Immunogenicity, Efficacy, and Effectiveness of Influenza Vaccines

Serum antibodies against hemagglutinin are considered to be correlates of vaccine-induced protection for inactivated influenza vaccines (IIVs)(8).  Higher 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 (9, 111-113). Most healthy children and adults have high titers of strain-specific antibody after IIV vaccination (112, 114). 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 [HAI] titer of 32 or 40) might not predict protection from infection on the individual level.

Compared with IIV, live attenuated influenza vaccine (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 increases in these parameters were noted among adults following receipt of either vaccine (115).

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 (116).

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 (117). 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

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 (118), ILI in younger working adults (37), and LCI (119) 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 (120, 121).

In addition to antigenic drift of circulating influenza viruses, vaccine viruses might undergo adaptive mutations during propagation in eggs.  In some instances, these mutations may result in antigenic differences between vaccine viruses and circulating viruses, which may in turn result in reduced vaccine effectiveness (122).  While the majority of influenza vaccines licensed in the United States are egg-based, two which use non-egg based technologies have been licensed in recent seasons.  These include a cell culture-based IIV4 Flucelvax Quadrivalent (ccIIV4, Seqirus) and a recombinant quadrivalent vaccine, Flublok (RIV4, Sanofi Pasteur).  Flucelvax Quadrivalent is produced via propagation of vaccine viruses in canine kidney cells instead of eggs (123).  Flublok Quadrivalent contains HA produced via recombinant methods in an insect cell line, and uses neither influenza viruses nor eggs in its production (124).  In a retrospective cohort analysis of Centers for Medicare and Medicaid (CMS) data including >13 million beneficiaries aged ≥65 years during the 2017-18 season, effectiveness of ccIIV4 was somewhat better than that of egg based vaccines (relative VE=11%, 95%CI 8—14% compared with standard-dose egg based quadrivalent inactivated vaccines); use of RIV4 was insufficient for analysis (125).  The authors concluded the modest relative benefit of ccIIV4 indicated that changes in egg propagated vaccine viruses were probably not sufficient to fully account for the relatively low VE observed during 2017-18.   More comparative studies are needed to elucidate potential benefits of non-egg based vaccines.

Inactivated influenza vaccines (IIVs) comprise the largest category of vaccines currently available. IIVs are administered by intramuscular injection.  They are manufactured using influenza viruses which have been inactivated, so no viral replication occurs after administration. Immunogenicity, effectiveness, and efficacy have been evaluated in children and adults.  However, in general, fewer data from randomized studies of efficacy against LCI outcomes are available for certain age groups (e.g., persons aged ≥65 years as compared with younger age groups).  Product-specific efficacy data from randomized trials are generally limited for some of the more recently licensed quadrivalent vaccines, many of which were licensed primarily on the basis of immunogenicity studies which demonstrated non-inferior immune response as compared with their earlier trivalent counterparts.  Efficacy and effectiveness studies in which different individual IIVs are compared are also limited, with the exception of some specific comparisons that are discussed in the sections that follow.

Since the introduction of quadrivalent IIV (IIV4) in the United States during the 2013–14 season, both trivalent (IIV3) and quadrivalent IIVs have been available. Both IIV3s and IIV4s contain an influenza A(H1N1) virus, an influenza A(H3N2) virus, and an influenza B virus (selected from one of the two influenza B virus lineages). IIV4s contain the viruses selected for IIV3s, and in addition contain a fourth virus, which is an influenza B virus selected from the second influenza B virus lineage (i.e., the lineage not contained in the trivalent vaccine). In general, pre-licensure studies of immunogenicity of the currently licensed IIV4s compared with corresponding IIV3 products from the same manufacturer have demonstrated superior immunogenicity for IIV4 for the added influenza B virus that is not included in IIV3, without interfering with immune responses to the remaining three vaccine viruses (126-133).

IIV4s were developed to provide better protection in seasons in which the predominant circulating influenza B lineage is not included in IIV3s.  However, effectiveness studies conducted during some seasons have demonstrated that IIV3 provided similar protection against circulating influenza B viruses of both lineages. For example, the U.S. Flu VE Network found that IIV3 provided statistically significant protection against both the included B lineage (66%; 95%CI 58, 73) and the non-included B lineage (51%; 95%CI 36, 63) during the 2012– 13 season, when both lineages co-circulated (134). Similarly, in an observational study conducted during the 2011-12 season, in which both B lineages co-circulated, effectiveness was similar for both (52%, 95%CI 8, 75% for B/Victoria; and 66%, 95%CI 38, 81% for B/Yamagata) (135). Cross-lineage protection was observed for IIV3 and ccIIV3 in a randomized trial (136); in another randomized trial of IIV3 there was no cross lineage protection (137).

Several 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 putatively 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<0.001 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 or P&I among children who had received only 1 dose (140); children who received 2 doses were protected against P&I. 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).  In a three-season (2015-16 through 2017-18) test-negative case-control study conducted among children aged 6 months through 8 years in Israel, IIV3 was effective for those who were fully vaccinated (VE=53.9%; 95%CI 38.6, 68.3), but not for those who were only partially vaccinated (VE=25.6%; 95%CI -3, 47) (142).  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 randomized controlled trials that used culture- or RT-PCR–confirmed influenza virus infections as the primary outcome. 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 (112). 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 1999–00. However, vaccination did not reduce culture-confirmed influenza illness significantly during 2000–01, when influenza attack rates were lower (3% versus 16% during 1999–20 season) (143).  More recently, in a multinational randomized trial which included over 12,000 children aged 6 through 25 months over 5 influenza seasons between 2011 and 2014 and compared IIV4 to non-influenza control vaccines, VE was 50% (95%CI 42, 57) against LCI of any severity and 63.2% (95%CI 49, 69) against moderate-to-severe influenza (defined as LCI with any of the following features: fever >39⁰C, otitis media, lower respiratory infection, serious extrapulmonary complications, intensive care unit admission, or need for supplemental oxygen for >8 hours) (144).

In observational studies for recent influenza seasons, vaccine effectiveness among children has varied by season.  In the U.S. Flu VE Network (within which the majority of vaccine used in recent seasons has been IIV3 or IIV4), estimated effectiveness against medically-attended influenza illness due to all types and subtypes during the 2016-17 season was 57% (95%CI 43, 68) for children aged 6 months through 8 years and 36% (95%CI 15, 52) for children aged 9 through 19 years (145).  For the 2017-18 season, estimated effectiveness was 68% (95%CI 55, 77) for children aged 6 months through 4 years and 32% (95%CI 16, 44) for children aged 5 through 17 years (146).

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 (147, 148). 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 (143). A 2017 systematic review concluded that receipt of influenza vaccine was associated with a small decrease in the occurrence of at least one episode of acute otitis media over a minimum of six months following vaccination; however, this decrease was not statistically significant (RR=0.84; 95%CI 0.69, 1.02) This result was pooled from 4 studies which included different vaccines (two of IIV3, one of IIV3 administered with measles/mumps/rubella vaccine, and one of LAIV3) (149). 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.

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 (150). 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 (37, 39). 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 (151).

In analyses of data from the U.S. Flu VE Network, (within which the majority of vaccine used in recent seasons has been IIV3 or IIV4), estimated effectiveness against MAARI due to all viral types and subtypes for adults aged 18 through 49 years was 19% (95%CI 0, 34) during the 2016-17 season (145) and 33% (95%CI 21, 44) during the 2017-18 season (146).  For those aged 50 through 64 years, estimated effectiveness during the 2016-17 season was 40% (95%CI 24, 53) (145).  During the 2017-18 season VE was 30% (95%CI 13, 44) for this age group (146).

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 (HDIIV3), adjuvanted IIV3 (aIIV3), and quadrivalent recombinant influenza vaccine (RIV4) in this age group is presented below.

Studies suggest that antibody responses to influenza vaccination are decreased in older adults. 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). 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 (152). 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 (8), 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 vaccine virus was well-matched to the circulating virus, but higher titers were required with poor match (153). Limited or no increase in antibody response is reported among elderly adults when a second dose is administered during the same season (154-156).

Because older adults have been recommended to receive routine annual influenza vaccine for many decades (75), there are relatively few randomized, placebo-controlled trials which estimate VE against LCI outcomes in this population.  One randomized controlled trial conducted among community-dwelling (not institutionalized) 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 (157). 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 HAI antibody 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 (117).

