaxo SmithKline	5.0 mL multidose vial	25.0	=E2=89=A518 yrs	1	Intramuscular
TIV	Afluria	CSL Biotherapies	0.5 mL prefilled syringe	0.0	=E2=89=A56 mos	1	Intramuscular
5.0 mL multidose vial	25.0
TIV High Dose**	Fluzone High-Dose	sanofi pasteur	0.5 mL prefilled syringe	0.0	=E2=89=A565 yrs	1	Intramuscular
LAIV=E2=80=A0=E2=80=A0	FluMist=C2=A7=C2=A7	MedImmune	0.2 mL sprayer, divided dose	0.0	2--49 yrs	1 or 2=C2=A7	Intranasal
* Immunization providers = should check=20 Food and Drug Administration--approved prescribing information for = 2010--11 influenza vaccines for the most updated information. =E2=80=A0=20 Trivalent inactivated vaccine. =C2=A7=20 Children aged 6 months--8 years who have never received a = seasonal=20 TIV before or who did not receive at least 1 dose of an influenza = A (H1N1)=20 2009 monovalent vaccine should receive 2 doses, spaced =E2=89=A54 = weeks apart.=20 Those children aged 6 months--8 years who were vaccinated for the = first=20 time in the 2009--10 season with the seasonal 2009--10 seasonal = vaccine=20 but who received only 1 dose should receive 2 doses of the = 2010--11=20 influenza vaccine formula, spaced =E2=89=A54 weeks apart. =C2=B6 For=20 adults and older children, the recommended site of vaccination is = the=20 deltoid muscle. The preferred site for infants and young children = is the=20 anterolateral aspect of the thigh. ** Trivalent inactivated vaccine high = dose. A 0.5-mL=20 dose contains 60 mcg each of A/California/7/2009 (H1N1)-like,=20 A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like = antigens. =E2=80=A0=E2=80=A0 Live=20 attenuated influenza vaccine. =C2=A7=C2=A7=20 FluMist is shipped refrigerated and stored in the = refrigerator at=20 36=C2=B0F--46=C2=B0F=20 (2=C2=B0C--8=C2=B0C)=20 after arrival in the vaccination clinic. The dose is 0.2 mL = divided=20 equally between each nostril. Health-care providers should consult = the=20 medical record, when available, to identify children aged 2--4 = years with=20 asthma or recurrent wheezing that might indicate asthma. In = addition, to=20 identify children who might be at greater risk for asthma and = possibly at=20 increased risk for wheezing after receiving LAIV, parents or = caregivers of=20 children aged 2--4 years should be asked: "In the past 12 months, = has a=20 health-care provider ever told you that your child had wheezing or = asthma?" Children whose parents or caregivers answer "yes" to this = question and children who have asthma or who had a wheezing = episode noted=20 in the medical record within the past 12 months should not receive = FluMist.

TABLE 3. Influenza = vaccination*=20 coverage levels for the 2006--07, 2007--08, and 2008--09 influenza = seasons, among population groups --- National Health Interview = Survey=20 (NHIS), United States, 2007--2009, and National Immunization = Survey (NIS),=20 2006--2008.
	2006--07 = season	2007--08 = season	2008--09 = season
	Crude sample = size=E2=80=A0	Influenza = vaccination=20 level	Crude sample = size	Influenza = vaccination=20 level	Crude sample = size	Influenza = vaccination=20 level
Population = Group	%	(95% CI=C2=A7)	%	(95% = CI)	%	(95% = CI)
Persons with an age = indication
Aged 6--23 mos (NIS=C2=B6)	9,710	31.8	(30.2--33.4)	11964	40.7	(39.1--42.2)	NA**	NA	NA
Aged 2--4 yrs	853	37.9	(34.2--41.7)	674	40.3	(35.8--45.0)	652	41.8)	(36.5--47.4)
Aged 50--64 yrs	3,746	36.0	(34.0--38.0)	3,258	38.4	(36.4--40.4)	3,136	40.1	(37.9--42.3)
Aged =E2=89=A565 yrs	3,086	65.6	(63.3--67.9)	2,658	66.3	(64.2--68.3)	2,455	65.5	(63.2--67.8)
Persons with high-risk = conditions=E2=80=A0=E2=80=A0
Aged 5--17 yrs	387	33.0	(26.2--40.7)	262	36.2	(29.3--43.6)	273	34.7	(27.8--42.3)
Aged 18--49 yrs	1,186	25.5	(22.4--28.9)	1,049	30.4	(27.1--34.0)	1,087	33.0	(29.7--36.4)
Aged 50--64 yrs	1,117	46.1	(42.8--49.4)	1,001	48.4	(44.7--52.2)	1,048	51.3	(47.2--55.3)
Aged 18--64 yrs	2,303	35.3	(33.0--37.7)	2,050	38.8	(36.2--41.4)	2,135	42.0	(39.3--44.6)
Persons without high--risk = conditions
Aged 5--17 yrs	3,307	17.5	(15.9--19.2)	2,925	21.1	(19.3--23.1)	2,906	24.6	(22.4--26.9)
