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Age-specific effects of vaccine egg adaptation and immune priming on A(H3N2) antibody responses following influenza vaccination.

ABSTRACT: A(H3N2) influenza vaccine effectiveness (VE) was low during the 2016-19 seasons and varied by age. We analyzed neutralizing antibody responses to egg- and cell-propagated A(H3N2) vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all vaccine-eligible age groups in 3 influenza seasons. Antibody responses to cell- versus egg-propagated vaccine viruses were significantly reduced due to the egg-adapted changes T160K, D225G, and L194P in the vaccine hemagglutinins. Vaccine egg adaptation had a differential impact on antibody responses across the different age groups. Immunologically naive children immunized with egg-adapted vaccines mostly mounted antibodies targeting egg-adapted epitopes, whereas those previously primed with infection produced broader responses even when vaccinated with egg-based vaccines. In the elderly, repeated boosts of vaccine egg-adapted epitopes significantly reduced antibody responses to the WT cell-grown viruses. Analysis with reverse genetic viruses suggested that the response to each egg-adapted substitution varied by age. No differences in antibody responses were observed between male and female vaccinees. Here, the combination of age-specific responses to vaccine egg-adapted substitutions, diverse host immune priming histories, and virus antigenic drift affected antibody responses following vaccination and may have led to the low and variable VE against A(H3N2) viruses across different age groups.

SUBMITTER: Liu F

PROVIDER: S-EPMC8262463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Impact of Immune Priming, Vaccination, and Infection on Influenza A(H3N2) Antibody Landscapes in Children.

Project description:BackgroundPreexisting antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination.MethodsWe enrolled 72 children (aged 7-17 years) in 2015-2016; all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-2015, with 12 becoming infected with A(H3N2) in 2014-2015. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and postvaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015.ResultsThe breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Postvaccination titers were the highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Prevaccination titers to the vaccine were the strongest predictors of postvaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2)-infected children in 2014-2015 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-2016 vaccination.ConclusionsA(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection.

| S-EPMC8145779 | biostudies-literature

Poor Immunogenicity, Not Vaccine Strain Egg Adaptation, May Explain the Low H3N2 Influenza Vaccine Effectiveness in 2012-2013.

Project description:BackgroundInfluenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity and mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A(H3N2). Low VE has been attributed to mismatches between the vaccine and circulating influenza strains and to the vaccine's elicitation of protective immunity in only a subset of the population. The low H3N2 VE in the 2012-2013 season was attributed to egg-adaptive mutations that created antigenic mismatch between the actual vaccine strain (IVR-165) and both the intended vaccine strain (A/Victoria/361/2011) and the predominant circulating strains (clades 3C.2 and 3C.3).MethodsWe investigated the basis of low VE in 2012-2013 by determining whether vaccinated and unvaccinated individuals were infected by different viral strains and by assessing the serologic responses to IVR-165, A/Victoria/361/2011, and 3C.2 and 3C.3 strains in an adult cohort before and after vaccination.ResultsWe found no significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. Vaccination increased titers to A/Victoria/361/2011 and 3C.2 and 3C.3 representative strains as much as to IVR-165. These results are consistent with the hypothesis that vaccination boosted cross-reactive immune responses instead of specific responses against unique vaccine epitopes. Only approximately one-third of the cohort achieved a ≥4-fold increase in titer.ConclusionsIn contrast to analyses based on ferret studies, low H3N2 VE in 2012-2013 in adults does not appear to be due to egg adaptation of the vaccine strain. Instead, low VE might have been caused by low vaccine immunogenicity in a subset of the population.

| S-EPMC6051447 | biostudies-literature

Role of Egg-adaptation Mutations in Low Influenza A(H3N2) Vaccine Effectiveness During the 2012-2013 Season.

Project description: Not available

| S-EPMC6186855 | biostudies-literature

Effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza A (H3N2) vaccine viruses.

Project description:Influenza A virus (subtype H3N2) causes seasonal human influenza and is included as a component of influenza vaccines. The majority of vaccine viruses are isolated and propagated in eggs, which commonly results in amino acid substitutions in the haemagglutinin (HA) glycoprotein. These substitutions can affect virus receptor-binding and alter virus antigenicity, thereby, obfuscating the choice of egg-propagated viruses for development into candidate vaccine viruses. To evaluate the effects of egg-adaptive substitutions seen in H3N2 vaccine viruses on sialic acid receptor-binding, we carried out quantitative measurement of virus receptor-binding using surface biolayer interferometry with haemagglutination inhibition (HI) assays to correlate changes in receptor avidity with antigenic properties. Included in these studies was a panel of H3N2 viruses generated by reverse genetics containing substitutions seen in recent egg-propagated vaccine viruses and corresponding cell culture-propagated wild-type viruses. These assays provide a quantitative approach to investigating the importance of individual amino acid substitutions in influenza receptor-binding. Results show that viruses with egg-adaptive HA substitutions R156Q, S219Y, and I226N, have increased binding avidity to α2,3-linked receptor-analogues and decreased binding avidity to α2,6-linked receptor-analogues. No measurable binding was detected for the viruses with amino acid substitution combination 156Q+219Y and receptor-binding increased in viruses where egg-adaptation mutations were introduced into cell culture-propagated virus. Substitutions at positions 156 and 190 appeared to be primarily responsible for low reactivity in HI assays with post-infection ferret antisera raised against 2012-2013 season H3N2 viruses. Egg-adaptive substitutions at position 186 caused substantial differences in binding avidity with an insignificant effect on antigenicity.

| S-EPMC5394856 | biostudies-literature

Neutralizing Antibody Responses to Antigenically Drifted Influenza A(H3N2) Viruses among Children and Adolescents following 2014-2015 Inactivated and Live Attenuated Influenza Vaccination.

Project description:Human influenza A(H3N2) viruses that predominated during the moderately severe 2014-2015 influenza season differed antigenically from the vaccine component, resulting in reduced vaccine effectiveness (VE). To examine antibody responses to 2014-2015 inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) among children and adolescents, we collected sera before and after vaccination from 150 children aged 3 to 17 years enrolled at health care facilities. Hemagglutination inhibition (HI) assays were used to assess the antibody responses to vaccine strains. We evaluated cross-reactive antibody responses against two representative A(H3N2) viruses that had antigenically drifted from the A(H3N2) vaccine component using microneutralization (MN) assays. Postvaccination antibody titers to drifted A(H3N2) viruses were higher following receipt of IIV (MN geometric mean titers [GMTs], 63 to 68; 38 to 45% achieved seroconversion) versus LAIV (MN GMT, 22; only 3 to 5% achieved seroconversion). In 9- to 17-year-olds, the highest MN titers were observed among IIV-vaccinated individuals who had received LAIV in the previous season. Among all IIV recipients aged 3 to 17 years, the strongest predictor of antibody responses to the drifted viruses was the prevaccination titers to the vaccine strain. The results of our study suggest that in an antigenically drifted influenza season, vaccination still induced cross-reactive antibody responses to drifted circulating A(H3N2) viruses, although higher antibody titers may be required for protection. Antibody responses to drifted A(H3N2) viruses following vaccination were influenced by multiple factors, including vaccine type and preexisting immunity from prior exposure.

| S-EPMC5051070 | biostudies-literature

Differential Antibody Recognition of H3N2 Vaccine and Seasonal Influenza Virus Strains Based on Age, Vaccine Status, and Sex in the 2017-2018 Season.

