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

Abstract

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.

HIV BG505 SOSIP.664 trimer with 3M-052-AF/alum induces human autologous tier-2 neutralizing antibodies

“…Neutralization titer was defined as the serum inhibitory dilution (ID50/ID80) or monoclonal antibody inhibitory concentration (IC50/IC80) at which relative luminescence units (RLU) were reduced by either 50% or 80% relative to control wells containing only virus and cells, after subtraction of background RLU (cells only). Serum samples testing positive against BG505/T332N were assayed for neutralization against a global panel of 9 heterologous tier-2 viruses: 246-F3_C10_2, 25710-2.43, BJOX002000.03.2, CH119.10, Ce1176_A3, Ce703010217_B6, CNE55, TRO.11, and X1632-S2-B10 (deCamp et al, 2014; Mkhize et al, 2023). Pseudovirus mutants using BG505 were used as previously described (Klasse et al, 2018).…”

Anticipating HIV viral escape – resistance to active and passive immunization

“…This subtype effect, where different subtypes exhibit varying sensitivity to bNAbs, is also observed with other clinically relevant bNAbs. Mkhize et al tested the 74 AMP placebo viruses (31 from the Africa trial and 43 from the Americas trial) against six other bNAbs undergoing clinical testing, including those targeting the CD4 binding site (VRC07-523LS, 3BNC117), V2 glycan (CAP256-25, PGDM1400), V3 glycan (PGT121, 10–1074), and MPER (10e8v4) [27 ▪▪ ]. They found not only that subtype differences exist, but that they are particularly evident in bNAbs targeting the V2 apex: in the Africa trial, two-thirds of the viruses were sensitive to CAP256.25 and PGDM1400, whereas only 10% and 40% of viruses from the Americas trial were sensitive to CAP256.25 and PGDM1400, respectively.…”

“…The virus panels used to evaluate bNAbs are based mainly on subtype B and C, and this observation emphasises the importance of expanding these to include other circulating subtypes. A comparison of the sensitivity of the AMP clade C placebo viruses and historical viruses collected between 1998 and 2010 showed an increased resistance to VRC07-523LS and CAP256.25 over time [27 ▪▪ ]. In addition to adults, passive immunization studies are also being performed in the context of prevention of mother to child transmission [28].…”

“…Assuming escape does occur, it should be restricted with combinations of antibodies designed so that the majority of circulating viruses are recognized by at least two antibodies. For example, a combination of a V2-apex and a V3-glycan bNAb (which often have nonoverlapping coverage) might provide high overall breadth/coverage, but most viruses would only be recognized by a single bNAb, thereby defeating the goal of combinations for prevention [27 ▪▪ ,34,35] (Fig. 3).…”

“…Unlike single antibodies, combinations of antibodies with complementary patterns of breadth (such as CD4bs, V2-apex and V3-glycan) provide ‘active’ coverage of most viruses by more than one antibody. Adapted from Mkhize et al [27 ▪▪ ].…”