Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
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 February 1, 2019; First published December 6, 2018
Citation Information: J Clin Invest. 2019;129(2):850-862. https://doi.org/10.1172/JCI123366.
View: Text | PDF
Categories: Research Article Immunology Vaccines

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

  • Text
  • PDF
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

×

Figure 1

Serological and B cell responses in experimentally infected mice.

Options: View larger image (or click on image) Download as PowerPoint
Serological and B cell responses in experimentally infected mice.
(A) Se...
(A) Serum endpoint total IgG titers were measured by ELISA using HA-FL (blue) or stabilized HA stem (red) in mice infected intranasally with PR8 (n = 6 per time point). Dotted lines denote the detection cutoff (1:100 dilution). Data represent the mean ± SEM. (B) Frequency of GC B cells (B220+IgD–CD38loGL7+) and memory B cells (B220+IgD–CD38hiGL7–) binding HA-FL (blue) or HA stem (red) (n = 6). Data represent the mean ± SEM. (C) Frequency of plasma cells (CD138+B220–IgD–) binding HA-FL (blue) or HA stem (red) (n = 6). Data represent the mean ± SEM. (D) HA bioavailability visualized by monoclonal anti–HA head or anti–HA stem antibody staining (white) and B220+ B cell staining (green). Scale bars: 100 μm.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts