4.8 Article

Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques

Journal

SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 657, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abl9605

Keywords

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Funding

  1. NIH [CHAVD UM1 AI44462, 5T32AI007384]
  2. IAVI Neutralizing Antibody Center
  3. Bill and Melinda Gates Foundation [OPP1170236, INV-004923]
  4. Translational Virology Core of the San Diego Center for AIDS Research (CFAR) grant NIH [AI036214]
  5. John and Mary Tu Foundation
  6. James B. Pendleton Charitable Trust
  7. U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
  8. DOE Office of Biological and Environmental Research
  9. National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
  10. NIH NIAID grant [CCHI AI142742]
  11. NIAID [75N9301900065]
  12. DOE Office of Science [DE-AC02-06CH11357]
  13. DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on the response to COVID-19
  14. Coronavirus CARES Act
  15. [R01AI073148]

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Immunization of macaques with SARS-CoV-2 spike protein generated potent cross-neutralizing antibody responses, effective against both SARS-CoV-2 and SARS-CoV-1, as well as most SARS-CoV-2 variants.
To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS-related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.

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