Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem.

Hyon-Xhi Tan,Adam K Wheatley,Jennifer A Juno,Julius Wong,Stephen J Kent,Jonathan W Yewdell,Danielle Tilmanis,Hannah G Kelly,Robyn Esterbauer,Sinthujan Jegaskanda,Yi Liu,Aeron C Hurt

doi:10.1172/jci123366

Abstract

Both natural influenza infection and current seasonal influenza vaccines primarily induce neutralizing antibody responses against highly diverse epitopes within the “head” of the viral hemagglutinin (HA) protein. There is increasing interest in redirecting immunity toward the more conserved HA stem or stalk as a means of broadening protective antibody responses. Here we examined HA stem–specific B cell and T follicular helper (Tfh) cell responses in the context of influenza infection and immunization in mouse and monkey models. We found that during infection, the stem domain was immunologically subdominant to the head in terms of serum antibody production and antigen-specific B and Tfh cell responses. Similarly, we found that HA stem immunogens were poorly immunogenic compared with the full-length HA with abolished sialic acid binding activity, with limiting Tfh cell elicitation a potential constraint to the induction or boosting of anti-stem immunity by vaccination. Finally, we confirm that currently licensed seasonal influenza vaccines can boost preexisting memory responses against the HA stem in humans. An increased understanding of the immune dynamics surrounding the HA stem is essential to inform the design of next-generation influenza vaccines for broad and durable protection.

Highlights

Influenza viruses cause significant global morbidity and mortality through seasonal epidemics and periodic pandemics
We first examined the spatial and temporal dynamics of HA and stem-specific humoral immunity during primary H1N1 influenza infection in C57BL/6 mice intranasally infected with A/ Puerto Rico/08/1934 (PR8)
Nonlethal infection, we observed the rapid development of a HA-FL–specific serum antibody response by day 7 after infection that peaked by day 28 and was maintained at high titers out to day 112 (Figure 1A)

Summary

Introduction

Influenza viruses cause significant global morbidity and mortality through seasonal epidemics and periodic pandemics. The effectiveness of influenza vaccination is limited by the focusing of humoral immunity on a cluster of highly mutable epitopes in the globular head domain of the viral hemagglutinin (HA). This results in neutralization that is notoriously strain specific and leaves human populations vulnerable to antigenically novel viruses arising from antigenic drift or emerging from zoonotic reservoirs. While targeting the stem has energized efforts to develop universal influenza vaccines [6, 7], stem-specific antibodies in humans are generally found at low serological concentrations [8], with only limited increases after seasonal immunization or infection [3, 9, 10]. Infection or immunization with highly novel influenza viruses, for example the 2009 pandemic H1N1 or avian

Methods

Results

Conclusion