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Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13474-13479. doi: 10.1073/pnas.1816300116. Epub 2019 Jun 18.

Outflanking immunodominance to target subdominant broadly neutralizing epitopes.

Author information

1
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; davide.angeletti@gu.se jyewdell@niaid.nih.gov.
2
Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden.
3
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
5
Ragon Institute of MGH, MIT, and Harvard University, Cambridge, MA 02139.
6
PhD Program in Virology, Division of Medical Sciences, Harvard University, Boston, MA 02115.
7
Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305.
8
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
9
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Abstract

A major obstacle to vaccination against antigenically variable viruses is skewing of antibody responses to variable immunodominant epitopes. For influenza virus hemagglutinin (HA), the immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem-only constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, coimmunization of full-length HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming immunodominance, with important implications for human vaccination.

KEYWORDS:

B cell; antibodies; hemagglutinin; immunodominance; influenza

PMID:
31213541
PMCID:
PMC6612916
[Available on 2019-12-18]
DOI:
10.1073/pnas.1816300116

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