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

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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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.

Original languageEnglish
Pages (from-to)850-862
Number of pages13
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Cite this

Tan, H. X., Jegaskanda, S., Juno, J. A., Esterbauer, R., Wong, J., Kelly, H. G., ... Wheatley, A. K. (2019). Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. Journal of Clinical Investigation, 129(2), 850-862. https://doi.org/10.1172/JCI123366
Tan, Hyon Xhi ; Jegaskanda, Sinthujan ; Juno, Jennifer A. ; Esterbauer, Robyn ; Wong, Julius ; Kelly, Hannah G. ; Liu, Yi ; Tilmanis, Danielle ; Hurt, Aeron C. ; Yewdell, Jonathan W. ; Kent, Stephen J. ; Wheatley, Adam K. / Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 850-862.
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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.",
author = "Tan, {Hyon Xhi} and Sinthujan Jegaskanda and Juno, {Jennifer A.} and Robyn Esterbauer and Julius Wong and Kelly, {Hannah G.} and Yi Liu and Danielle Tilmanis and Hurt, {Aeron C.} and Yewdell, {Jonathan W.} and Kent, {Stephen J.} and Wheatley, {Adam K.}",
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Tan, HX, Jegaskanda, S, Juno, JA, Esterbauer, R, Wong, J, Kelly, HG, Liu, Y, Tilmanis, D, Hurt, AC, Yewdell, JW, Kent, SJ & Wheatley, AK 2019, 'Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem', Journal of Clinical Investigation, vol. 129, no. 2, pp. 850-862. https://doi.org/10.1172/JCI123366

Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. / Tan, Hyon Xhi; Jegaskanda, Sinthujan; Juno, Jennifer A.; Esterbauer, Robyn; Wong, Julius; Kelly, Hannah G.; Liu, Yi; Tilmanis, Danielle; Hurt, Aeron C.; Yewdell, Jonathan W.; Kent, Stephen J.; Wheatley, Adam K.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 850-862.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Tan, Hyon Xhi

AU - Jegaskanda, Sinthujan

AU - Juno, Jennifer A.

AU - Esterbauer, Robyn

AU - Wong, Julius

AU - Kelly, Hannah G.

AU - Liu, Yi

AU - Tilmanis, Danielle

AU - Hurt, Aeron C.

AU - Yewdell, Jonathan W.

AU - Kent, Stephen J.

AU - Wheatley, Adam K.

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