Influenza Vaccine Immunogenicity and Effectiveness
Estimates of vaccine efficacy (i.e., prevention of illness among vaccinated persons enrolled in controlled clinical trials) and vaccine effectiveness (i.e., prevention of illness in vaccinated populations) of influenza vaccines depend on many factors, including the age and immunocompetence of the vaccine recipient, the degree of similarity between the viruses in the vaccine and those in circulation, study design, diagnostic testing measures, and the outcome being measured. Studies of influenza vaccine efficacy and effectiveness have used a variety of outcome measures, including the prevention of ILI, medically attended acute respiratory illness (MAARI), LCI, P&I-associated hospitalizations or deaths, and prevention of seroconversion to circulating influenza virus strains. Efficacy or effectiveness for more specific outcomes such as LCI typically are higher than for less specific outcomes such as MAARI because the causes of MAARI include infections with other pathogens that influenza vaccination would not be expected to prevent (95).
Observational studies, particularly those that compare less-specific outcomes among vaccinated populations to those among unvaccinated populations, are more subject to biases than studies using laboratory-confirmed outcomes. For example, an observational study that finds that influenza vaccination reduces overall mortality among elderly persons might be biased if healthier persons in the study are more likely to be vaccinated and thus less likely to die for any reason (96,97). Observational studies that use a case-positive, control test-negative study design (in which all participants present with illness, and case/control status is assigned on the basis of influenza testing) might be less subject to frailty bias (98).
For studies assessing laboratory-confirmed outcomes, estimates of vaccine efficacy and effectiveness also might be affected by the specificity of the diagnostic tests used. A 2012 simulation study found that for each percentage point decrease in diagnostic test specificity for influenza virus infection, vaccine effectiveness would be underestimated by approximately 4% (99). Randomized controlled trials that measure LCI virus infections (by viral culture or reverse transcription polymerase chain reaction [RT-PCR]) as the outcome are the most persuasive evidence of vaccine efficacy, but such data are not available for all populations.
A study of data from the National Inpatient Sample (a large database of hospital discharge data comprising approximately 8 million records annually from approximately 1,000 hospitals, representing 46 states as of 2011) noted a decrease in the number of hospitalizations associated with P&I of 295,000 (95% CI = 139,000–451,000) and a decrease of 13,600 P&I-associated inpatient deaths (95% CI = 2,700–24,400) for October 2008 through December 2011, compared with what would have been expected on the basis of previous rates (100). This time period correlates with that of expansion of the target groups for annual influenza vaccination to include all persons aged ≥6 months. However, it is not possible to definitively attribute these decreases directly to increased vaccination.
Immune Response Following Vaccination
Humoral and cell-mediated responses to influenza vaccination among children and adults have been studied. Serum antibodies (10,101) are considered to be correlates of vaccine-induced protection for inactivated influenza vaccines (IIVs). Increased levels of antibody induced by vaccination decrease the risk for illness caused by strains that are antigenically similar to those strains of the same type or subtype included in the vaccine (11,102–104). Most healthy children and adults have high titers of strain-specific antibody after IIV vaccination (103,105). However, although immune correlates such as achievement of certain antibody titers after vaccination correlate well with immunity on a population level, reaching a certain antibody threshold (typically defined as a hemagglutination inhibition antibody or HAI titer of 32 or 40) might not predict protection from infection on the individual level.
Compared with IIV, LAIV induces lower levels of serum antibodies but induces cellular immune responses more effectively. The magnitude of this effect differs among adults and children. One study of children aged 6 months–9 years and adults aged 22–49 years noted a significant increase in influenza A-specific interferon γ-producing CD4+ and CD8+ T-cells among children following receipt of LAIV but not following receipt of IIV. No significant increase in these parameters was noted among adults following receipt of either vaccine (106).
Immune responses elicited by influenza vaccines are generally strain-specific. Antibody against one influenza virus type or subtype generally confers limited or no protection against another type or subtype, nor does it typically confer protection against antigenic variants of the same virus that arise by antigenic drift. However, among adults, vaccination can cause a “back boost” of antibody titers against influenza A(H3N2) viruses that have been encountered previously either by vaccination or natural infection (107).
Studies using a serological definition of influenza virus infection have raised concerns that dependence on a serological diagnosis of influenza in clinical trials might lead to overestimation of vaccine efficacy because of an “antibody ceiling” effect in adult participants with historic exposures to both natural infections and vaccination (108). This could result in the decreased likelihood that antibody increases can be observed in vaccinated participants after influenza infection with circulating viruses, as compared with adult participants in control arms of trials. Thus, vaccinated participants might be less likely to show a fourfold increase in antibody levels after influenza infection with circulating viruses compared with unvaccinated participants in such studies. Whether there is a substantial antibody ceiling effect in children, particularly younger children without extensive experience with influenza antigens, is not known.
Influenza Vaccine Effectiveness and Match Between Vaccine and Circulating Viruses
The viral composition of influenza vaccines must be determined months in advance of the start of each season, to allow enough time for manufacture and distribution of vaccine. Selection of viruses is based on consideration of global influenza surveillance data, from which decisions are made regarding the viruses most likely to circulate during the upcoming season. During some seasons, because of antigenic drift among influenza A viruses or change in predominant lineage among B viruses, circulating viruses might differ from those included in the vaccine. Seasonal influenza vaccine effectiveness can be influenced by mismatches to circulating influenza viruses. Good match between vaccine and circulating viruses was associated with increased protection against MAARI-related ED visits and hospitalizations among older persons (109), ILI in younger working adults (49), and LCI (110) in observational studies. Results from other investigations suggest that influenza vaccine can still provide some protection against influenza and outcomes such as influenza-associated hospitalizations, even in seasons when match is suboptimal (111,112). In addition to antigenic drift of circulating influenza viruses, vaccine viruses might undergo adaptive mutations during propagation in eggs that also can contribute to an antigenic differences between vaccine virus and circulating viruses, which in some cases, has been suggested to contribute to reducing vaccine effectiveness (113).
Duration of Immunity
The composition of influenza vaccines is changed in most seasons, with one or more vaccine strains replaced annually to provide protection against viruses that are anticipated to circulate. Evidence from some clinical trials indicates that protection against viruses that are antigenically similar to those contained in the vaccine extends at least for 6–8 months, particularly in nonelderly populations. In some situations, duration of immunity might be longer, and such effects can be detected if circulating influenza virus strains remain antigenically similar for multiple seasons. For example, three years after vaccination with the A/Hong Kong/68 vaccine (i.e., the 1968 pandemic vaccine), effectiveness was 67% for prevention of influenza caused by the A/Hong Kong/68 virus (114). Serum HAI influenza antibodies elicited by vaccination remained detectable in children vaccinated with LAIV for >1 year after vaccination (115). In one community-based nonrandomized open-label trial, continued protection from MAARI during the 2000–01 influenza season was demonstrated in children who received only a single dose of LAIV3 during the previous season (116). A review of four trials (three randomized blinded and one open-label) of LAIV3 conducted among young children aged 6 months through 18 years reported that efficacy against A(H1N1) and A(H3N2) was similar at 9–12 months postvaccination to efficacy at 1–<5 months postvaccination; for B strains, efficacy was still comparable at 5–7 months postvaccination. Two randomized trials and one open-label study reported residual efficacy through a second season without revaccination, albeit at lower levels than observed in the first season (117).
Several more recent observational studies have attempted to evaluate changes in influenza vaccine effectiveness over the course of a single influenza season. Some of these studies have noted a decrease in vaccine effectiveness, particularly against influenza A(H3N2) viruses, most markedly among older adults (118–121). However, this effect has not been observed consistently across age groups and seasons, and might be partially attributable to factors such as increased circulation of antigenically drifted variants over the course of the influenza season. These issues are discussed in more detail below (see Timing of Vaccination).
Immunogenicity, Efficacy, and Effectiveness of IIV
IIVs are administered by intramuscular or intradermal injection and contain nonreplicating virus. Immunogenicity, effectiveness, and efficacy have been evaluated in children and adults, although fewer data from randomized studies are available for certain age groups (e.g., persons aged ≥65 years). Since the introduction of quadrivalent IIV in the United States during the 2013–14 season, both trivalent (IIV3) and quadrivalent (IIV4) IIVs have been available. Both IIV3s and IIV4s contain an A(H1N1) virus, an A(H3N2) virus, and a B virus. IIV4s contain the viruses selected for IIV3s, and in addition contain a fourth virus, which is a B virus selected from the opposite lineage of that selected for IIV3s. Data directly comparing effectiveness of IIV3 versus IIV4 are not available. However, the U.S. Influenza Vaccine Effectiveness Network found that IIV3 provided statistically significant protection against both the included B lineage (66%; 95% CI = 58–73) and the nonincluded B lineage (51%; 95% CI = 36–63) during the 2012–13 season when both lineages co-circulated (122). In general, prelicensure studies of immunogenicity of the currently licensed IIV4s compared with corresponding IIV3 products (e.g., Fluzone Quadrivalent versus Fluzone, Fluarix Quadrivalent versus Fluarix, and Flulaval Quadrivalent versus Flulaval) demonstrated superior immunogenicity for IIV4 for the added influenza B virus without interfering with immune responses to the remaining three vaccine viruses (123–130).
Children
Children aged ≥6 months typically develop protective levels of antibodies against specific influenza virus strains after receiving the recommended number of doses of seasonal IIV (101,105,131–134). Immunogenicity studies using the A(H1N1)pdm09 monovalent vaccine indicated that 80%–95% of vaccinated children developed protective antibody levels to the 2009 A(H1N1) influenza virus after 2 doses (135,136); response after 1 dose was 50% for children aged 6–35 months and 75% for those aged 3–9 years (137).
Studies involving seasonal IIV among young children have demonstrated that 2 vaccine doses provide better protection than 1 dose during the first season a child is vaccinated. In a study during the 2004–05 season of children aged 5–8 years who received IIV3 for the first time, the proportion of children with protective antibody responses was significantly higher after 2 doses than after 1 dose of IIV3 for each antigen (p = 0.001 for influenza A[H1N1]; p = 0.01 for influenza A[H3N2]; and p = 0 0.001 for influenza B) (138). Vaccine effectiveness is lower among children aged <5 years who have never received influenza vaccine previously or who received only 1 dose in their first year of vaccination than it is among children who received 2 doses in their first year of being vaccinated. A retrospective study of billing and registry data among children aged 6–21 months conducted during the 2003–04 season found that although receipt of 2 doses of IIV3 was protective against office visits for ILI, receipt of 1 dose was not (139). Another retrospective cohort study of children aged 6 months through 8 years, the majority of whom received IIV3 (0.8% received LAIV3), also conducted during the 2003–04 season, found no effectiveness against ILI among children who had received only 1 dose (140). In a case-control study of approximately 2,500 children aged 6–59 months conducted during the 2003–04 and 2004–05 seasons, being fully vaccinated (having received the recommended number of doses) was associated with 57% effectiveness (95% CI = 28–74) against LCI for the 2004–05 season; a single dose was not significantly effective (too few children in the study population were fully vaccinated during the 2003–04 season to draw conclusions) (141). The results of these studies support the recommendation that all children aged 6 months–8 years who are being vaccinated for the first time should receive 2 doses separated by at least 4 weeks (see Children Aged 6 Months Through 8 Years).