Other evidence of effectiveness of influenza vaccines among older adults is derived from observational studies and from analyses of health care system data. A 2018 Cochrane review of influenza vaccine effectiveness studies among older adults concluded that older adults who are vaccinated may have a lower risk of influenza (RR=0.42, 95%CI 0.27, 0.66), with the evidence quality characterized as “low certainty” because of the paucity of randomized clinical trials (158).  A 2014 review of data from 35 test-negative design case-control studies involving community-dwelling elderly 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), and the effect was stronger when the vaccine viruses matched circulating viruses. Vaccine was effective during sporadic activity, but only when vaccine matched (OR=0.69; 95%CI 0.48, 0.99) (159).

Influenza vaccine effectiveness against medically-attended influenza illness among adults aged ≥65 years is also assessed annually by the U.S. Flu VE Network.  In recent seasons, IIV3 and IIV4 have been the predominant type used with this network.  For the 2016-17 and 2017-18 seasons, estimated effectiveness of influenza vaccines was not statistically significant for this age group (145, 146).

Influenza vaccination might reduce risk for influenza-related hospitalizations among older adults with and without other high-risk conditions (160-164).   A test-negative case-control analysis from a multinational European network noted moderate vaccine effectiveness against hospitalization among persons aged ≥65 years during the 2015-16 season.  Estimated vaccine effectiveness was 42% (95%CI 22, 57) for influenza A(H1N1)pdm09 and 52% (95%CI 24, 70) for influenza B.  Vaccine effectiveness estimates were similar for both virus types among persons with diabetes, cancer, lung, and heart disease, except in the instance of influenza B among persons with heart disease, for which vaccine effectiveness was not statistically significant (165).  A systematic review and meta-analysis of test-negative case-control studies of vaccine effectiveness for influenza-associated hospitalizations among older adults reported pooled VE of 48% (95%CI 37, 59) for influenza A(H1N1)pdm09 viruses, 37% (95%CI 24, 50) for influenza A(H3N2) viruses, and 38% (95%CI 23, 53) for influenza B viruses.  Vaccine effectiveness for H3N2 viruses varied substantially depending upon match of circulating viruses with vaccine viruses: 43% (95%CI 33, 53) when vaccine viruses were antigenically similar, vs. 14% (95%CI -3, 30) when they were not (166).

Some studies of severe influenza illness among older adults have used less specific, non-LCI outcomes such as all-cause mortality of hospitalizations associated with influenza-related diagnostic codes.  Such methods have been challenged because results might not be adjusted adequately to control for frailty bias or for the possibility that healthier persons might be more likely to be vaccinated than less healthy persons (106, 107, 167). Several studies that have used methods to account for unmeasured confounding have reported effectiveness estimates for nonspecific serious outcomes such as P&I hospitalizations or all-cause mortality among community-dwelling older persons of ~10% or less (168-170). In a test-negative case-control study of community-dwelling adults aged ≥65 years, effectiveness of 2010–11 seasonal influenza vaccine against hospitalization for LCI was 42% (95%CI 29, 53).  By type and subtype, estimated effectiveness was 40% (95%CI 26, 52) for influenza A(H3N2) and 90% (95%CI 51, 98) for influenza A(H1N1); no significant reduction was seen against influenza B (13%; 95%CI -77, 58) (171). In a study covering the 2007-08 through 2010-11 seasons, among outpatients aged ≥65 years presenting with ARI with RT-PCR-confirmed influenza, self-rated symptom severity was less for those who had been vaccinated than for those who had not (172). An analysis of data from the Influenza Hospitalization Surveillance Network (FluSurv-NET) for the 2012-13 season found no difference in symptom severity in vaccinated vs unvaccinated adults, but length of ICU stay was shorter for those aged 50 through 64 years who had been vaccinated (173). A subsequent study from the same network for 2013-14 found vaccination to be associated with reduced length of hospital and ICU stay among persons aged 50-64 years and ≥65 years, as well as lower odds of in-hospital death in these age groups (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). 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 (177, 178).

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 specifically for this age group, in addition to standard-dose unadjuvanted IIVs and RIVs. Specific discussion of HD-IIV3, aIIV3, and RIV4 for older adults is discussed below (see HD-IIV3, aIIV3, and RIV4 for Older Adults).

Passive transfer of anti-influenza antibodies from vaccinated women to neonates has been documented (179-181). Protection of infants though maternal vaccination has been observed in several studies. 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, 5) in preventing LCI in their breastfed infants during the first 6 months of life (182). 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 (183). In a study conducted in Mali in which pregnant women were randomized to receive either IIV3 or quadrivalent meningococcal vaccine (as a non-influenza control vaccine) during the third trimester and infants were followed to detect LCI through 6 months of age, vaccine efficacy against LCI among the infants was 67.9% (95%CI 35.1, 85.3) through 4 months and 57.3% (95%CI 30.6, 74.4) through 5 months; by six months of follow up efficacy was 33.1% (95%CI 3.7, 53.9) (184). A randomized placebo-controlled trial of year-round influenza vaccination in Nepal (where influenza circulates year-round, rather than seasonally), vaccine efficacy against LCI among infants 0–6 months of age was 30% (95%CI 5, 48) for the full study period. Vaccines with two different HA compositions were used during this period; vaccine efficacy for the vaccine used during the first period was 16% (95%CI -19, 41), while that for the latter was 60% (95%CI 26, 88) (185).

Among observational studies, in a matched case-control study of infants admitted to a large urban hospital in the United States during 2000–2009, 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) (186). A prospective cohort study among Native Americans reported that infants aged <6 months of vaccinated mothers had a 41% lower risk of LCI (RR=0.59; 95%CI 0.37, 0.93) and a 39% lower risk of ILI-associated hospitalization (RR=0.61; 95%CI 0.45, 0.84) (187). 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 unvaccinated mothers (aOR=0.55; 95%CI = 0.32, 0.95) (188). In a case control study covering the 2010-11 and 2011-12 influenza seasons, vaccination of pregnant women reduced their risk of LCI by approximately half (189).  In a multiseason (2010-2016), multinational test-negative case-control study which included 19,450 pregnant women, IIV was protective against hospitalizations associated with LCI (VE 40%, 95%CI 12, 59) (190).

Data evaluating clinical efficacy and effectiveness of vaccination among populations with specific chronic medical conditions are variable, with more data being available for some conditions than others.  As is the case with influenza vaccine effectiveness in general, effectiveness estimates vary with the seasons and outcomes studied, as well as the health condition(s) of the recipients.  These factors make it difficult to draw generalizable conclusions regarding effectiveness of influenza vaccines for individuals with some health conditions.

A recent TND case-control study covering four seasons (2012-13 through 2015-16) reported a moderate protective effect of vaccination against LCI (VE 41%; 95%CI 35, 47) among persons with at least one recognized high-risk medical condition.  This estimate was somewhat lower than that obtained for those without such conditions (VE=48%; 95%CI 43; 52; p=0.02 for comparison).  Among children, VE was estimated to be 51% (95%CI 39, 61) for those with a high-risk condition and 52% (95%CI 44; 58) for those without such conditions; these estimates did not differ significantly (p=0.31).   For adults aged ≥18 years, VE was 38% (95%CI 30–45%) among those with high-risk conditions and 44% (95%CI 38, 50%) for those without (p=0.21) (191).

 Pulmonary Conditions

Much of the literature concerning influenza vaccine effectiveness among children with pulmonary conditions focuses on asthma.  In a nonrandomized controlled trial during the 1992–93 season involving 137 children with moderate to severe asthma, VE against laboratory-confirmed influenza A(H3N2) infection was 54% (p<0.01) among children aged 2 through 6 years and 78% (p<0.01) among children aged ≥7 through 14 years; VE against laboratory-confirmed influenza B infection was 60% (p<0.01) among children aged ≥7 through 14 years, but was 22% and nonsignificant (p>0.05) for the younger age group (192).  Among adults with asthma in a four-season TND case-control study, vaccine effectiveness against LCI was estimated to be 27% (95%CI 10, 41), lower than that for adults without high risk conditions (VE=44%; 95%CI 38, 50; p=0.02) (191).

Studies of the association between vaccination and prevention of asthma exacerbations have provided variable results. A retrospective uncontrolled cohort study based on medical and vaccination records during three seasons (1993–94 through 1995–96) among asthmatic children aged 1 through 6 years showed an association between receipt of IIV3 and reduced rates of exacerbations in two of the three seasons (193). In a study of 80 asthmatic children aged 3–18 years, vaccination was associated with a lower risk of oral steroid use (OR=0.29; 95%CI 0.10, 0.84) (194). A 2012-13 season study of 93 children with mild persistent asthma between the ages of 1 and 14 years, found that vaccinated children had significantly fewer ARI episodes (2.2 vs 6.9, p<0.001) and asthma exacerbations (1.6 vs. 6.2, p<0.001), as well as less use of bronchodilators (1.6 vs 6.2, p>0.001) and systemic steroids (0.1 vs 1.1, p<0.001) (195). In the year following vaccination, these children also had fewer hospitalizations (0.2 vs 1.3, p<0.001) and shorter length of stay (5.3 vs 7.2, p<0.034) (195). Other studies have noted no benefit of influenza vaccination against asthma exacerbation among children (196, 197).  Several studies (198-200) indicate that vaccination does not appear to increase risk of asthma exacerbations.

Asthma exacerbations are commonly treated with systemic steroid medications, which may potentially interfere with immune responses.  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 (201).

A multi-center prospective cohort study of patients with COPD over the 2011-15 influenza seasons enrolling 4,198 patients estimated an overall adjusted VE against influenza-related hospitalizations to be 37.5% (95%CI 27, 46) (202). Estimates over the first 3 years of the study ranged between 43%-49%, though protection was significantly lower in the final year due to vaccine and circulating strain mismatch (aVE=6%; 95%CI -24, 28).  Some observational studies reported an association between influenza vaccination and lower all-cause mortality among persons with COPD (203, 204)

Cardiovascular Conditions

Limited influenza vaccine effectiveness data are available for children with cardiovascular conditions. In an analysis of data for individuals with high-risk conditions from a test-negative case-control study conducted over four seasons, only 8% of children aged <18 years presented with heart disease; an adjusted effectiveness estimate was not calculated due to the limited sample size (191).  Among adults with cardiovascular conditions, the same observational study reported an estimated vaccine effectiveness of 47% (95%CI 35, 58).

Some evidence suggests that acute respiratory infections might trigger atherosclerosis-related acute vascular events (205). Several studies have suggested protective efficacy of influenza vaccination against vascular events. In one randomized study, participants with known coronary artery disease who received IIV3 had 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 outcome including cardiovascular death, nonfatal MI, 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) (206, 207). A randomized placebo-controlled trial found a reduced risk of a composite cardiac ischemic event endpoint (including cardiovascular death, myocardial infarction, coronary revascularization or hospitalization for myocardial ischemia) one year after vaccination compared with placebo (HR=0.54; 95%CI 0.29, 0.99) (208); there was no reduction in risk for cardiovascular death alone or for a second composite endpoint which did not include hospitalization for myocardial ischemia. A third randomized study found association between vaccination and reduced risk of a composite endpoint including death, hospitalization for acute coronary syndrome, hospitalization for heart failure, and hospitalization for stroke at 12 months postrandomization (aHR=0.67; 95%CI 0.51, 0.86), but not cardiovascular death (0.62; 95%CI 0.34, 1.12) (209).  In a systematic review and meta-analysis including the studies described above, vaccination was effective at reducing or preventing 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 (210).

A retrospective study covering 13 influenza seasons found that among elderly adults, vaccination was associated with lower risk of hospitalization associated with diagnostic codes for MI (aOR=0.80; 95%CI 0.76, 0.84), and ischemic stroke (aOR=0.80; 95%CI 0.77, 0.82) (211). However, these data contrast with a more recent case series analysis which revealed an association between influenza and MI, and found that vaccination did not attenuate this increased risk (45).

Use of statin medications (a class of drugs commonly prescribed to persons with vascular disease) have been evaluated for potential associations with diminished response to influenza vaccine. 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 (GMTs) 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, and lovastatin) (212). A retrospective cohort study covering nine influenza seasons found reduced effectiveness of influenza vaccine against MAARI among statin users (213); however, this study did not evaluate confirmed influenza illness. In a population-based study of 3,285 adults aged 45 years and over covering the 2004-5 through 2014-15 influenza seasons, statin use was associated with lower vaccine effectiveness against LCI due to H3N2 viruses (vaccine effectiveness=45%; 95%CI 27, 59 for statin nonusers vs. -21%; 95%CI -84, 20 for statin users); statin use was not associated with lower vaccine effectiveness against H1N1pdm09 or B viruses (214).  In a large observational TND case-control study retrospectively including 11,692 participants aged ≥ 45 years who were enrolled over 6 influenza seasons (2011-2 through 2016-17),  overall vaccine effectiveness was 38% (95%CI 32, 44) (215), and was not meaningfully changed after adjustment for statin use.  Upon stratification, VE was estimated to be 36% (95%CI 22, 47) among statin users compared to 29% (95%CI 32, 45) among non-users.  Statin use alone was not significantly associated with decreased VE in analyses by viral type/subtype, and type of statin (synthetic or non-synthetic) did not have a significant effect on VE.

Neurologic and Neuromuscular Disorders

Among adults with neurologic disorders, a TND case-control study over four seasons reported effectiveness against LCI of 49% (95%CI 22, 66), which was similar to those without any high-risk conditions (44%; 95%CI 38, 50, p=0.30) (191).  No vaccine effectiveness estimate was reported for children, as there were few children with neurologic disorders in this sample.

 Renal Disorders

In a small study of pediatric patients with renal disease, seroconversion and seroprotection rates and changes in GMTs after vaccination were similar among those with chronic renal insufficiency, those on hemodialysis, and healthy controls (216). Among adults, studies have shown adequate immune responses among persons with chronic renal insufficiency on dialysis (217, 218).  In a four-season test-negative case-control study, estimated influenza vaccine effectiveness was 32% (95%CI -6, 57) among adults with renal diseases; though not statistically significant, this estimate did not differ significantly compared to healthy patients without any high-risk conditions (p=0.39) (191).  A systematic review and meta-analysis which reviewed 5 observational studies of patients with end-stage renal disease receiving dialysis reported adjusted effectiveness against all-cause mortality of 32% (95%CI 24, 39), against cardiac death of 16% (95%CI 2, 29), and against hospitalization due to influenza and pneumonia (VE=14%, 95%CI 7, 20) (219); evidence was judged to be of very low quality for all outcomes.

 Hepatic Disorders

Most available data concerning influenza vaccination of persons with hepatic conditions come from adult populations.  In a small prospective study among patients who either had cirrhosis or who were inactive carriers of hepatitis B, there were no significant differences in seroprotective response rates between these persons and healthy controls (220).  Similar results were observed in studies evaluating the immunogenicity of IIV3 among persons with cirrhosis, hepatitis B and hepatitis C (221, 222).  In a prospective study of 311 persons with cirrhosis, IIV3 reduced the rate of ILI (14% vs. 23%; p= 0.064) and of culture-positive influenza (2.3% vs. 8.8%; p= 0.009) in the vaccinated group when compared to healthy controls (223). Vaccination was also associated with reduced risk of hepatic decompensation (p=0.018).  A retrospective study of persons with chronic hepatitis B infection found lower rates of hospitalization among vaccinated individuals (16.29 vs. 24.02 per 1,000 person-years) (224). Among adults enrolled within a prospective TND study over the 2012-13 through 2015-16 influenza seasons, VE in outpatients with liver diseases was 61% (95%CI 31, 78) (191).

Metabolic Disorders and Diabetes

Studies of adults with diabetes have reported an association between vaccination and reduced risk of hospitalizations for acute respiratory illness, MI, congestive heart failure, stroke, or death (220, 225, 226).  However, studies using LCI outcomes are limited. A prospective TND study has reported significant influenza vaccine effectiveness against any LCI among outpatient adults with diabetes (aVE=46%, 95%CI 30, 58) (191).

Obesity

A prospective study 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 (227). A study comparing 1-month and 12-month post-vaccination immune response showed that obese persons mounted a vigorous initial antibody response to IIV3 (228); however, higher BMI was associated with a decline in influenza antibody titers after 12 months post-vaccination. A second study of older adults reported immunogenicity of IIV3 was similar in obese and normal-weight older adults, with a slight increase in seroconversion for the influenza A(H3N2) virus among those who were obese, but not for the other vaccine components (229).  In a non-randomized prospective study of a school-based vaccination program in the 2010-11 season, VE against PCR-confirmed influenza was 72.7% (95%CI 25.7, 90.0%) in obese children and 63.5% (95%CI 34.6, 79.6%) in non-obese children, though the difference was not statistically significant (230).

Autoimmune and Inflammatory Disorders

Literature evaluating the efficacy and effectiveness of the influenza vaccine among children with inflammatory diseases is limited.  Among analyses from studies of children with conditions such as rheumatic arthritis and inflammatory bowel disease, some suggest immune response to vaccine comparable to healthy controls while others suggest a diminished response, particularly among those on immunomodulatory therapy (231-235).  Some have noted less responsiveness to influenza B as compared with influenza A vaccine components.

