Extended in vivo activity of VRC01 HIV-1 prophylaxis entails initial protective efficacy and subsequent breakthrough infections
Abstract
The two parallel antibody-mediated prevention (AMP) efficacy trials evaluated whether intravenous infusion of the anti-CD4 binding site broadly neutralizing antibody VRC01 prevents HIV-1 acquisition. Here, we analyzed HIV-1 acquisition in AMP through the week 104 final study visit. Against viruses considered highly sensitive to VRC01 [80% inhibitory concentration (IC 80 ) < 1 microgram/milliliter], VRC01 prophylaxis maintained cumulative prevention efficacy of 66.3% (95% confidence interval: 32.4, 83.2%), suggesting that the antibody successfully blocked or cleared these infections. In the post–week 80 period (after the final dose at week 72), HIV diagnosis and resistance to VRC01 were more frequent and greater in the VRC01 groups versus placebo. For instance, more HIV diagnoses with viruses considered moderately sensitive or resistant to VRC01 (IC 80 ≥ 5 microgram/milliliter) were made in the VRC01 groups compared with placebo groups (11 versus 1). Plausibly, as in vivo VRC01 concentration waned, suppressed viruses—often evolving greater resistance because of selective pressure—emerged as detectable infections. Our findings suggest that, whereas single antibodies can block sensitive strains, multiple antibodies are likely required to prevent both viral escape and breakthrough infections.
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Authors: Allan C. deCamp, Michal Juraska, Li Li, Craig A. Magaret, Brian D. Williamson, Hongjun Bai, Yunda Huang, Elena E. Giorgi, Lily Zhang, Lindsay N. Carpp, Srilatha Edupuganti, Nyaradzo Mavis Mgodi, Kevin Gillespie, Beatrix Haddock, Pedro Gonzáles, Robinson L. Cabello, Catherine Orrell, Javier R. Lama, Fatima Laher, Erica Maxine Lazarus, Jorge Sánchez, Ian Frank, Juan Hinojosa, Magdalena E. Sobieszczyk, Pamela Grace Mukwekwerere, Joseph M. Makhema, Lindsey Robert Baden, Kelly E. Seaton, John Hural, M. Juliana McElrath, Simbarashe G. Takuva, April Kaur Randhawa, Nidhi K. Kochar, Estelle Piwowar‐Manning, Deborah J Donnell, Nirupama Sista, P. Andrew, Shelly Karuna, James G. Kublin, Glenda Gray, Myron S. Cohen, Dan H. Barouch, Georgia D. Tomaras, Morgane Rolland, David C. Montefiori, Lynn Morris, James I. Mullins, Carolyn E. Williamson, Lawrence Corey, Peter B. Gilbert
Institutions: Brigham and Women's Hospital, University of Pennsylvania, University of Washington, Johns Hopkins University, Harvard University, Emory University, Duke University, University of the Witwatersrand, University of Pretoria, University of Cape Town, South African Medical Research Council, Columbia University Irving Medical Center, Beth Israel Deaconess Medical Center, Duke Medical Center, Asociación Civil Impacta Salud y Educación, University of KwaZulu-Natal, National Health Laboratory Service, National University of San Marcos, Family Health International 360, University of North Carolina Health Care, University of Zimbabwe, Fred Hutch Cancer Center, Henry M. Jackson Foundation, Walter Reed Army Institute of Research, Centre for the AIDS Programme of Research in South Africa, Kaiser Permanente Washington Health Research Institute, Perinatal HIV Research Unit, Institute of Infectious Disease and Molecular Medicine, Via Libre