Estimates of the efficacy of IIV among children aged ≥6 months vary by season and study design. Limited efficacy data are available for children from studies that used culture- or RT-PCR–confirmed influenza virus infections as the primary outcome. A large randomized trial compared rates of RT-PCR–confirmed influenza virus infections among 4,707 children aged 6–71 months who received IIV3, IIV3 with MF59 adjuvant (aIIV3; not currently licensed for children in the United States), or a control vaccine (meningococcal conjugate vaccine or tickborne encephalitis vaccine). During the two seasons of the study (2007–08 and 2008–09), efficacy of IIV3 versus control vaccine was 43% (95% CI = 15–61). Efficacy of aIIV3 versus control was 86% (95% CI = 74–93) (142). In a randomized trial conducted during five influenza seasons (1985–90) in the United States among children aged 1–15 years, receipt of IIV3 reduced culture-positive influenza by 77% (95% CI = 20–93) during A(H3N2) years and 91% (95% CI = 64–98) during A(H1N1) years (103). A single-season placebo-controlled study that enrolled 192 healthy children aged 3–19 years found the efficacy of IIV3 was 56% (p<0.05) among those aged 3–9 years and 100% among those aged 10–18 years (143); influenza infection was defined either by viral culture or by a postseason antibody rise in HI titer among symptomatic children from whom no other virus was isolated. In a randomized, double-blind, placebo-controlled trial conducted during two influenza seasons among 786 children aged 6–24 months, estimated efficacy was 66% (95% CI = 34–82) against culture-confirmed influenza illness during 1999–2000. However, vaccination did not reduce culture-confirmed influenza illness significantly during 2000–2001, when influenza attack rates were lower (3% versus 16% during 1999–2000 season) (144).
Receipt of IIV was associated with a reduction in acute otitis media in some studies but not in others. Two studies reported that IIV3 decreases the risk for otitis media among children (145,146). However, a randomized, placebo-controlled trial conducted among 786 children aged 6 through 24 months (mean age: 14 months) indicated that IIV3 did not reduce the proportion of children who developed acute otitis media during the study (144). Influenza vaccine effectiveness against a nonspecific clinical outcome such as acute otitis media, which is caused by a variety of pathogens and typically is not diagnosed by use of influenza virus detection methods, would be expected to be lower than effectiveness against LCI.
Younger Adults
One dose of IIV tends to be immunogenic in healthy adults aged <65 years. A 2012 meta-analysis found a pooled IIV3 efficacy against RT-PCR or culture-confirmed influenza of 59% (95% CI = 51–67) among adults aged 18–65 years for eight of twelve seasons analyzed in 10 randomized controlled trials (147). Vaccination of healthy adults was associated with decreased work absenteeism and use of health care resources in some studies, when the vaccine and circulating viruses are well-matched (49,148). In another study of healthy working adults conducted during the 2012–13 season, no significant difference in missed work hours between vaccinated and unvaccinated subjects was noted (149).
Older Adults
Older adults have long been recognized as a high-risk group for severe influenza illness, and have been recommended to receive annual influenza vaccination since the 1960s (75). Historically, most effectiveness data in this population pertain to standard-dose IIVs, which contain 15 µg of HA of each vaccine virus per dose. Discussion of the more recently licensed high-dose IIV3 occurs below.
Most studies suggest that antibody responses to influenza vaccination are decreased in older adults. It is likely that increasing dysregulation of the immune system with aging contributes to the increased likelihood of serious complications of influenza infection (150). A review of HAI antibody responses to IIV3 in 31 studies found that 42%, 51%, and 35% of older adults (aged ≥58 years) seroconverted to A(H1N1), A(H3N2), and B vaccine antigens, respectively, compared with 60%, 62%, and 58% of younger persons (aged <58 years) (151). When seroprotection (defined as an HAI titer ≥40) was the outcome, 69%, 74%, and 67% of older adults versus 83%, 84%, and 78% of younger adults achieved protective titers to A(H1N1), A(H3N2), and B antigens, respectively. Although an HAI titer ≥40 is considered to be associated with approximately 50% clinical protection from infection, this standard was established in young healthy adults (11), and few data suggest that such antibody titers represent a correlate of protection among elderly adults. An analysis of serologic data from a randomized controlled efficacy trial of high-dose IIV among the elderly found that an HAI titer of ≥40 corresponded to 50% protection (similar to the recognized threshold for younger adults) when the assay virus was well-matched to the circulating virus but higher titers were required with poor match (152). Limited or no increase in antibody response is reported among elderly adults when a second dose is administered during the same season (153–155).
Most data concerning vaccine effectiveness among community-dwelling older adults comes from observational studies. One randomized controlled trial conducted among community-dwelling persons aged ≥60 years found IIV3 to be 58% effective (95% CI = 26–77) against serologically confirmed influenza illness during the 1991–92 season, during which vaccine viruses were considered to be well-matched to circulating strains (156). The outcome used for measuring the efficacy estimate was seroconversion to a circulating influenza virus and symptomatic illness compatible with clinical influenza infection, rather than viral culture or PCR-confirmed influenza infection. Use of such outcomes raises concern that seroconversion after symptomatic illness will be less likely among vaccinated persons who have higher levels of pre-existing anti-HA antibody that than among those not vaccinated, leading to an overestimate of the true vaccine efficacy. This phenomenon was demonstrated in a clinical trial conducted among healthy adults aged 18 through 49 years (108).
Other evidence of effectiveness of influenza vaccines among older adults is derived from observational studies and from analyses of health care system data. A 2010 Cochrane review of influenza vaccine effectiveness studies among community-dwelling persons aged ≥65 years pooled data from 75 studies (randomized, quasi-randomized, cohort, and case-control studies) to assess efficacy against LCI or ILI (157). IIV3 was not significantly effective against LCI, ILI, or pneumonia. The quality of the pooled evidence was rated as generally low because of the paucity of randomized clinical trials. A different team of investigators subsequently performed a meta-analysis of these data, but using a different stratification method and examining a smaller number of clinically relevant outcomes. Using these methods, the authors estimated vaccine effectiveness for LCI of approximately 49% (95% CI = 33–62), and for ILI of 39% (95% CI = 35–43) (158). A more recent systematic review, published in 2014, included pooled data from 35 test-negative design case-control studies involving community-dwelling elderly. This review concluded that although influenza vaccine was not significantly effective during periods of localized influenza activity (defined as cases limited to one administrative unit of a country or reported from a single site), influenza vaccine was effective against LCI irrespective of vaccine match or mismatch to the circulating viruses during regional (OR: 0.42; 95% CI = 0.30–0.60 when matched; OR 0.57; 95% CI = 0.41–0.79 when not matched) and widespread outbreaks (OR: 0.54; 95% CI = 0.46–0.62 when matched; OR 0.72; 95% CI = 0.60–0.85 when not matched), although the effect was stronger when the vaccine matched (159). Vaccine was effective during sporadic activity, but only when vaccine matched (OR: 0.69; 95% CI = 0.48–0.99).
