Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants

Abstract

VRC01 is being evaluated in the AMP efficacy trials, the first assessment of a passively administered broadly neutralizing monoclonal antibody (bnAb) for HIV-1 prevention. A key analysis will assess serum VRC01-mediated neutralization as a potential correlate of protection. To prepare for this analysis, we conducted a pilot study where we measured longitudinal VRC01 serum concentrations and serum VRC01mediated neutralization in 47 and 31 HIV-1 uninfected AMP participants, respectively. We applied four different statistical approaches to predict serum VRC01-mediated neutralization titer against Envpseudotyped viruses, including breakthrough viruses isolated from AMP placebo recipients who became HIV-1 infected during the trial, using VRC01 serum concentration and neutralization potency (IC50 or IC80) of the VRC01 clinical lot against the same virus. Approaches 3 and 4, which utilized pharmacokinetics/ pharmacodynamics joint modeling of concentration and neutralization titer, generally performed the best or comparably to Approaches 1 and 2, which, respectively, utilized only measured and model-predicted concentration. For prediction of ID80 titers against breakthrough viruses, Approaches 1 and 2 rendered comparable performance to Approaches 3 and 4, and could be reasonable approaches to adopt in practice as they entail reduced assay cost and less complicated statistical analysis. Our results may be applied to future studies of other bnAbs and bnAb combinations to maximize resource efficiency in serum neutralization titer measurement.

Serum AZD7442 (tixagevimab–cilgavimab) concentrations and in vitroIC50 values predict SARS‐CoV‐2 neutralising antibody titres

“… 31 , 32 Furthermore, an analysis of the broadly neutralising anti‐HIV envelope glycoprotein mAb, VRC01, illustrated that predicted nAb titres (calculated as VRC01 serum concentration/ in vitro IC 50 ) were comparable with measured titres for several HIV strains. 33 , 34 The suitability of predicted nAb titres as a surrogate for measured nAb titres across multiple variants, as demonstrated in this report, in turn supports the use of a predicted nAb endpoint to facilitate effective comparisons of nAb titres across variants for which the baseline nAb levels are expected to be different, because of differences in vaccine antigens and variant exposure (e.g. ancestral SARS‐CoV‐2 and contemporary Omicron subvariants).…”

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

“…We previously reported that, in VRC01 recipients in the HVTN 104 trial (healthy, uninfected participants at low risk of HIV-1 acquisition) and in VRC01 recipients in the AMP trials who remained HIV-1 negative through at least the week 88 visit, the experimentally measured serum ID 80 titer of VRC01 against a given virus was well estimated by PT 80 , defined as an individual's VRC01 serum concentration divided by the IC 80 of the VRC01 drug product against the same virus (refs. 11,12 , respectively) (Fig. 1).…”

Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition

“…Although formal evaluations of antidrug antibodies in participants, including persons infected with breakthrough isolates, are under way, analyses of VRC01 levels in the pharmacokinetics substudy have revealed no decline in VRC01 concentration or neutralizing activity in serum over successive infusions. 11,29,30 Highly potent antibodies with dosing intervals of 3 to 6 months are now in clinical development, and early-phase clinical trials of two-bnAb (ClinicalTrials.gov numbers, NCT04173819 and NCT04212091) and two-and three-bnAb (NCT03928821) combinations are being conducted. 31 In addition, both bispecific (NCT03875209) and trispecific (NCT03705169) bnAbs are in clinical development.…”