Among adults with Crohn’s disease or ulcerative colitis, a prospective randomized comparison study found no significant difference in immune response to IIV4 between healthy controls and patients with inflammatory bowel disease, though immune response did vary based on drug therapy (patients were receiving immunomodulatory monotherapy, anti-tumor necrosis factor-α [anti-TNF-α] single-agent therapy, or some combination of the two at the time of vaccination) (236).  Immune response in the setting of rheumatoid arthritis may be diminished but is generally satisfactory (237-240), even when immunomodulatory agents are used, though decreases in antibody levels have been reported with increasing time post-vaccination (238).  One such study found timing of vaccination in relation to timing of immunotherapy, such as infliximab (anti-TNF-ɑ), had no effect on seroprotection (241). Another study, a prospective multicenter randomized clinical trial among adults with rheumatoid arthritis, found that more patients who took a 2-week pause/discontinuation from methotrexate therapy seroconverted to all four strains of the 2016-17 IIV4 than those who continued with routine therapy (75.5% vs 54.5%, p<0.001) (242).

Persons with Malignancies 

Predictors of successful seroconversion in children with cancer noted in some studies have included higher white cell count, lymphocyte count, IgG levels, increasing age, phase of therapy, and completion of therapy (243-249).  Immunogenicity was evaluated in a two season prospective cohort study of 259 children and young adults on chemotherapy (250). Of the 157 pre- and post-vaccination serologic samples, 62% seroresponded to at least one influenza A subtype post-vaccination. There was no statistically significant difference in the proportion of seroresponders compared to non-seroresponders with RT-PCR confirmed influenza or ILI (11% vs. 19%, respectively).  However, the study was not powered to detect a difference in this outcome. Additional analysis of predictors failed to show any significant relationship between cancer type and seroresponse (stratified as acute lymphoblastic leukemia vs solid/brain tumors) or vaccination during chemotherapy treatment and seroresponse.

In a retrospective review of 498 patient-seasons occurring between the 2010-2011 and 2012-2013 influenza seasons, there was no significant difference in the overall rates of influenza between children with acute leukemia who had been appropriately vaccinated and those who had not in any individual season (251). There was also no significant difference in the rate of ILI between vaccinated and unvaccinated patients overall or in any individual season, suggesting IIV3 did not protect children with acute leukemia against LCI or ILI.  In a prospective study of 100 children and adolescents aged 6 months through 18 years who were within 4 weeks of receiving or completing immunosuppressive therapy for cancer, the infection occurred among 2% among the vaccinated cases (n=2/100), compared to 6.8% among the unvaccinated community controls (n=11/161); adjusted for age group and tumor type, VE against LCI was 72% (95%CI −26, 94)(243).

A case-control study of adults with malignant lymphoma found that 10% of the 29 subjects in the group with lymphoma were able to mount a 4-fold increase in titer to one of the influenza A vaccine antigens, compared to 45% of the control group (n=29). Among the those with lymphoma, none responded to both A and B antigens, whereas 24% (n=7) age-matched controls had a 4-fold titer to both A and B antigens contained in the vaccine (252).  In a systematic review of 16 studies measuring the serological response and clinical outcomes of patients with solid cancer or hematologic malignancies after influenza vaccination, decreased rates of seroconversion were reported among those receiving chemotherapy compared to those not receiving chemotherapy, though protective HAI antibody titers were still achieved among those receiving chemotherapy (253).

One study compared adjuvanted IIV3 with unadjuvanted IIV3 among 67 allogeneic hematopoetic stem cell transplant recipients, and found seroconversion rates were not significantly higher with the adjuvanted vaccine (254).  In a randomized double-blind study comping immunogenicity and safety of HD-IIV3 and SD-IIV3 among allogenic hematopoetic stem cell transplant recipients, post-vaccination GMTs were higher in the high-dose group for influenza A(H1N1) and influenza A(H3N2) (p=0.45 and p=0.004, respectively) (255). Also, HD IIV3 had a significantly higher percentage of individuals with titers ≥40 against the A/H3N2 vaccine component. Both the HD and adjuvanted vaccines are currently only licensed for use in persons ≥65 years of age within the US.

Persons with compromised immunity due to congenital immunodeficiencies, HIV infection, or medications are potentially at an increased risk of influenza-associated complications.  However, the conditions that result in immune compromise are heterogeneous, and susceptibility to influenza and its complications and responsiveness to vaccination may vary with the specific disease state and its severity in a given individual.  Among enrollees within a test-negative case-control study over the 2012-16 influenza seasons, adjusted vaccine effectiveness against LCI among adults ≥ 18 years with immunosuppressive conditions as a group (defined by the presence of medical encounters with ICD-10 diagnostic codes) was estimated to be 46% (95%CI 26, 60) (191). By virus type, vaccine effectiveness was significant against influenza A(H3N2) (47%; 95%CI 24, 68) and influenza B (49%; 95%CI 9, 71), but not against influenza A(H1N1) (34%; 95%CI -14, 61) (191).

HIV-infected persons with minimal AIDS-related symptoms and normal or near-normal CD4+ T lymphocyte cell counts who receive IIV have been shown to develop adequate antibody responses (256, 257).  Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, IIV might not induce protective antibody titers (256, 258); a second dose of vaccine might not improve immune response (258, 259).  In a randomized study comparing the immunogenicity of high-dose versus standard-dose IIV3 among HIV-infected adults (10% of whom had CD4 counts under 200 cells/µL), seroprotection rates were higher in the high-dose group for all three viruses (260). However, in a comparative study of 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 (261).

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 (262). In a randomized study conducted among 506 HIV-infected adults, (349 on antiretroviral treatment and 157 treatment-naïve) efficacy of IIV3 against LCI was 75% (95%CI 9, 96) (263).  In a randomized study of a two-dose regimen of IIV3 versus placebo conducted among 410 children aged 6-59 months (92% receiving ART), and estimated vaccine efficacy was 18% (95%CI 0, 62).  The authors suggested that poor immunogenicity and drift of the circulating A(H3N2) viruses might have contributed to the poor vaccine efficacy observed in this study (264).

Observational studies suggest that immunogenicity among persons with solid organ transplants varies according to factors such as transplant type, time from transplant, and immunosuppressive regimen (265).  In a study of pediatric liver transplant patients, one month after vaccination, the majority of patients had seroprotective levels of antibody against all strains of vaccine antigens (67%, 56% and 56% against A/H3N2, A/H1N1 and B respectively) (266). Predictors of seroprotection included age and time since transplantation.

Among persons who have undergone kidney transplantation, seroresponse rates have been observed that were similar or slightly reduced compared with healthy persons (267-271). Antibody response among persons who were 6 months post kidney transplant were lower than observed for healthy controls in one prospective study (269). In another, among persons 3–10 years post- kidney transplant, the postvaccination seroprotection rate was 93% to A(H1N1) (270).  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 (aHR=0.82; 95%CI 0.76, 0.89; p<0.001) in one study (272).

A study which compared antibody response to IIV3 among liver transplant recipients (on average, 3 years post-transplant), persons with cirrhosis, and cirrhosis, and healthy controls, noted significantly lower post-vaccination titers among the transplant recipients compared with controls (273).  However, titers ≥1:40 were noted in 68% of transplant recipients after 1 dose of IIV3.  Another study noted seroprotection rates were lower if vaccination occurred within the four months after the transplant procedure (274).

In a prospective observational study which compared immune response to IIV3 and 23-valent pneumococcal vaccine among and of 16 persons who were one year post-heart transplant vs. healthy controls, response to IIV3 was significantly reduced in transplant recipients though approximately 50% of patients had seroprotection against two of the three vaccine antigens. Immune response among transplant recipients to each vaccine strain was significantly lower compared to controls; furthermore, following additional booster vaccination 4 weeks after the initial dose, antiviral titers in transplant patients remained nearly identical 4 weeks after initial vaccination, and 8 weeks after booster injection (275). This finding contrasts with that from an additional randomized controlled trial comparing multiple doses of IIV3 among persons who had received various solid organ transplants (kidney, liver, heart, and lung), which found seroprotection rates were higher at 10 weeks post-vaccination among those who received two doses, but did not have a significantly lasting effect one year post-vaccination (276).

