Journal
NATURE
Volume 548, Issue 7665, Pages 108-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature23301
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Funding
- International AIDS Vaccine Initiative Neutralizing Antibody Consortium through Collaboration for AIDS Vaccine Discovery grant [OPP1084519]
- NIH [R21 AI120791, R01 GM105826]
- Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant [UM1AI100663]
- IOS [1257829]
- USDA-NIFA grant [CSREES 2008-35204]
- James and Jessie Minor Chair in Immunology
- IAVI
- Bill AMP
- Melinda Gates Foundation
- Ministry of Foreign Affairs of Denmark
- Irish Aid
- Ministry of Finance of Japan
- World Bank
- Ministry of Foreign Affairs of the Netherlands
- Norwegian Agency for Development Cooperation (NORAD)
- United Kingdom Department for International Development (DFID)
- United States Agency for International Development (USAID)
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No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP1, have improved the elicitation of potent isolate-specific antibody responses in rabbits(2) and macaques(3), but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length(4-9). Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 crossclade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of crossclade isolates (n = 117) with a potent median IC50 of 0.028 mu g ml(-1). Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.
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