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Nature. 2017 Aug 3;548(7665):108-111. doi: 10.1038/nature23301. Epub 2017 Jul 20.

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California 92037, USA.
2
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
4
International AIDS Vaccine Initiative, New York, New York 10004, USA.
5
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
7
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843, USA.
8
Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medical, Kansas State University, Manhattan, Kansas 66506, USA.
9
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02129, USA.

Abstract

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 SOSIP, have improved the elicitation of potent isolate-specific antibody responses in rabbits and macaques, 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. 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 cross-clade 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 cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg 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.

PMID:
28726771
PMCID:
PMC5812458
DOI:
10.1038/nature23301
[Indexed for MEDLINE]
Free PMC Article

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