High-dose IIV3 was more immunogenic than standard-dose IIV3 in a randomized trial in 161 adult solid organ transplant recipients (277). In a comparison of the immunogenicity of adjuvanted IIV3 with unadjuvanted IIV3 among 67 allogeneic hematopoietic stem cell transplant recipients, seroconversion rates were not significantly higher with the adjuvanted vaccine (254).  Both of these vaccines are currently only licensed for use in persons ≥65 years of age.

RIV was initially licensed as the trivalent vaccine, Flublok (RIV3, Protein Sciences, Meriden, Connecticut). A quadrivalent formulation, Flublok Quadrivalent, was licensed in 2016 (RIV4; now produced by Sanofi Pasteur, Swiftwater, Pennsylvania). For the 2018-19 season, only RIV4 will be available in the U.S.  RIV4 contains 45 µg of HA protein per vaccine virus component (180 µg total). The HA proteins are produced via the introduction of the genetic sequence for the HA into an insect cell line (Spodoptera frugiperda) via a baculovirus viral vector. This process uses neither live influenza viruses nor eggs (124).

As a relatively new type of influenza vaccine, fewer post-marketing effectiveness data are available for RIVs than IIVs. Initial licensure of RIV3 was for persons aged 18 through 49 years. In pre-licensure studies comparing RIV3 versus placebo among persons aged 18 through 49 years, serum antibody responses were induced to all three vaccine components (278). In a randomized placebo-controlled study conducted among healthy persons aged 18 through 49 years during the 2007–08 influenza season (124, 279), 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. Of note, more precise estimation of vaccine effectiveness against matched strains was not possible because 96% of isolates in this study did not antigenically match the strains represented in the vaccine (124). Estimated vaccine effectiveness without regard to match was 44.6% (95%CI 18.8, 62.6) (279).

In October 2014, the approved age indication for RIV3 was expanded to ≥18 years on the basis of data from randomized trials demonstrating adequate immunogenicity among persons aged ≥50 years (280, 281). More recently, a pre-licensure randomized controlled trial of RIV4 vs. a licensed comparator IIV4 was performed among persons aged ≥50 years during the 2014-15 season (282, 283). This study is discussed in a later section (see HD-IIV3, aIIV3, and RIV4 for Older Adults). The immunogenicity of RIV4 was comparable with that of a licensed comparator IIV4 among 18 through 49-year-olds in a randomized trial (284).  When evaluated in children 6 through 59 months of age, RIV3 was found be safe but less immunogenic than comparable volumes of IIV3, particularly among children <36 months of age (285). RIV4 is not licensed for children <18 years of age.

Given the high risk of severe influenza illness and lesser benefit of vaccination among older adults, substantial efforts have gone toward the development and study of new influenza vaccines intended to provide better immunity in this age group.  Vaccines recently licensed specifically for persons aged ≥65 years include high-dose IIV3 (HD-IIV3; Fluzone High-Dose) and adjuvanted IIV3 (aIIV3; Fluad). In recent years, studies have been conducted comparing the benefits for older adults of these vaccines, as well as for quadrivalent recombinant influenza vaccine (RIV4; Flublok Quadrivalent), with those conferred by standard-dose, unadjuvanted IIVs (SD-IIVs).  Some have been studies of LCI-related outcomes (Table). For each of these vaccines, there is at least some evidence of benefit as compared with SD-IIVs. However, there are currently no published studies comparing these HD-IIV3, aIIV3, and RIV4 directly to one another against LCI-associated outcomes among older adults.

The only 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 (180 µg total), four times the amount of HA in standard-dose IIVs (286). Licensure was based on superior immunogenicity compared with standard-dose IIV3 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 (287-289). In pre-licensure studies, pre-specified criteria for superiority (defined by a lower bound of the 95%CI for the ratio of geometric mean HAI 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%) were met for influenza A(H1N1) and influenza A(H3N2) virus antigens, but not for the influenza B virus antigen (for which criteria for non-inferiority were met) (288, 290).

Superior efficacy of Fluzone High-Dose compared to Fluzone SD-IIV3 was demonstrated in a large randomized comparative efficacy trial conducted among nearly 32,000 persons aged ≥65 years over the 2011–12 and 2012–13 influenza seasons (291). The primary endpoint of this study was efficacy of HD-IIV3 relative to SD-IIV3 in preventing culture- or RT-PCR-confirmed influenza caused by any influenza viral types or subtypes, and associated with protocol-defined ILI. Protocol-defined ILI was specified as occurrence of at least one respiratory symptom (sore throat, cough, sputum production, wheezing, or difficulty breathing) concurrent with at least one systemic symptom (temperature >99.0°F, chills, tiredness, headaches or myalgia). For this outcome, the study reported 24.2% (95%CI 9.7, 36.5) greater relative efficacy of the HD-IIV3 compared to SD-IIV3 for protection against LCI caused by any viral type or subtype. The pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95%CI of vaccine efficacy of Fluzone High-Dose relative to Fluzone >9.1%) was met (286). For a secondary outcome, prevention of culture-confirmed influenza caused by viral types/subtypes similar to those contained in the vaccine and associated with modified CDC-defined ILI (temperature >99°F with cough or sore throat), the relative efficacy of HD-IIV3 vs. SD-IIV3 was 51.1% (95%CI 16.8, 72.0) (291).  While this study did not initially examine health care utilization, pneumonia, and deaths confirmed to be due to influenza; a subsequent analysis of these data examined all-cause hospitalizations, deaths, and pneumonia cases judged to be related to influenza.   In this analysis, in which serious adverse events (SAEs) from the study were evaluated for possible relatedness to influenza illness by blinded physician reviewers, HD-IIV3 was associated with a relative vaccine efficacy of 39.8% (95%CI 19.3, 55.1) for serious pneumonia and 17.7% (95%CI 6.6, 27.4) for serious cardiopulmonary events possibly related to influenza; relative efficacy against all-cause hospitalizations was lower (6.9%, 95%CI 0.5, 12.8) (292).

In addition to the analyses of clinical outcomes described above, healthcare consumption data derived from this trial were used to perform a cost-effectiveness analysis (293). Mean participant medical costs in the study were lower among those who received HD-IIV3 ($1376.52) than those who received SD-IIV3 ($1492.64; difference=-115.62; 95%CI -264.18, 35.48). Mean societal costs were also lower among the HD-IIV3 participants ($1506.48 vs. $1634.50; difference=-128.02; 95%CI -286.89, 33.30). A probabilistic sensitivity analysis indicated that the HD-IIV3 is 93% likely to be cost saving relative to SD-IIV3.

A cluster-randomized trial conducted during the 2013-14 season among residents of 823 U.S. nursing homes (409 facilities in which residents received HD-IIV3 and 414 in which they received SD-IIV3) evaluated the risk of hospital admissions related to pulmonary or influenza-like illnesses (294). The nursing home facilities included 75,917 residents aged 65 years and older, 53,008 of whom were considered long-stay residents. Outcomes were identified via Medicare hospital claims data, which were matched to 38,256 residents. The incidence of respiratory-related admissions was significantly lower among the facilities randomized to HD-IIV3 (adjusted relative risk [aRR]=0.873; 95%CI 0.776, 0.982). Also significantly lower were rates for pneumonia admissions (aRR=0.791; 95%CI 0.267, 0.953), and all-cause hospital admissions (aRR=0.915; 95%CI 0.863, 0.970).

An observational study conducted during the 2010-11 season among patients aged ≥65 years receiving primary care at Veterans Health Administration medical centers noted no significant differences in effectiveness of HD-IIV3 vs. SD-IIV3 for hospitalizations with a discharge diagnosis for influenza or pneumonia. Receipt of HD-IIV3 was also not associated with lower rates of all-cause hospitalization.  However, for the subset of participants aged ≥85 years, receipt of HD-IIV3 was associated with lower risk of hospitalization for pneumonia and influenza (risk ratio=0.52; 95%CI 0.29, 0.9) (295).  In a retrospective cohort study of Veterans Health Administration patients during the 2015-16 season, HD-IIV3 was associated with a relative effectiveness of 25% (95%CI 2, 43%) for pneumonia/influenza hospitalizations compared to SD-IIV3.  Relative effectiveness against laboratory-confirmed influenza was 38% (95%CI -5, 65%) (296).

HD-IIV3 has also been evaluated among persons aged ≥65 years through analysis of Medicare data. Among 929,730 HD-IIV3 recipients and 1,615,545 SD-IIV3 recipients during the 2012-13 season, receipt of HD-IIVs was associated with fewer non-laboratory confirmed but probable influenza infections (defined as receipt of a rapid influenza diagnostic test followed by a prescription for oseltamivir, relative VE=22%; 95%CI 15, 29) and hospital admissions with a billing code for influenza (relative VE=22%; 95%CI 16, 27) (297). In an analysis of Medicare data from the 2012-13 and 2013-14 seasons (including 1,039,645 recipients of HD-IIV and 1,683,264 recipients of SD-IIV during 2012–13, and 1,508,176 HD-IIV and 1,877,327 SD-IIV recipients during 2013–14), receipt of HD-IIV3 was associated with reduced risk of death relative to SD-IIV3 during the 2012-13 season (36.4%; 95%CI 9.0%, 56%), when A(H3N2) viruses predominated; but not during the 2013-14 season (2.5%; 95%CI –47%, 35%], in which A(H1N1) viruses predominated (298).

The only adjuvanted influenza vaccine in the U.S., Fluad (aIIV3; Seqirus, Holly Springs, North Carolina), was initially licensed in the U.S. in November 2015. It contains the oil-in-water adjuvant, MF59 (299). Like HD-IIV3, it is licensed specifically for persons aged ≥65 years.  Several studies have compared aIIV3 with SD-IIV3; however, fewer data are available than for HD-IIV3, and there have been no randomized trials of relative efficacy against LCI among older adults. In a comparison of immunogenicity of aIIV3 and unadjuvanted IIV3, aIIV3 met criteria for non-inferiority for all three vaccine viruses based on predefined thresholds for seroconversion rate differences and GMT ratios; criteria for superiority were not met (299, 300). A Canadian observational study of 282 persons aged ≥65 years (165 receiving aIIV3, 62 receiving SD-IIV3, and 55 unvaccinated) conducted during the 2011–12 season that compared Fluad with unadjuvanted IIV3 reported an estimated relative effectiveness of Fluad against LCI among the 227 vaccinated participants of 63% (95%CI 4, 86) (301). Some differences in the populations receiving each vaccine were described (in two of three health authorities participating, persons aged 75 years and older and those in long-term care facilities were preferentially given aIIV3; in the third, those in long term care facilities received aIIV3 and all others received SD-IIV3). A prospective study of 107,661 medical records covering 170,988 person-seasons during the 2006-07 through 2008-09 influenza seasons reported lower relative risk of hospitalizations coded for influenza and pneumonia among persons aged 65 years and older who received aIIV3 as compared with IIV3 (relative risk=0.75; 95%CI 0.57, 0.98) (302). An observational study conducted in Italy during the 2010-11 and 2011-12 seasons, in which unadjuvanted SD-IIV3 was used during the first season and aIIV3 during the second season, reported that aIIV3 was more effective in preventing hospitalizations coded for pneumonia and influenza (not LCI) among recipients aged ≥75 years (adjusted VE=53%; 95%CI 33, 68 for aIIV3 vs. adjusted VE=46%; 95%CI 24, 62 for IIV3), while unadjuvanted SD-IIV3 was more protective than aIIV3 for recipients aged 65 through 74 years (adjusted VE=53%; 95%CI 3, 78 for IIV3 vs. adjusted VE=34%; 95%CI 24, 65) (303). That the two vaccines were not compared during the same season is a limitation of this study.

Flublok Quadrivalent (RIV4; Sanofi Pasteur, Swiftwater, Pennsylvania) is licensed for persons aged ≥18 years. Fewer data are available concerning the relative effectiveness of RIV4 compared with other licensed vaccines for this age group than is currently the case for HD-IIV3. In a study comparing RIV3 with IIV3 among persons aged ≥65 years, seroconversion rates against influenza A(H1N1) and A(H3N2) were higher in the RIV3 group. Response was inferior for influenza B; however, this result is difficult to interpret as the B antigens were different in the two vaccines (281). In a pre-licensure randomized controlled trial of Flublok Quadrivalent vs. IIV4 among 8,604 persons aged ≥50 years during the 2014-15 season, RIV4 was more effective in prevention of LCI than IIV4, with a relative efficacy of 30% (95%CI 10, 47). This season was characterized by a predominance of drifted A(H3N2) viruses, and consequent poor match between vaccine and circulating viruses (283, 304).  While the study was not powered for statistical significance for relative efficacy by influenza virus type or subtype, results showed a trend towards non-inferior relative efficacy for Flublok Quadrivalent against influenza A, but not against influenza B (for which there were fewer cases). Relative efficacy for all A(H3N2) was 36% (95%CI 14, 53) and for influenza B was 4% (95%CI -72, 46). The RIV4 influenza B antigens were well matched to circulating strains. In a subanalysis of data from those aged ≥65 years against all influenza A and B, RIV4 was not significantly more effective than IIV4 against RT-PCR-confirmed protocol-defined ILI (relative efficacy=17%; 95%CI -20, 43), but was more effective than IIV4 against culture-confirmed protocol-defined ILI (relative efficacy=42%; 95%CI 9, 65).

LAIV contains live influenza viruses which replicate in the nasopharynx following intranasal administration. Each season, the vaccine viruses are produced via genetic reassortment from a master strain that includes genes conferring three phenotypic characteristics: attenuation (to restrict reactogenicity and pathogenicity), temperature sensitivity (to restrict replication in the lower respiratory tract), and cold adaptation (to permit replication in the nasopharynx) (305).  Intranasal administration of LAIV appears to induce both serum and nasal secretory antibodies, as well as cell-mediated immune responses, but antibody response is not a reliable correlate of protection (306).

LAIV3 (FluMist; AstraZeneca/MedImmune, Gaithersburg, Maryland) was licensed in the United States in 2003. The humoral immunogenicity of LAIV was demonstrated in a number of studies (307–309). Subsequently, LAIV4 (FluMist Quadrivalent) was licensed in 2012, and replaced LAIV3 beginning with the 2013–14 season. Pre-licensure studies comparing HAI antibody responses following LAIV4 to LAIV3 demonstrated noninferiority of LAIV4 among healthy children and adults ≤49 years (310, 311).

In a large randomized, double-blind, placebo-controlled trial among 1,602 healthy children aged 15–71 months conducted during 1996-97 and 1997-98, LAIV3 demonstrated efficacy against culture-confirmed influenza (312, 313). During the first season, when vaccine and circulating virus strains were well matched, efficacy was 94% (95%CI 88, 97) for participants who received 2 doses separated by >6 weeks, and 89% (95%CI 65, 96) for those who received 1 dose (312). During the second season, when the A(H3N2) component in the vaccine was not well matched with circulating viruses, 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) (313). 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 and 73.5% (95%CI 63.6, 81) after 2 doses during the first year of the study (314).  In the second year, VE estimates following a single dose were 73.6% (33.3, 91.2) and 65.2% (31.2,88.8) among those who had received 2 doses, or 1 dose, respectively, during the first year. Other two-season, randomized, placebo-controlled trials have demonstrated similar efficacy rates of LAIV3 among young children (315, 316).

Other studies have noted protection from outcomes other than LCI with LAIV3 use. In a 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 (317). Receipt of LAIV3 resulted in 21% fewer febrile illnesses (95%CI 11, 30) and 30% fewer febrile otitis media diagnoses (95%CI 18, 45) in a randomized controlled trial (312). 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) (318).

A randomized, double-blind, placebo-controlled trial of LAIV3 effectiveness among 4,561 healthy working adults aged 18 through 64 years conducted during the 1997–98 influenza season (when the vaccine and circulating A(H3N2) viruses were not well matched) noted no significant decrease in the frequency of febrile illnesses among LAIV3 recipients compared with placebo. However, vaccine recipients had an 18.8% reduction in severe febrile illnesses (95%CI 7.4, 28.8), and a 23.6% reduction in febrile upper respiratory tract illnesses (95%CI 12.7, 33.2); as well as 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 (319). Estimated efficacy of LAIV3 against influenza confirmed by culture or RT-PCR in a randomized, placebo-controlled study among 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 (320-322).

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 (320-325). 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 (326).

Several studies, comparing LAIV3 with IIV3 prior to the 2009 pandemic demonstrated superior efficacy of LAIV3 against LCI among young children (323, 327-330).  A randomized controlled trial conducted among 7,852 children aged 6–59 months during the 2004–05 influenza season demonstrated a 54.9% reduction (95%CI 45.4, 62.9) in cases of culture-confirmed influenza among children who received LAIV3 compared with those who received IIV3. In this study, LAIV3 efficacy was higher compared with IIV3 against antigenically drifted viruses and well-matched viruses (328). LAIV3 provided 31.9% relative efficacy (95%CI 1.1, 53.5) in preventing culture-confirmed influenza compared with IIV3 in one study conducted among children aged ≥6 years and adolescents with asthma (329) and 52.4% relative efficacy (95%CI 24.6, 70.5) compared with IIV3 among children aged 6–71 months with recurrent respiratory tract infections (327).

In June 2014, on the basis of the data from two randomized comparative trials of LAIV3 vs. IIV3 among healthy children, the ACIP made a preferential recommendation for LAIV3 for healthy children aged 2 through 8 years who have no contraindications or precautions (331). However, subsequent 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 no statistically significant effectiveness of LAIV4 against influenza A(H1N1)pdm09 among children aged 2 through 17 years (332-334). 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) (335). During the 2014-15 season, when antigenically drifted A(H3N2) viruses predominated, neither LAIV4 nor IIV provided significant protection among U.S. children aged 2 through 17 years; LAIV4 did not offer greater protection than IIV for these viruses (336-338), in contrast to earlier studies in which LAIV3 provided better protection than LAIV against drifted H3N2 viruses (328). LAIV4 exhibited significant effectiveness against circulating influenza B viruses in these U.S. studies. Based on these influenza vaccine effectiveness data for the 2013–14 and 2014–15 seasons, the ACIP concluded that a preference of LAIV4 over IIV was no longer warranted (339).

The diminished effectiveness of LAIV4 against A(H1N1)pdm09 during the 2013-14 season 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 (340). Exposure during U.S. distribution of some LAIV lots to temperatures above those recommended for storage was also considered a potential contributing factor (341). This led to development and inclusion of a different influenza A(H1N1)pdm09 virus, A/Bolivia/559/2013(H1N1), in LAIV4 for 2015-16 (342).  A(H1N1)pdm09 viruses were again predominant during this season.  However, data from the U.S. Flu VE Network, U.S. Department of Defense, and MedImmune demonstrated no statistically significant effectiveness of LAIV4 among children aged 2 through 17 years against A(H1N1)pdm09 (343). 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, the ACIP made the interim recommendation that LAIV4 should not be used for the 2016–17 influenza season (344). This recommendation was extended into the 2017-18 season (345).

Estimates of the effectiveness of LAIV against A(H1N1)pdm09 during the 2013-14 and 2015-16 seasons were not consistent among all studies and all countries. While most estimates were statistically insignificant, point estimates varied. In the United Kingdom, estimated effectiveness of LAIV4 among 2 through 17 year olds during the 2015-16 season was 57.6% (95%CI 25.1, 76.0) for all influenza, 41.5% (95%CI -8.5, 68.5) for A(H1N1)pdm09, and 81.4% (95%CI 39.6, 94.3) against influenza B (346). In Finland during the 2015-16 season, effectiveness of LAIV4 among 2-year-olds was 50.7% (95%CI 28.4, 66.1) against all influenza, 47.9% (95%CI 21.6, 65.4) for influenza A (presumably predominantly H1N1pdm09), and 57.2% (95%CI 0.0, 81.7) for influenza B (347). In addition to the different age group under study (2 year olds vs. 2 through 17 year olds), these results contrast with those of the U.S. and the United Kingdom, in that the estimate for influenza A is statistically significant, whereas that for influenza B is not (and has a lower point estimate). In both the United Kingdom and Finland, as in the U.S., the point estimates for effectiveness of LAIV against H1N1pdm09 were lower for LAIV than for IIV.

In Canada, data collected with the Sentinel Provider Site Surveillance Network (SPSN) for both 2013-14 and 2015-16 showed similar point estimates for effectiveness against A(H1N1)pdm09 for LAIV (LAIV3 in 2013-14 and LAIV4 in 2015-16) and IIV; however, the estimate for LAIV in each case was not statistically significant (likely due to the small sample size in these analyses)  (348).  Two other Canadian studies, a cluster-randomized comparative trial of LAIV3 and IIV3 conducted among Hutterite populations in Alberta and Saskatchewan during the 2012-13 through 2013-14 seasons (349) and a test-negative case-control study comparing LAIV and IIV conducted in Alberta during the 2012-13 through 2015-16 seasons (350), showed no overall difference in effectiveness between the two vaccine types.  The Canadian National Advisory Committee on Immunization (NACI) concluded that for the 2016-17 season, the Canadian preference of the use of LAIV for 2 through 17 year olds was no longer supported by the available data (351).

The mechanism for the decreased effectiveness of LAIV4 against A(H1N1)pdm09 that was observed during 2013-14 and 2015-16 has been the subject of considerable investigation. Vaccine virus interference associated with the introduction of the fourth virus in LAIV has been cited as a potential contributing factor. However, reduced effectiveness against influenza A(H1N1)pdm09 was also noted with LAIV3 in the U.S. during 2010-11 (335). It has also been hypothesized that differences in prior vaccine coverage among children may contribute to differences in replicative fitness in different populations, leading to differences in effectiveness. However, analyses of U.S. data from the US Flu VE Network revealed no significant effect of prior vaccination (335). Investigations by the manufacturer, presented to the ACIP in February (352) and October 2017 (353), revealed reduced replicative fitness of both the A/California/7/2009 and A/Bolivia/559/2013 (H1N1) LAIV viruses, which is currently accepted as the primary root cause of poor effectiveness against circulating H1N1pdm09 influenza viruses (354).

In February 2018, the manufacturer presented data to ACIP from a US pediatric shedding and immunogenicity study of a new LAIV4 A(H1N1)pdm09-like virus, A/Slovenia/2903/2015. This study was conducted among 200 children aged 2 through <4 years, assigned 1:1:1 to receive LAIV3 containing A/Bolivia/559/2013, LAIV4 containing A/Bolivia/559/2013, or LAIV4 containing A/Slovenia/2903/2015. A/Slovenia/2903/2015 was shed by a higher proportion of children during days 4 through 7 following the first dose of vaccine than the comparator A(H1N1)pdm09-like viruses. A/Slovenia/2903/2015 also induced significantly higher antibody responses than A/Bolivia/559/2013. Seroconversion rates to A/Slovenia/2903/2015 were comparable to seroconversion rates obtained in response to pre-pandemic A(H1N1) LAIV strains used during seasons in which the vaccine was observed to be effective against A(H1N1) viruses (355).  Additional data discussed at ACIP included a combined individual patient-level data analysis of the effectiveness of LAIV4 and IIV during the 2013-14 through 2015-16 seasons, using data pooled from 5 US observational studies, and a systematic review and meta-analysis of LAIV effectiveness for the 2010-11 through 2016-17 seasons, which included data from within and outside the US (355). These analyses of previous seasons’ data revealed that while LAIV4 was poorly effective or ineffective against influenza A(H1N1)pdm09 viruses in most studies, it generally was effective against influenza B viruses, and generally no less effective than IIV against influenza A(H3N2) viruses.

For the 2018-19 and 2019-20 U.S. influenza seasons, ACIP has again recommended that LAIV4 was an acceptable option for vaccination of persons for whom it is appropriate.  No U.S. effectiveness estimates are available for the 2018-19 season, during which the vaccine contained A/Slovenia/2903/2015 as the influenza A(H1N1)pdm09 component.

The composition of influenza vaccines changes in most seasons, with one or more vaccine viruses replaced annually to provide protection against viruses that are anticipated to circulate. Even in seasons in which vaccine composition does not change, annual vaccination has been recommended because of decline in protective antibodies over time post-vaccination (356-358).  Observed rates and degrees of decline have varied. One study of HA and NA antibody levels following vaccination of adults noted a slow decline, with an estimated time to 2-fold decline of >600 days (359). A review of studies reporting post-vaccination seroprotection rates among adults aged ≥60 years noted that seroprotection levels meeting the Canadian Committee of Proprietary Medicinal Products standards were maintained for ≥4 months for the H3N2 component in all 8 studies and for the H1N1 and B components in 5 of 7 studies (360).