Influenza vaccination might reduce the frequency of secondary complications and risk for influenza-related hospitalization and death among community-dwelling adults aged ≥65 years with and without high-risk medical conditions (160–164). However, these studies have been conducted using medical record databases and did not use reductions in LCI illness as an outcome of interest. Such methods have been challenged because results might not be adjusted adequately to control for the possibility that healthier persons might be more likely to be vaccinated than less healthy persons (96,97,165–168). In a study of medical record data on influenza-associated hospitalizations associated with two A(H3N2) outbreaks in 1982–1983 and 1985–1986, vaccination was associated with a reduction in P&I hospitalizations among those aged ≥65 years (37% [95% CI = 15–53] in 1982–1983 and 39% [95% CI = 19–53] in 1985–1986) (169). A test-negative case-control study of community-dwelling adults aged ≥65 years noted that receipt of 2010–11 seasonal influenza vaccine was associated with a 42% reduction (95% CI = 29–53) in hospitalizations for LCI. When analyzed by type/subtype, the reduction was 40% (95% CI = 26–52) for influenza A(H3N2) and 90% (95% CI = 51–98) for influenza A(H1N1); no benefit was seen against influenza B (13%; 95% CI = -77–58) (170). A seven-season study (2002–03 through 2008–09) found that in every season, vaccinated elderly participants were significantly less likely to be hospitalized for P&I compared with unvaccinated persons (adjusted odds ratio [aOR] ranged from 0.67 to 0.86 over the seven seasons; p<0.001 to <0.030); no significant decrease was observed in the risk for outpatient visits (171). Several studies using methods to account for unmeasured confounding have reported that among community-dwelling older persons for nonspecific serious outcomes such as P&I hospitalizations or all-cause mortality is ~10% or less, which is more plausible than higher estimates from earlier studies (172–174).
Influenza infection is a common cause of morbidity and death among institutionalized older adults. Influenza vaccine effectiveness in preventing respiratory illness among elderly persons residing in nursing homes has been estimated at 20%–40% (175,176). A Cochrane review of 64 studies demonstrated that vaccination was more effective for persons living in institutional settings than for community-dwellers (177). However, documented outbreaks among well-vaccinated nursing-home populations suggest that vaccination might not have discernable effectiveness, particularly when circulating strains are drifted from vaccine strains (178,179).
The desire to improve immune response and vaccine effectiveness among adults aged ≥65 years has led to the development and licensure of vaccines intended to promote a better immune response in this population. Currently, both a high-dose IIV3 and an aIIV3 are licensed for this age group, in addition to standard-dose unadjuvanted IIV3 and IIV4. The only currently licensed high-dose IIV, Fluzone High-Dose (Sanofi Pasteur, Swiftwater, Pennsylvania), is licensed for persons aged ≥65 years and has been available since the 2010–11 influenza season. It is a trivalent formulation containing 60 µg of HA of each vaccine virus per dose, compared with 15 µg of each vaccine virus per dose in standard-dose IIVs. Licensure was based on superior immunogenicity compared with standard-dose IIV in this age group. Immunogenicity data from three studies of high-dose IIV3 among persons aged ≥65 years indicated that vaccine with four times the HA antigen content of standard-dose vaccine elicited substantially higher HAI titers (180–182). Prespecified criteria for superiority in one clinical trial study was defined by a lower bound of the 95% CI for the ratio of geometric mean HI titers of >1.5, and a lower bound of the 95% CI for the difference in seroconversion rates (fourfold rise of HI titers) of >10%. These criteria were met for influenza A(H1N1) and influenza A(H3N2) virus antigens, but not for the influenza B virus antigen (for which criteria for noninferiority were met) (181,183). Subsequently, a large randomized comparative efficacy trial of high-dose versus standard-dose IIV3 conducted among over 31,000 persons aged ≥65 years over the 2011–12 and 2012–13 influenza seasons found 24.2% greater relative efficacy of the high-dose IIV3 for protection against LCI caused by any viral type or subtype associated with protocol-defined ILI (184).
A second vaccine licensed specifically for this age group, Fluad (Seqirus, Holly Springs, North Carolina), is an MF59-adjuvanted trivalent IIV (aIIV3). This new vaccine is anticipated to be available for the 2016–17 season. Further information is provided below (see Recently Licensed Influenza Vaccine Products).
Pregnant Women and Neonates
IIV induces protective levels of antibody in pregnant women (185). Passive transfer of anti-influenza antibodies from vaccinated women to neonates has been documented (185–187). In a randomized controlled trial conducted in Bangladesh, vaccination of pregnant women during the third trimester resulted in a 36% reduction in respiratory illness with fever among these women, as compared with women who received pneumococcal polysaccharide vaccine. In addition, influenza vaccination of mothers was 63% effective (95% CI = 5–85) in preventing LCI in their breastfed infants during the first 6 months of life (188). A randomized placebo-controlled trial of IIV3 among HIV-infected and uninfected women in South Africa reported efficacy against RT-PCR–confirmed influenza of 50.4% (95% CI = 14.5–71.2) among the HIV-uninfected mothers and 48.8% (95% CI = 11.6–70.4) among their infants (189). In a matched case-control study of infants admitted to a large urban hospital in the United States during 2000–2009, investigators found that maternal vaccination was associated with significantly lower likelihood of hospitalization for LCI among infants aged <6 months (91.5%; 95% CI = 61.7–98.1) (190). A prospective cohort study among Native Americans reported that infants aged <6 months of vaccinated mothers had a 41% reduction of the risk for LCI in the inpatient and outpatient settings (RR: 0.59; 95% CI = 0.37–0.93) and a 39% reduction in risk for ILI-associated hospitalization (RR: 0.61; 95% CI = 0.45–0.84) (191). In a study of 1,510 infants aged <6 months, those of vaccinated mothers were less likely to be hospitalized with LCI than those of nonvaccinated mothers (aOR: 0.55; 95% CI = 0.32–0.95) (192).
