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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 5

Stem immunogens fail to selectively recall stem antibodies in preimmune mice and macaques.

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Stem immunogens fail to selectively recall stem antibodies in preimmune ...
Mice infected intranasally with PR8 and immunized on day 56 were analyzed for (A) serum endpoint total IgG titers measured by ELISA on day 56 (black box shows before immunization) and day 70 (white box shows 2 weeks after immunization) using HA-FL or HA stem proteins (n = 10 from 2 independent experiments with groups of 5 animals) and (B) frequency of GC B cells (B220+IgD–CD38loGL7+) stained with HA-FL and HA stem probes (PR8) measured by flow cytometry (n = 5). Box boundaries represent the 25th and 75th percentiles, the inner line represents the median, and whiskers represent minimum and maximum values. Data indicate the mean ± SEM. *P < 0.05, by Mann-Whitney U test. Macaques (n = 6) infected intranasally with A/Auckland/1/2009 and immunized on day 56 with seasonal IIV4 or HA stem immunogen were analyzed for (C) serum endpoint total IgG titers measured by ELISA using CA09 HA-FL (blue) or stabilized CA09 HA stem (red) proteins and (D) frequency of IgG+ memory B cells (CD19+IgD–IgG+) binding CA09 HA-FL (blue) or stabilized CA09 HA stem (red) probes measured by flow cytometry within cryopreserved PBMC samples. Dotted lines denote the detection cutoff (dilution 1:100).
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