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Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem
Hyon-Xhi Tan, … , Stephen J. Kent, Adam K. Wheatley
Hyon-Xhi Tan, … , Stephen J. Kent, Adam K. Wheatley
Published December 6, 2018
Citation Information: J Clin Invest. 2019;129(2):850-862. https://doi.org/10.1172/JCI123366.
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Research Article Immunology Vaccines

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

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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.

Authors

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

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Figure 4

Antigen specificity of Tfh cells following immunization or infection in mice.

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Antigen specificity of Tfh cells following immunization or infection in ...
(A) Tfh cells were quantified in the 2 draining ILNs on day 14 after vaccination with PR8 HA-FL or stem KLH antigens (n = 5). (B–D) Antigen-specific Tfh cells were identified either by OX-40 upregulation in combination with ICOS++ or CD25 coexpression or CD154 expression following 18 hours of stimulation with HA head or HA stem peptide pools. Antigen-specific responses are presented after background subtraction using a DMSO control (dotted line indicates no change above background). Samples were collected on day 14 after immunization or infection with PR8 HA-FL (n = 12), stem KLH protein (n = 10), or 50 TCID50 PR8 virus (n = 5). Error bars indicate the median and IQR. **P < 0.01, by Wilcoxon matched-pairs test.
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