Persons with Chronic Medical Conditions
Because of the long-standing recommendation for annual influenza vaccination of persons with chronic medical conditions, there are relatively few published studies describing the efficacy of inactivated influenza vaccines among populations with specific high-risk conditions. In the pediatric literature, most published studies of this nature focus on asthma. In a nonrandomized controlled trial during the 1992–93 season involving 137 children who had moderate to severe asthma, vaccine efficacy against laboratory-confirmed influenza A(H3N2) infection was 54% among children aged 2 through 6 years and 78% among children aged ≥7 through 14 years; vaccine efficacy against laboratory-confirmed influenza B infection was 60% among children aged ≥7 through 14 years, but nonsignificant for the younger age group (193). In a two-season study of 349 asthmatic children, IIV3 vaccine was associated with a 55% reduction in the occurrence of ARI in children aged <6 years (95% CI = 20–75; p = 0.01), but no association was noted among children aged 6 through 12 years (194).
The association between vaccination and prevention of asthma exacerbations is unclear. A retrospective uncontrolled cohort study based on medical and vaccination records during three seasons (1993–94 through 1995–96) found that asthmatic children aged 1 through 6 years showed an association between receipt of IIV3 and reduced rates of exacerbations in two out of three seasons (195). In a study of 80 asthmatic children aged 3–18 years, current influenza vaccination status was associated with a significant reduction (OR: 0.29, 95% CI = 0.10–0.84) in oral steroid use in the 12 months before the survey (196). Other studies have failed to show any benefit against asthma exacerbation (197,198).
A small study evaluated immune response to IIV3 among asthmatic children who were receiving prednisone for asthma exacerbation symptoms. Among 109 children aged 6 months through 18 years, 59 of whom had no asthma symptoms and 50 of whom were symptomatic and required prednisone, no difference was noted in antibody response to A(H1N1) and A(H3N2) following receipt of IIV3. Response to the B component of the vaccine was significantly better in the prednisone group (199).
There is some evidence to suggest that vaccine effectiveness among adults aged <65 years with chronic medical conditions might be lower than that reported for healthy adults. In a case-control study conducted during the 2003–04 influenza season, when the vaccine was a suboptimal antigenic match to many circulating virus strains, effectiveness for prevention of LCI (tests used were not specified) illness among adults aged 50–64 years with high-risk conditions was 48% (95% CI = 21–66) compared with 60% (95% CI = 43–72) for healthy adults. For influenza-related hospitalizations, effectiveness varied more substantially by risk status: among those with high-risk conditions, vaccine effectiveness was 36% (95% CI = 0–63) whereas it was 90% (95% CI = 68–97) among healthy adults (200).
Some observational studies have found large reductions in hospitalizations or deaths for adults with chronic medical conditions. For example, in a case-control study conducted during 1999–2000 in the Netherlands among 24,928 persons aged 18 through 64 years with underlying medical conditions, vaccination was reported to reduce deaths attributable to any cause by 78% and reduce hospitalizations attributable to acute respiratory or cardiovascular diseases by 87%. (201). Among patients with diabetes mellitus, vaccination was associated with a 56% reduction in any complication, a 54% reduction in hospitalizations, and a 58% reduction in deaths (202). Effects of this magnitude on nonspecific outcomes are likely to have been caused by confounding from unmeasured factors (e.g., dementia and difficulties with self-care) that are associated strongly with the measured outcomes (96,97).
A randomized controlled trial conducted among 125 adults in Thailand with chronic obstructive pulmonary disease (COPD) observed that vaccine efficacy was 76% (95% CI = 32–93) in preventing influenza-associated acute respiratory infection (defined as respiratory illness associated with HAI titer increase and/or positive influenza antigen on indirect immunofluorescence testing) during a season when circulating influenza viruses were well-matched to vaccine viruses (203). A systematic review of studies of influenza vaccine among COPD patients identified evidence of reduced risk for exacerbation from vaccination (204). Eleven trials were included but only six of these were specifically performed in COPD patients. The others were conducted on elderly and high-risk persons, some of whom had chronic lung disease. However, a systematic review that focused on studies of adults and children with asthma concluded that evidence was insufficient to demonstrate benefit of vaccination in this population (205).
Evidence suggests that acute respiratory infections might trigger atherosclerosis-related acute vascular events (206). Some studies have attempted to evaluate the impact of vaccination on such events. Several randomized controlled trials have suggested protective efficacy of influenza vaccination against vascular events. The FLUVACS study randomized participants with known coronary artery disease to IIV3 or placebo and followed up at 6 months, 1 year and 2 years. Vaccination was associated with lower cardiovascular mortality (RR: 0.25; 95% CI = 0.07-0.86 at 6 months and RR: 0.34; 95% CI = 0.17–0.71 at 1 year) and lower risk for a composite endpoint including cardiovascular death, nonfatal myocardial infarction, or severe ischemia (RR: 0.50; 95% CI = 0.29-0.85 at 6 months and 0.59; 95% CI = 0.40–0.86 at 1 year) compared with controls (207,208). In the FLUCAD study, a randomized trial of 658 participants with coronary artery disease, rates of coronary ischemic events at 12 months were significantly lower in the vaccinated group (hazard ratio [HR]: 0.54; 95% CI = 0.29–0.99) (209). Another composite endpoint, major CV events (including cardiovascular death, myocardial infarction, or coronary revascularization) was not significantly different between vaccinated and placebo groups. In a trial of 439 participants with acute coronary syndrome, influenza vaccination resulted in a significant reduction of major coronary adverse events (adjusted HR [aHR]: 0.67; 95% CI = 0.51–0.86), but not cardiovascular death (0.62; 95% CI = 0.34–1.12) (210). A pooled analysis of these data with those of the FLUVACS study showed a significant reduction of major cardiovascular events (pooled effectiveness 44%; 95% CI = 25–58), cardiovascular deaths (pooled effectiveness: 60%; 95% CI = 29–78); and hospitalization (pooled effectiveness 51%; 95% CI = 16–72) in vaccinated participants at one-year follow up (211). A self-controlled case series study conducted through medical record review of over 17,000 persons aged ≥18 years who had experienced a stroke found a reduction of 55% in the risk for stroke in the first 1–3 days after vaccination; subsequent reductions were 36% at 4–7 days, 30% at 8–14 days, 24% at 15–28 days, and 17% at 29–59 days (212).
