Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem
AuthorTan, H-X; Jegaskanda, S; Juno, JA; Esterbauer, R; Wong, J; Kelly, HG; Liu, Y; Tilmanis, D; Hurt, AC; Yewdell, JW; ...
Source TitleJournal of Clinical Investigation
PublisherAMER SOC CLINICAL INVESTIGATION INC
University of Melbourne Author/sJuno, Jennifer; Wheatley, Adam; Jegaskanda, Sinthujan; Hurt, Aeron; Esterbauer, Robyn; Tan, Hyon Xhi; Wong, Julius; Kelly, Hannah; Liu, Yi; Kent, Stephen; ...
AffiliationMicrobiology and Immunology
Melbourne School of Population and Global Health
Document TypeJournal Article
CitationsTan, H. -X., Jegaskanda, S., Juno, J. A., Esterbauer, R., Wong, J., Kelly, H. G., Liu, Y., Tilmanis, D., Hurt, A. C., Yewdell, J. W., Kent, S. J. & Wheatley, A. K. (2019). Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. JOURNAL OF CLINICAL INVESTIGATION, 129 (2), pp.850-862. https://doi.org/10.1172/JCI123366.
Access StatusOpen Access
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.
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