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

Abstract

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.

Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals

“…Additional serum samples pre-and post-vaccination were obtained from Stanford University (Fluzone 2009-2010, young 18-51, elderly >70) (Sasaki et al, 2011), the University of Rochester (Fluarix 2016-2017, young 18-51, elderly >65) as well as from Duke University Medical Center in 2012-2013 (Cobey et al, 2018).…”

Successes and failures of the live-attenuated influenza vaccine, can we do better?

“…Alternatively, low efficacy could be due to a vaccine's reduced ability to generate an immune response. There are many reasons why a vaccine might not be sufficiently immunogenic [23,24]: problems might have arisen with the strain contained in the vaccine during production [25], the age of the host (influenza vaccines result in lower immune responses in people over 65 years old [26,27]) or pre-existing immunity affecting the ability of the vaccine's immunogenicity [28]. The latter is called negative interference.…”

Estimating Vaccine-Driven Selection in Seasonal Influenza

“…For instance, epitope-based Hamming distances could underestimate the immunological effects of glycosylation sites, which easily disrupt antibody binding [ 44 ]. For HI distances, antisera raised in naive ferrets can have different specificities compared to antisera from humans, because previous exposures affect the generation of new immune responses [ 71 , 72 , 73 ]. Nonetheless, traditional measures of antigenic distance partly correlate with VE [ 69 , 70 ].…”

“… 2012–2013 In adults, the vaccine fails to induce responses to novel mutations on the vaccine strain’s HA. [ 71 ] The vaccine is poorly immunogenic against circulating strains in general. Little vaccine-driven selection is expected.…”