Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses against Influenza Virus

Assaf Amitai, Maya Sangesland, Ralston M. Barnes, Daniel Rohrer, Nils Lonberg, Daniel Lingwood, Arup K. Chakraborty

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The antibody repertoire possesses near-limitless diversity, enabling the adaptive immune system to accommodate essentially any antigen. However, this diversity explores the antigenic space unequally, allowing some pathogens like influenza virus to impose complex immunodominance hierarchies that distract antibody responses away from key sites of virus vulnerability. We developed a computational model of affinity maturation to map the patterns of immunodominance that evolve upon immunization with natural and engineered displays of hemagglutinin (HA), the influenza vaccine antigen. Based on this knowledge, we designed immunization protocols that subvert immune distraction and focus serum antibody responses upon a functionally conserved, but immunologically recessive, target of human broadly neutralizing antibodies. We tested in silico predictions by vaccinating transgenic mice in which antibody diversity was humanized to mirror clinically relevant humoral output. Collectively, our results demonstrate that complex patterns in antibody immunogenicity can be rationally defined and then manipulated to elicit engineered immunity.

Original languageEnglish
Pages (from-to)573-588.e9
JournalCell Systems
Volume11
Issue number6
DOIs
StatePublished - 16 Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

A.A. and A.K.C. acknowledge support from NIH , grant number 2U19AI057229-16 . D.L. was supported by the NIH ( R01AI137057 , DP2DA042422 , R01AI124378, and R01AI153098 ), the Harvard University Milton Award, and the Gilead Research Scholars Program . M.S. was supported by the NSF Graduate Research Fellowship Program and an NIH fellowship ( F31Al138368 ). The authors thank Lingwood lab members Julia Bals, Vintus Okonkwo and Thalia Bracamonte Moreno for generating the recombinant HA immunogens used in this study.

FundersFunder number
Gilead Research Scholars Program
National Science FoundationF31Al138368
National Institutes of HealthR01AI137057, 2U19AI057229-16, R01AI124378, R01AI153098, DP2DA042422
National Institute of Allergy and Infectious DiseasesR01AI155447
Harvard University

    Keywords

    • B cell
    • affinity maturation
    • antibody targeting
    • germinal center
    • immunodominance
    • in silico
    • in vivo
    • influenza virus
    • universal
    • vaccine

    Fingerprint

    Dive into the research topics of 'Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses against Influenza Virus'. Together they form a unique fingerprint.

    Cite this