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 language | English |
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Pages (from-to) | 573-588.e9 |
Journal | Cell Systems |
Volume | 11 |
Issue number | 6 |
DOIs | |
State | Published - 16 Dec 2020 |
Externally published | Yes |
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.
Funders | Funder number |
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Gilead Research Scholars Program | |
National Science Foundation | F31Al138368 |
National Institutes of Health | R01AI137057, 2U19AI057229-16, R01AI124378, R01AI153098, DP2DA042422 |
National Institute of Allergy and Infectious Diseases | R01AI155447 |
Harvard University |
Keywords
- B cell
- affinity maturation
- antibody targeting
- germinal center
- immunodominance
- in silico
- in vivo
- influenza virus
- universal
- vaccine