Extended in vivo activity of VRC01 HIV-1 prophylaxis entails initial protective efficacy and subsequent breakthrough infections
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 M. Mgodi, Kevin Gillespie, Beatrix Haddock, Pedro Gonzales, Robinson Cabello, Catherine Orrell, Javier R. Lama, Fatima Laher, Erica M. Lazarus, Jorge Sanchez, Ian Frank, Juan C. Hinojosa, Magdalena E. Sobieszczyk, Pamela G. Mukwekwerere, Joseph Makhema, Lindsey R. Baden, Kelly E. Seaton, John Hural, M. Juliana McElrath, Simbarashe Takuva, April K. Randhawa, Nidhi Kochar, Estelle Piwowar-Manning, Deborah J. Donnell, Nirupama Sista, Philip Andrew, Shelly T. Karuna, James G. Kublin, Glenda E. Gray, Myron S. Cohen, Dan H. Barouch, Georgia D. Tomaras, Morgane Rolland, David C. Montefiori, Lynn Morris, James I. Mullins, Carolyn Williamson, Lawrence Corey, Peter B. GilbertThe 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.