Nonetheless, concerns have arisen regarding waning of protection within the course of a single influenza season, particularly among adults. Recent observational studies have evaluated changes in influenza vaccine effectiveness over the course of a single influenza season. Some have noted decline in vaccine effectiveness over the course of a season (361-370).  In some studies this effect has been more pronounced for influenza A(H3N2) than influenza A(H1N1) and influenza B viruses, and among older adults.  A test negative case-control study of children and adults conducted in Navarre, Spain during the 2011–12 season noted a decline in vaccine effectiveness, from 61% (95%CI 5, 84) in the first 100 days after vaccination to 42% (95%CI -39, 75) between days 100–119 and then to -35% (95%CI -211, 41) after ≥120 days. Being vaccinated >120 days before diagnosis was associated with increased risk for influenza, compared with vaccinated <100 days prior (OR=3.45; 95%CI 1.10, 10.85; p = 0.034). This effect was most pronounced among persons aged ≥65 years, among whom the OR for influenza was 20.81 (95%CI 2.14, 202.71; p = 0.009) for persons vaccinated >120 days before diagnosis versus those vaccinated <100 days before diagnosis (362). A similar study conducted in the United Kingdom, also during the 2011–12 season, estimated an overall vaccine effectiveness against A(H3N2) of 53% (95%CI 0, 78) among those vaccinated <3 months prior, and 12% (95%CI -31, 41) for those vaccinated ≥3 months prior. The proportion of older participants was too small to detect a substantial difference in vaccine effectiveness in this age group (364). An additional case-control analysis from the 2007–08 season revealed a modest but significant increase in the OR for A(H3N2) influenza every 14 days after vaccination among young children (OR for influenza increasing 1.2 for each 14-day interval for children aged 2 years) and older adults (1.3 for each 14-day interval for adults aged 75 years). This pattern was not observed among older children and younger adults (361).

In addition to the single-season studies above, several multi-season studies have noted intra-season waning of influenza vaccine effectiveness (366-368, 371, 372).  A multi-season (2011-12 through 2014-15) analysis from Spain noted that persons aged ≥65 years who were vaccinated later in the season had a lower risk of hospital admission for influenza than those who were vaccinated earlier in the season (366).  An analysis of the 2011-12 through 2014-15 seasons from the U.S. Flu VE Network found that vaccine effectiveness declined by about 7% per month for H3N2 and influenza B, and 6—11% per month for H1N1pdm09. Vaccine effectiveness remained greater than zero for at least five to six months after vaccination (371). In an analysis of data from a European multicenter study covering the 2010-11 through 2014-15 seasons, vaccine effectiveness against influenza A(H3N2) viruses declined from 50.6% (95%CI 30.0, 61.1) 38 days after vaccination to 0% (95%CI -18.1, 15.2) 111 days after vaccination.  For influenza B viruses, vaccine effectiveness declined from 70.7% (95%CI 51.3, 82.5) 44 days post-vaccination to 24.1% (95%CI -57.4, 60.8) by the end of the season.  Vaccine effectiveness for influenza A(H1N1) viruses remained relatively stable, from 55.3% (95%CI 37.9, 67.9)  at day 54 to 50.3 (95%CI 34.8, 62.1%) at the end of the season (368).  In a multi-season (2010-11 through 2013-14) study of US Department of Defense non-active duty beneficiaries, vaccine effectiveness against all influenza and against influenza A(H3N2) viruses was statistically significant and comparable at 15-90 days and 91-180 days after vaccination, though was insignificant from 181 days onwards.  Vaccine effectiveness against influenza B viruses was no longer significant by 91 days post-vaccination (367).

Overall, waning effects have not been observed consistently across age groups and virus subtypes in different populations, and the observed decline in protection could be attributable to bias, unmeasured confounding, or the late season emergence of antigenic drift variants that are less well-matched to the vaccine strain.  Nonetheless, these findings raise considerations for timing of vaccination.  Delaying timing of vaccination may be beneficial in some seasons, but this is dependent upon the presence and rate of decline in immunity (373).  This issue is complicated by the variability of the timing of onset of influenza activity each season, which precludes prediction of the optimal time to vaccinate this season.  The potential negative effects of deferring vaccination until later in the season, such as missed opportunities to vaccinate, programmatic issues associated with vaccinating a defined population in a more constrained time period, and vaccinating after the start of influenza circulation, are also important considerations (374).

Observations of a potential negative effect of repeat vaccination on vaccine effectiveness were initially made during the 1970s (375-378). A number of recent studies have indicated that response to, and effectiveness of, influenza vaccine during any given season may be modified by receipt of vaccine in prior seasons. In a study conducted among healthy 30- through 60-year olds during the 1983-84 through 1987-88 seasons, during which whole-virus seasonal IIV3s were used (with the exception of addition of a monovalent split-virus A(H1N1) to supplement the trivalent vaccine in 1986), moderate reductions in serum antibody response during the last seasons of the study were associated with increased number of annual exposures to vaccine over the previous seasons.  However, no decrease in protection against infection was noted (379).

In more recent studies, decreased vaccine effectiveness associated with vaccination in the previous season has not been noted consistently (380-382). In a community-based study in Michigan conducted in 2010-11 (during which influenza A[H3N2] viruses predominated), overall vaccine effectiveness was low and not significant (31%; 95%CI -7, 55%). When stratified by whether vaccine had been received the previous season, vaccine effectiveness was lower in 2010-11 among those who had been vaccinated during both 2010-11 and 2009-10 (-45%; 95%CI -226, 35), as compared with those who received vaccine during only the latter season (62%; 95%CI 17, 82%) (382). In a similarly designed study in the same community conducted during the 2013-14 season, when H1N1pdm09 predominated, no negative effect of prior season vaccination was observed (380). A study in Australia conducted over the 2010 through 2015 seasons noted no significant difference in effectiveness of hospitalization for influenza illness between those vaccinated in the current season only (35%; 95%CI 21, 46) vs the prior season only (33%; 95%CI 17, 47).  Vaccine effectiveness was highest among those who had received vaccine during both seasons (51%; 95%CI 45, 57) (381).

Other studies have evaluated vaccination history over more than one prior season. A case-control study conducted in a healthcare system in Wisconsin, examined VE against influenza A(H3N2) and influenza B viruses over eight seasons between 2004-05 and 2012-13.  Participants were classified as frequent vaccinees (had received IIV during 4 or 5 of the previous 5 seasons), infrequent vaccinees (received IIV during 1 to 3 of the previous 5 seasons) or nonvaccinees (received no IIV during the previous 5 seasons). Current season vaccination was effective regardless of previous vaccination history. Considering vaccination history for only current and prior seasons, effectiveness was similar for those who were vaccinated during the current season only, the previous season only, or both seasons. However, in an analysis using 5 seasons of vaccination history, there were significant differences in vaccine effectiveness among frequent vaccinees as compared with nonvaccinees (383). In a Spanish study which evaluated the effectiveness of vaccination against H1N1pdm09 from the 2010-11 through 2015-16 seasons, the highest effectiveness was seen among those who had received the current season vaccine and also had received 1-2 doses in earlier seasons.  Effectiveness was lower among those vaccinated in the current season after >2 prior doses (384).   Other multi-season studies, including a four-season (2011-12 through 2014-15) study in Canada (385) and a six-season (2011-12 through 2016-17) study in Sweden (386), did not find a negative impact of repeated vaccination on influenza vaccine effectiveness.

Systematic reviews of studies of repeated vaccination have reported somewhat varied findings.  A review of four randomized controlled trials of LAIV3 vs. placebo administered to a total of 6,090 children over 2 consecutive seasons found that VE against antigenically matched strains was highest for those who received LAIV3 for both seasons (VE=86.7%; 95%CI 76.8, 92.4).  In contrast, VE was lower for receipt of LAIV3 in season 2 only (VE=56.4%; 95%CI 37.0, 69.8) (387). A review of 20 observational studies of all vaccine types found a negative effect of vaccination in two consecutive seasons as compared with vaccination in the current season only for influenza A(H3N2) and influenza B viruses, but not for influenza A(H1N1)pdm09 viruses (388).  A review of studies conducted during the 2010-11 through 2014-15 seasons noted considerable heterogeneity in estimates of the effect of prior year vaccination. Negative effects were most pronounced for influenza A(H3N2) viruses during the 2014-15 season (378).  A larger review of studies conducted between the 1983-84 and 2016-17 seasons included 5 randomized controlled trials and 28 observational studies concluded that the reviewed evidence did not support a negative effect of revaccination over consecutive seasons, but also noted heterogeneity and imprecision in effect estimates (389).  Such variation might perhaps be expected given the variability of circulating viruses VE in different seasons, the large variety of different influenza vaccines available in different seasons and different geographic areas, and the different populations under study.  The authors note that the overall quality of the studies reviewed was very low, and that the possibility of reduced effectiveness could not be ruled out.

Negative effects of prior vaccination on VE have not been observed consistently across all studies and seasons, and may differ by influenza virus type or subtype. Better understanding of these effects is needed in order to guide recommendations. Importantly, in most studies in which a negative effect of prior vaccination was observed, vaccination during the current season (with or without prior season vaccination) was more protective than being unvaccinated in the current season.