31.2 Immune System Study Guide Answers
Oliver Parkes
Estimates of vaccine efficacy (i.e., prevention of illness among vaccinated persons enrolled in controlled clinical trials) and vaccine effectiveness (i.e., prevention of illness in vaccinated populations) of influenza vaccines depend on many factors, including the age and immunocompetence of the vaccine recipient, the degree of similarity between the viruses in the vaccine and those in circulation, study design, diagnostic testing measures, and the outcome being measured. Studies of influenza vaccine efficacy and effectiveness have used a variety of outcome measures, including the prevention of ILI, medically-attended acute respiratory illness (MAARI), LCI, P&I-associated hospitalizations or deaths, and prevention of seroconversion to circulating influenza virus strains. Efficacy or effectiveness estimates for more specific outcomes such as LCI typically are higher than for less specific outcomes such as MAARI because the causes of MAARI include infections with other pathogens that influenza vaccination would not be expected to prevent (105).
Randomized controlled trials that measure LCI virus infections (by viral culture or reverse transcription polymerase chain reaction [RT-PCR]) as the outcome provide the best and most persuasive evidence of vaccine efficacy, but such data are not available for all populations. Such studies are difficult to perform in populations for which influenza vaccination is already recommended. Observational studies, particularly those that compare non-influenza-specific outcomes among vaccinated populations to those among unvaccinated populations, are more subject to biases than studies using laboratory-confirmed outcomes. For example, an observational study that finds that influenza vaccination reduces overall mortality among elderly persons might be biased if healthier persons in the study are more likely to be vaccinated and thus less likely to die for any reason (106). Bias due to frailty (a characteristic which can be associated with both a lower likelihood of vaccination and increased likelihood of severe illness) is also a concern in observational studies(107). Observational studies that use a test-negative design (TND, in which all participants present with illness, and case/control status is assigned on the basis of influenza testing) might be less subject to frailty bias (108).
For studies assessing laboratory-confirmed outcomes, estimates of vaccine efficacy and effectiveness also might be affected by the specificity of the diagnostic tests used. A 2012 simulation study found that for each percentage point decrease in diagnostic test specificity for influenza virus infection, vaccine effectiveness would be underestimated by approximately 4% in classic case-control studies (109). In a simulation study which evaluated the effects of different values of influenza diagnostic test sensitivity and specificity on vaccine effectiveness estimates from cohort, classic case-control, and test-negative designs, it was concluded that misclassification of case/control status resulted in slightly more biased VE estimates for test-negative studies than for other designs. However, the degree of bias was not thought to be meaningful when realistic combinations of attack rates, sensitivity, and specificity were considered (110).
The CDC U.S. Influenza Vaccine Effectiveness (U.S. Flu VE) Network, a collaboration of 5 U.S. sites, produces annual estimates of vaccine effectiveness against outpatient MAARI, using a test-negative case-control design. Results are stratified by age group and vaccine type (when there is sufficient use of a specific vaccine to permit a VE estimate). VE estimates from this network for selected recent seasons are summarized in some of the sections that follow. Further information concerning methods, summaries of additional results, and links to reports are available.
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.
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).
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.
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 g 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.
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.
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).
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
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).
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