Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials

The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.Author summary: HIV-1 viruses from the Antibody Mediated Prevention (AMP) trials, obtained in 2016–2020, represent our most recent panel of transmitted viruses in the population. Reference virus strains that are currently used to evaluate broadly neutralizing antibodies (bnAb) for passive immune trials and assess the quality of vaccine induced antibody responses, were collected between 1998 and 2010. As HIV-1 continues to evolve, virus panels may need to be updated from time to time. Sequences were obtained from participants infected with HIV-1 from both the African (HVTN 703/HPTN081) and the Americas/European (HVTN 704/HPTN085) AMP trials. These viruses were then tested in a neutralization assay with 8 bnAbs under clinical development. Comparing the neutralization coverage with older viruses, we found that recent viruses have become more resistant to VRC07-523LS and CAP256.25 antibodies. Predictive modelling identified triple bnAb combinations that would be effective at neutralizing HIV-1 strains from different geographical regions. Reference panels that include recently transmitted HIV-1 strains provide important information that can be used to design bnAb combinations to consider for prevention studies.