VRC-01-LS

Broadly neutralizing antibodies (bnAbs) are evaluated as possible alternatives to standard antiretroviral treatment (ART) for maintaining control of HIV-1 replication and may enhance immune responses to reduce or control the viral reservoir. However, the immunological and virological effects of bnAbs in infants and children are unknown. We conducted a detailed analysis of proviral reservoir dynamics and antiviral immune responses in a unique group of young children from Botswana who started ART at birth and then stopped standard ART while receiving the bnAbs 10-1074 and VRC01-LS in a subsequent clinical trial. No quantitative changes in frequencies of proviral sequences were observed during bnAb treatment, but selection of genome-intact proviruses in transcriptionally repressive heterochromatin regions occurred in some study participants. Faster viral rebound following standard ART cessation was linked to elevated proportions of KIR2DL1-positive NK cells. In contrast, delayed viral rebound and more limited viral reservoir size were associated with elevated proportions of NKG2A-positive NK cells and with the HLA-B-21M signal peptide polymorphism. HIV-specific T cell responses were low in all study participants and unrelated to viral reservoir sizes or clinical outcomes following ART interruption. These results suggest that, in young children, specific NK cell subsets and KIR-HLA interactions might be linked to HIV-1 rebound kinetics after substitution of standard ART with bnAbs.

VRC01 and VRC01LS are a pair of parental and LS‐modified anti‐HIV IgG1‐backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose. Using nonlinear mixed‐effects models, we conducted the first population pharmacokinetics analysis of VRC01/LS concentrations in serum and rectal tissue, a primary site of HIV transmission. Serum concentration was described as a one‐compartment model in equilibrium with one tissue compartment, with first‐order elimination in both compartments. The model was parameterized with micro‐constants to estimate volumes of distribution for serum and tissue, serum–tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half‐life estimates were derived from the governing differential equations. To account for rectal biopsy heterogenicity between individuals, three normalization approaches were used: tissue weight adjusted, IgG concentration adjusted, and protein concentration adjusted. All three approaches rendered consistent estimates. Based on protein‐concentration‐normalized data, VRC01LS (vs VRC01) exhibited ∼10‐fold higher concentrations over time in blood and rectal tissues, and faster blood‐to‐tissue distribution (K12 = 0.61 vs 0.13/day). Median elimination half‐life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum.