Antibody prophylaxis may mask subclinical SIV infections in macaques

Christopher A. Gonelli, Hannah A. D. King, SungYoul Ko, Christine M. Fennessey, Nami Iwamoto, Rosemarie D. Mason, Ashley Heimann, Dillon R. Flebbe, John-Paul Todd, Kathryn E. Foulds, Brandon F. Keele, Jeffrey D. Lifson, Richard A. Koup and Mario Roederer ()
Additional contact information
Christopher A. Gonelli: National Institutes of Health
Hannah A. D. King: National Institutes of Health
SungYoul Ko: National Institutes of Health
Christine M. Fennessey: Frederick National Laboratory for Cancer Research
Nami Iwamoto: National Institutes of Health
Rosemarie D. Mason: National Institutes of Health
Ashley Heimann: National Institutes of Health
Dillon R. Flebbe: National Institutes of Health
John-Paul Todd: National Institutes of Health
Kathryn E. Foulds: National Institutes of Health
Brandon F. Keele: Frederick National Laboratory for Cancer Research
Jeffrey D. Lifson: Frederick National Laboratory for Cancer Research
Richard A. Koup: National Institutes of Health
Mario Roederer: National Institutes of Health

Nature, 2025, vol. 639, issue 8053, 205-213

Abstract: Abstract Broadly neutralizing antibodies (bNAbs) show potential to prevent human immunodeficiency virus (HIV-1) infection in humans1. However, there are limited data on the antibody concentrations required to prevent infection. Clinical trials of bNAb prophylaxis have demonstrated partial efficacy2, but the sampling frequency typically does not allow precise timing of infection events and concurrent antibody levels. Here, using simian immunodeficiency virus (SIV) infection of rhesus macaques, we show that although potent bNAbs can delay the onset of acute viremia, subclinical infections occur while bNAb levels remain high. Serial SIV challenge of monkeys given partially and fully neutralizing bNAbs revealed that ‘viral blips’—low and transient plasma viremia—often occur while serum bNAb concentrations are well above currently accepted protective levels. To understand the precise timing of the infections resulting in such blips, we performed plasma viral sequencing on monkeys that were serially challenged with genetically barcoded SIV after bNAb administration. These analyses showed that subclinical infections occurred in most animals that were given potent bNAb prophylaxis. These subclinical infections occurred while antibody concentrations were 2- to 400-fold higher than the levels required to prevent fully viremic breakthrough infection. This study demonstrates that immunoprophylaxis can mask subclinical infections, which may affect the interpretation of prophylactic HIV-1 bNAb clinical trials.

Date: 2025
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DOI: 10.1038/s41586-024-08500-y

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