Aged 18--49 yrs	7,905	15.3	(14.2--16.4)	6,467	17.0	(15.7--18.3)	6,083	19.3	(18.1--20.7)
Aged 50--64 yrs	2,619	31.8	(29.5--34.1)	2,248	34.1	(31.7-36.6)	2,083	34.3	(31.8--36.9)
Pregnant women=C2=A7=C2=A7	177	13.4	(8.5--20.5)	113	24.2	(15.1--36.6)	177	11.3	(6.4--19.0)
Health-care workers=C2=B6=C2=B6	850	44.4	(40.2--48.7)	1,037	49.0	(45.1--52.8)	NA	NA	NA
Household contacts of persons at high = risk,=20 including children aged <5 years***
Aged 5--17 yrs	741	26.0	(21.5--31.1)	968	24.8	(21.4--28.6)	997	26.0	(23.6--30.3)
Aged 18--49 yrs	1,349	17.0	(15.0--19.4)	1,753	19.5	(17.1--22.1)	1,775	23.7	(21.4--26.2)
* Answered yes to this = question,=20 "During the past 12 months, have you had a flu shot (flu spray)," = and=20 answered the follow-up question "What was the month and year of = your most=20 recent shot (spray), which were asked during a face-to-face = interview=20 conducted any day during March through August. =E2=80=A0=20 Population sizes by subgroups are available at http://www.cdc.gov/flu/professionals/vaccin= ation/pdf/influenza_vaccine_target_populations.pdf. =C2=A7 95%=20 confidence interval. =C2=B6 NIS=20 uses provider-verified vaccination status to improve the accuracy = of the=20 estimate. The NIS estimate for the 2008--09 season will be = available=20 summer or fall 2010. Data not yet available. = =E2=80=A0=E2=80=A0=20 Adults categorized as being at high risk for = influenza-related=20 complications self-reported one or more of the following: 1) ever = being=20 told by a physician they had diabetes, emphysema, coronary heart = disease,=20 angina, heart attack, or other heart condition; 2) having a = diagnosis of=20 cancer during the preaceding 12 months (excluding nonmelanoma skin = cancer)=20 or ever being told by a physician they have lymphoma, leukemia, or = blood=20 cancer during the previous 12 months (postcoding for a cancer = diagnosis=20 was not yet completed at the time of this publication so this = diagnosis=20 was not included in the 2006--07 season data.); 3) being told by a = physician they have chronic bronchitis or weak or failing kidneys; = or 4)=20 reporting an asthma episode or attack during the preceding 12 = months. For=20 children aged <18 years, high-risk conditions included ever = having been=20 told by a physician of having diabetes, cystic fibrosis, sickle = cell=20 anemia, congenital heart disease, other heart disease, or = neuromuscular=20 conditions (seizures, cerebral palsy, and muscular dystrophy), or = having=20 an asthma episode or attack during the preceding 12 months. =C2=A7=C2=A7 Aged=20 18--44 years, pregnant at the time of the survey, and without = high-risk=20 conditions. =C2=B6=C2=B6=20 Adults were classified as health-care workers if they were = currently=20 employed in a health-care occupation or in a health-care--industry = setting, on the basis of standard occupation and industry = categories=20 recoded in groups by CDC's National Center for Health Statistics. = * Interviewed sample child = or adult=20 in each household containing at least one of the following: a = child aged=20 <5 years, an adult aged =E2=89=A565 years, or any person aged = 5--17 years at=20 high risk (as defined in previous footnote for adults at high = risk). To=20 obtain information on household composition and high-risk status = of=20 household members, the sampled adult, child, and person files from = NHIS=20 were merged. Interviewed adults who were health-care workers or = who had=20 high-risk conditions were excluded. Information could not be = assessed=20 regarding high-risk status of other adults aged 18--64 years in = the=20 household; therefore, certain adults aged 18--64 years who live = with an=20 adult aged 18--64 years at high risk were not included in the = analysis.=20 Also note that although the recommendation for children aged 2--4 = years=20 was not in place during the 2005--06 season, children aged 2--4 = years were=20 included in these calculations as if the recommendation already = was in=20 place to facilitate comparison of coverage data for subsequent=20 years.

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