Project description:BackgroundAn antigenic mismatch between the vaccine and circulating H3N2 strains was hypothesized to contribute to the severity of the 2017-2018 season in North America.MethodsSerum and nasal washes were collected from influenza positive and negative patients during the 2017-2018 season to determine neutralizing antibody (nAb) titers and for influenza virus sequencing, respectively.ResultsThe circulating and vaccine H3N2 virus strains were different clades, with the vaccine strain being clade 3C.2a and the circulating viruses being 3C.2a2 or 3C.3a. At enrollment, both the H3N2 negative and positive patients had greater nAb titers to the egg-adapted vaccine virus compared to the cell-grown vaccine but the H3N2-negative population had significantly greater titers to the circulating 3C.2a2. Among H3N2-positive patients, vaccination, younger age, and female sex were associated with greater nAb responses to the egg-adapted vaccine H3N2 virus but not to the cell-grown vaccine or circulating viruses.ConclusionsFor the 2017-2018 circulating viruses, mutations introduced by egg adaptation decreased vaccine efficacy. No increased protection was afforded by vaccination, younger age, or female sex against 2017-2018 circulating H3N2 viruses.

| S-EPMC7488199 | biostudies-literature

Seasonal influenza vaccination expands hemagglutinin-specific antibody breadth to older and future A/H3N2 viruses.

Project description:History of influenza A/H3N2 exposure, especially childhood infection, shape antibody responses after influenza vaccination and infection, but have not been extensively studied. We investigated the breadth and durability of influenza A/H3N2-specific hemagglutinin-inhibition antibodies after live-attenuated influenza vaccine in children (aged 3-17 years, n = 42), and after inactivated influenza vaccine or infection in adults (aged 22-61 years, n = 42) using 14 antigenically distinct A/H3N2 viruses circulating from 1968 to 2018. We found that vaccination and infection elicited cross-reactive antibody responses, predominantly directed against newer or future strains. Childhood H3-priming increased the breadth and magnitude of back-boosted A/H3N2-specific antibodies in adults. Broader and more durable A/H3N2-specific antibodies were observed in repeatedly vaccinated adults than in children and previously unvaccinated adults. Our findings suggest that early A/H3N2 exposure and frequent seasonal vaccination could increase the breadth and seropositivity of antibody responses, which may improve vaccine protection against future viruses.

| S-EPMC9232600 | biostudies-literature

Convergent antibody evolution and clonotype expansion following influenza virus vaccination.

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| S-EPMC7899375 | biostudies-literature

Timescales of influenza A/H3N2 antibody dynamics.

Project description:Human immunity influences the evolution and impact of influenza strains. Because individuals are infected with multiple influenza strains during their lifetime, and each virus can generate a cross-reactive antibody response, it is challenging to quantify the processes that shape observed immune responses or to reliably detect recent infection from serological samples. Using a Bayesian model of antibody dynamics at multiple timescales, we explain complex cross-reactive antibody landscapes by inferring participants' histories of infection with serological data from cross-sectional and longitudinal studies of influenza A/H3N2 in southern China and Vietnam. We find that individual-level influenza antibody profiles can be explained by a short-lived, broadly cross-reactive response that decays within a year to leave a smaller long-term response acting against a narrower range of strains. We also demonstrate that accounting for dynamic immune responses alongside infection history can provide a more accurate alternative to traditional definitions of seroconversion for the estimation of infection attack rates. Our work provides a general model for quantifying aspects of influenza immunity acting at multiple timescales based on contemporary serological data and suggests a two-armed immune response to influenza infection consistent with competitive dynamics between B cell populations. This approach to analysing multiple timescales for antigenic responses could also be applied to other multistrain pathogens such as dengue and related flaviviruses.

| S-EPMC6117086 | biostudies-literature

Evaluation of Influenza Vaccine Effectiveness Among Young Children Receiving Consecutive Versus Nonconsecutive Vaccination During Influenza A(H3N2)-Predominant Seasons.

Project description:A test-negative case-control analysis of 1478 children aged 6 months to 8 years of age seeking care at an emergency/urgent care setting with influenza like illness during the 2016-17 and 2018-19 (H3N2 predominant) influenza seasons demonstrated that influenza vaccine effectiveness did not vary significantly by the prior seasons' vaccination status.Clinical trials registrationNCT02979626.

| S-EPMC8023305 | biostudies-literature

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