Statin medications, a class of drugs commonly used among persons with vascular disease, are known to have immunomodulatory effects. A posthoc analysis of data from a randomized clinical trial comparing MF59-adjuvanted IIV3 and unadjuvanted IIV3 among persons aged ≥65 years demonstrated lower geometric mean titers following vaccination among persons receiving chronic statin therapy (by 38% [95% CI = 27–50] for A(H1N1), by 67% [95% CI = 54–80] for A(H3N2), and by 38% [95% CI = 28–49] for B). The effect was more pronounced among those receiving synthetic statin drugs (fluvastatin, atorvastatin, and rosuvastatin) relative to those receiving fermentation-derived statins (pravastatin, simvastatin, lovastatin, and Advicor) (213). A retrospective cohort study covering nine influenza seasons found reduced effectiveness of influenza vaccine against MAARI among statin users (214); however, this study did not evaluate confirmed influenza illness. Further study of the specific impact of statins on influenza vaccine effectiveness is needed.
Multiple studies indicate that vaccination might be beneficial for persons with chronic liver disease. A prospective study of 311 persons with cirrhosis, 198 of whom received IIV3 and the remainder of whom were unvaccinated, noted reduction in the rates of ILI (14% versus 23%; p = 0.064) and of culture-positive influenza (2.3% versus 8.8%; p = 0.009) in the vaccinated group (215). Review of data from Taiwan’s National Health Insurance program from 2000 through 2009 noted a lower hospitalization rate among persons with chronic hepatitis B infection who had been vaccinated compared with those who had not (16.29 versus 24.02 per 1,000 person-years) (216).
Studies of the immunogenicity and effectiveness of seasonal influenza vaccine among persons with obesity have shown conflicting results. An evaluation of immunogenicity of influenza vaccine conducted among pregnant and postpartum women reported that seroconversion rates among obese women were lower than those among normal-weight participants, but the difference was not statistically significant (217). Two other observational studies focused on the impact of obesity on postvaccination immune response. One study comparing 1-month and 12-month postvaccination immune response showed that obese persons mounted a vigorous initial antibody response to IIV3 (218). However, higher BMI was associated with a decline in influenza antibody titers after 12 months postvaccination. A second study of older adults reported that immunogenicity of IIV3 was similar in obese and normal-weight older adults, with a slight increase in seroconversion for the A/H3N2 virus but not for the other viruses (219). In a small study involving 51 children aged 3–14 years with varying BMI measurements (220), seroprotection rates at 4 weeks postvaccination were significantly higher against influenza A(H1N1)pdm09 strain in the overweight/obese group (p<0.05) when compared with the normal-weight group. This difference diminished over time, with the antibody response similar or slightly higher in overweight/obese children when measured 4 months postvaccination. A test-negative case-control study of hospitalized adult patients reported an unadjusted vaccine effectiveness against LCI hospitalizations of 79% (95% CI = -6– 96); after adjusting for obesity, the vaccine effectiveness estimate increased to 86% (95% CI = 19–97); the presence of obesity increased the odds of laboratory-confirmed influenza by 2.8 times (221).
Immunocompromised Persons
In general, HIV-infected persons with minimal AIDS-related symptoms and normal or near-normal CD4+ T-lymphocyte cell counts who receive IIV develop adequate antibody responses (222–224). Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, IIV might not induce protective antibody titers (224,225); a second dose of vaccine does not improve immune response (225,226). In an investigation of an influenza A outbreak at a residential facility for HIV-infected persons, vaccine was most effective at preventing ILI among persons with >100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL (227). In a randomized placebo-controlled trial conducted in South Africa among 506 HIV-infected adults, including 349 persons on antiretroviral treatment and 157 who were antiretroviral treatment-naïve, efficacy of IIV3 for prevention of culture- or RT-PCR–confirmed influenza illness was 75% (95% CI = 9–96) (228).
In a randomized study comparing the immunogenicity of high-dose versus standard-dose IIV3 among 195 HIV-infected adults aged ≥18 years (10% of whom had CD4 counts under 200 cells/µL), seroprotection rates were higher in the high-dose group for A(H1N1) (96% versus 87%; p = 0.029) and influenza B (91% versus 80%; p = 0.030). Both vaccines were well-tolerated (229). However, in a comparative study of 41 children and young adults aged 3–21 years with cancer or HIV infection, high-dose IIV3 was no more immunogenic than standard-dose IIV3 among the HIV-infected recipients (230).
Several observational studies suggest that immunogenicity among persons with solid organ transplants varies according to factors such as transplant type, time from transplant, and varying immunosuppressive regimen. Overall seroprotective and seroconversion responses have ranged from 15% to 93% with lower responses seen in lung transplant and greater responses several years after kidney transplant (231). In one study, kidney transplant recipients who were 3–10 years posttransplant had a 93% seroprotection rate to A(H1N1) antigen after vaccination (232). Among persons with kidney or heart transplants, seroresponse rates were similar or slightly reduced compared with healthy persons (232–237). However, a small study involving participants with liver transplants indicated a reduced immunologic response to influenza vaccinations (238). Response rates were lowest if vaccination occurred within the four months after the transplant procedure (239). A study of persons with a history of kidney transplant found that influenza vaccination in the first year after transplant was associated with a lower rate of transplant rejection (aHR: 0.77; 95% CI = 0.69–0.85; p<0.001) and death (0.82; 95% CI = 0.76–0.89; p<0.001) (240).
Immunogenicity, Efficacy, and Effectiveness of LAIV
LAIV virus strains replicate in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not understood completely but appear to involve both serum and nasal secretory antibodies, as well as cell-mediated immune responses. The immunogenicity of LAIV3 has been assessed in multiple studies (241–245).
The single LAIV licensed in the United States was originally a trivalent vaccine (FluMist; MedImmune, Gaithersburg, Maryland). FluMist Quadrivalent was licensed by FDA in 2012, and replaced the trivalent formulation beginning with the 2013–14 season. Prelicensure studies comparing LAIV4 to LAIV3 demonstrated that HAI antibody responses to LAIV4 were noninferior to responses to LAIV3 among healthy children and adults ≤49 years (246–248). LAIV4 might confer increased protection against seasonal influenza B by targeting more than one influenza B lineage. No comparative efficacy or effectiveness data for LAIV4 versus LAIV3 are available.
LAIV3 in Children
A large randomized, double-blind, placebo-controlled trial among 1,602 healthy children aged 15–71 months assessed the efficacy of LAIV3 against culture-confirmed influenza during two seasons (1996–98) (249,250). During the first season, when vaccine and circulating virus strains were well-matched, efficacy against culture-confirmed influenza was 94% (95% CI = 88–97) for participants who received 2 doses of LAIV3 separated by >6 weeks, and 89% (95% CI = 65–96) for those who received 1 dose (249). During the second season, when the A(H3N2) component in the vaccine was not well-matched with circulating virus strains, efficacy for 1 dose was 86% (95% CI = 75–92) for this virus. The overall efficacy for any influenza during the two seasons was 92% (95% CI = 88–94) (250). In a randomized placebo-controlled trial comparing 1 dose versus 2 doses of LAIV3 in 3,200 vaccine-naïve children aged 6–35 months in South Africa, Brazil, and Argentina during the 2001 and 2002 seasons, efficacy was 57.7% (95% CI = 44.7–67.9) after 1 dose of LAIV3 and 73.5% (95% CI = 63.6–81) after 2 doses (251) during the first year of the study. Other two-season, randomized, placebo-controlled trials have demonstrated similar efficacy rates of LAIV3 among young children, ranging from 85% to 89% among children in childcare (252) to 64% to 70% for children in eight regions in Asia (253). LAIV3 efficacy in preventing LCI also has been demonstrated in studies comparing the efficacy of LAIV with IIV rather than with a placebo (see Comparisons of LAIV3/4 and IIV Efficacy or Effectiveness).
Effectiveness studies have demonstrated that LAIV3 use among healthy children was associated with reduced risk of outcomes other than LCI. In one community-based, nonrandomized open-label study, reductions in MAARI were observed during the 2000–01 season among children who received 1 dose of LAIV3 during 1999–2000 or 2000–2001), even though antigenically drifted influenza A(H1N1) and B viruses were circulating during the latter season (116). Receipt of LAIV3 resulted in 21% fewer febrile illnesses (95% CI = 11–30) and 30% fewer febrile otitis media (95% CI = 18–45) (249). A meta-analysis of six placebo-controlled studies concluded that the effectiveness of LAIV3 against acute otitis media associated with culture-confirmed influenza among children aged 6–83 months was 85% (95% CI = 78–90) (254).
LAIV3 in Younger Adults
A randomized, double-blind, placebo-controlled trial of LAIV3 effectiveness among 4,561 healthy working adults aged 18 through 64 years assessed multiple endpoints, including reductions in self-reported respiratory tract illness without laboratory confirmation, work loss, health care visits, and medication use during influenza outbreak periods. The study was conducted during the 1997–98 influenza season, when the vaccine and circulating A(H3N2) viruses were not well-matched. The frequency of febrile illnesses was not significantly decreased among LAIV3 recipients compared with those who received placebo. However, vaccine recipients had significantly fewer severe febrile illnesses (19% reduction) and febrile upper respiratory tract illnesses (24% reduction); and significant reductions in days of illness, days of work lost, days with health care provider visits, and use of prescription antibiotics and over-the-counter medications (255). Estimated efficacy of LAIV3 against influenza confirmed by either culture or RT-PCR in a randomized, placebo-controlled study among approximately 1,200-2,000 young adults was 48% (95% CI = -7–74) in the 2004–05 influenza season, 8% (95% CI = -194–67) in the 2005–06 influenza season, and 36% (95% CI = 0–59) in the 2007–08 influenza season; efficacy in the 2004–05 and 2005–06 seasons was not significant (256–258).
Comparisons of LAIV3/4 and IIV Efficacy or Effectiveness
Studies comparing the efficacy of IIV3 to that of LAIV3 among adults have been conducted in a variety of settings and populations using several different outcomes. Among adults, most comparative studies demonstrated that LAIV3 and IIV3 have similar efficacy, or that IIV3 was more efficacious (259). One randomized, double-blind, placebo-controlled challenge study that was conducted among 92 healthy adults aged 18–45 years assessed the efficacy of both LAIV3 and IIV3 in preventing influenza infection when artificially challenged with wild-type strains that were antigenically similar to vaccine strains (245). The overall efficacy in preventing laboratory-documented influenza illness (defined as respiratory symptoms with either isolation of wild-type influenza virus from nasal secretions or fourfold and/or greater HAI antibody response to challenge) from all three influenza strains combined was 85% for LAIV3 and 71% for IIV3 when study participants were challenged 28 days after vaccination by viruses to which they were susceptible before vaccination. The difference in efficacy between the two vaccines was not statistically significant in this small study (245). In a randomized, double-blind, placebo-controlled trial conducted among young adults during the 2004–05 influenza season, when the majority of circulating A(H3N2) viruses were antigenically drifted from that season’s vaccine viruses, the efficacy of LAIV3 and IIV3 against culture-confirmed influenza was 57% (95% CI = -3–82) and 77% (95% CI = 37–92), respectively. The difference in efficacy was not statistically significant and was attributable primarily to a difference in efficacy against influenza B (256). Similar studies conducted among adults during the 2005–06 and 2007–08 influenza seasons found no significant difference in vaccine efficacy in the 2005–06 season (257) but did find a 50% relative efficacy of IIV3 compared with LAIV3 in the 2007–08 season (258). An observational study conducted among military personnel aged 17–49 years over the 2004–05, 2005–06, and 2006–07 influenza seasons indicated that persons who received IIV3 had a significantly lower incidence of health care encounters resulting in diagnostic coding for P&I compared with those who received LAIV3 (adjusted incidence rate ratio [aIRR]: 0.57 [95% CI = 0.51–0.64] for the 2004–05 season, 0.79 [95% CI = 0.72–0.87] for the 2005–06 season, and 0.80 [95% CI = 0.74–0.86] for the 2006–07 season) (260). However, in a retrospective cohort study comparing LAIV3 and IIV3 among 701,753 nonrecruit military personnel and 70,325 new recruits, among new recruits, incidence of ILI was lower among those who received LAIV3 than IIV3. The previous vaccination status of the recruits was not stated; it is possible that this population was relatively naïve to vaccination compared with previous service members who were more likely to have been vaccinated routinely each year (261).
Several studies comparing LAIV3 with IIV3 prior to the 2009 pandemic demonstrated superior efficacy of LAIV3 among young children (259). A randomized controlled trial conducted among 7,852 children aged 6–59 months during the 2004–05 influenza season demonstrated a 55% reduction in cases of culture-confirmed influenza among children who received LAIV3 compared with those who received IIV3 (262). In this study, LAIV3 efficacy was higher compared with IIV3 against antigenically drifted viruses and well-matched viruses. An open-label, nonrandomized, community-based influenza vaccine trial conducted among 7,609 children aged 5–18 years during an influenza season when circulating A(H3N2) strains were poorly matched with strains contained in the vaccine also indicated that LAIV3, but not IIV3, was effective against antigenically drifted A(H3N2) viruses. In this study, children who received LAIV3 had significant protection against LCI (37%) and P&I events (50%) (263). LAIV3 provided 32% increased protection in preventing culture-confirmed influenza compared with IIV3 in one study conducted among children aged ≥6 years and adolescents with asthma (264) and 52% increased protection compared with IIV3 among children aged 6–71 months with recurrent respiratory tract infections (265).
On the basis of these data, in June 2014, ACIP recommended that when immediately available, LAIV should be used for healthy children aged 2 through 8 years who have no contraindications or precautions. However, analysis of data from three observational studies of LAIV4 vaccine effectiveness for the 2013–14 season (the first season in which LAIV4 was available) revealed low effectiveness of LAIV4 against influenza A(H1N1)pdm09 among children aged 2 through 17 years (266,267). Analysis of data from the U.S. Influenza Vaccine Effectiveness Network for the 2010–11 through 2013–14 seasons noted that children aged 2 through 17 years who received LAIV had similar odds of influenza regardless of receipt of LAIV3 or IIV3 during 2010–11 through 2012–13; however, during the 2013–14 season odds of influenza were significantly higher for those who received LAIV4 (OR: 5.36; 95% CI = 2.37–12.13 for children aged 2 through 8 years; OR: 2.88; 95% CI = 1.62–5.12 for children aged 2 through 17 years) (268). During this season, the H1N1pdm09 virus predominated for the first time since the 2009 pandemic. The diminished effectiveness against H1N1pdm09 was hypothesized to be attributable to reduced stability and infectivity of the A/California/2009/(H1N1) vaccine virus, conferred by a single amino acid mutation in the stalk region of the HA protein (269). Moreover, although one large randomized trial observed superior relative efficacy of LAIV3 compared with IIV3 against antigenically drifted H3N2 influenza viruses during the 2004–05 season (262), analysis of observational data from the U.S. Influenza Vaccine Effectiveness Network for the early 2014–15 season (in which antigenically drifted H3N2 viruses were predominant) indicated that neither LAIV4 nor IIV provided significant protection in children aged 2 through 17 years; LAIV4 did not offer greater protection than IIV for these viruses (270). Based on these influenza vaccine effectiveness data for the 2013–14 and 2014–15 seasons, ACIP concluded that a preference of LAIV4 over IIV was no longer warranted (6).
For the 2015–16 season, to address stability concerns surrounding the A/California/7/2009(H1N1) HA, HA from a different influenza A(H1N1) virus was included in LAIV4 (A/Bolivia/559/2013(H1N1). In June 2016, ACIP reviewed data pertaining to effectiveness of LAIV444 and IIV in the United States for the 2015–16 season (271). During this season, in which A(H1N1)pdm09 viruses were predominant, analysis of data from the U.S. Influenza Vaccine Effectiveness Network showed no significant vaccine effectiveness among children aged 2 through 17 years for LAIV4 for all influenza A and B viruses combined (3%; 95% CI = -49–37) or for influenza A(H1N1)pdm09 (-21%; 95% CI = -108–30). A Department of Defense analysis similarly noted no statistically significant vaccine effectiveness of LAIV4 against influenza A(H1N1) in this age group for the 2015–16 season. Data presented by MedImmune to ACIP on June 22, 2016 included a somewhat higher point estimate for LAIV4 effectiveness against influenza A(H1N1) (50%), but this value was not statistically significant. Conversely, estimated effectiveness of IIV against these viruses among children aged 2 through 17 years was significant across all three studies. Following review of this information in June 2016, ACIP made the interim recommendation that LAIV4 should not be used for the 2016–17 influenza season.
Immunogenicity, Efficacy, and Effectiveness of RIV
RIV, available as a trivalent vaccine, Flublok (RIV3; Protein Sciences, Meriden, Connecticut) was licensed by FDA in 2013. This vaccine contains 135 µg of purified HA proteins (45 µg for each virus). The HA proteins are produced in an insect cell line; this process uses neither live influenza viruses nor eggs.
As a relatively new product, fewer postmarketing effectiveness data are available for RIV3 than IIVs. Initial licensure was for persons aged 18 through 49 years. In prelicensure studies comparing RIV3 versus placebo among persons aged 18 through 49 years, serum antibody responses were induced to all three vaccine components (272). In a randomized placebo-controlled study conducted among healthy persons aged 18 through 49 years during the 2007–08 influenza season (273,274), estimated vaccine effectiveness for CDC-defined ILI with a positive culture for influenza virus was 75.4% (95% CI = -148.0–99.5) against matched strains; more precise estimation of vaccine effectiveness was not possible because 96% of isolates in this study did not antigenically match the strains represented in the vaccine (273). Estimated vaccine effectiveness without regard to match was 44.6% (95% CI = 18.8–62.6) (274).
Although RIV3day tiv was licensed initially for use in persons aged 18 through 49 years, in October 2014, the approved age indication was expanded to ≥18 years on the basis of data from randomized trials demonstrating adequate immunogenicity among persons aged ≥50 years (275,276); effectiveness data are not yet available for this age group.
