Defining and modeling HIV-1-specific antibody function in HIV-1-exposed Infants passively Infused with broadly neutralizing antibodies in the IMPAACT P1112 trial.

Abstract Despite the significant reduction in HIV-1 vertical transmission with the implementation of antiretroviral therapy (ART) to pregnant and breastfeeding parents, in 2022, 130,000 new pediatric HIV-1 infections occurred, disproportionately impacting infants who constitute 10% of new infections but just 2% of the global population. More than half of these infections resulted from breastmilk transmission. Thus, there is a critical need for new strategies that could complement ART-based interventions for prevention of breastmilk HIV-1 transmission. One of the most promising strategies under development is passive immunization with broadly neutralizing antibodies (bnAbs). The safety and pharmacokinetics of bnAbs in infants were recently evaluated in the IMPAACT P1112 trial, one of only a handful of trials of its kind. IMPAACT P1112 was an open-label, dose-escalating, phase 1, multicenter study of the safety and pharmacokinetics of the CD4 binding site (CD4bs) bnAbs VRC01, VRC01LS, and VRC07-523LS in HIV-1-exposed infants. The bnAbs were well tolerated and high concentrations were achieved in serum, but the ability of the serum from the passively immunized infants to neutralize viruses found in breastmilk has not been evaluated. Importantly, two efficacy trials evaluating the VRC01 bnAb to prevent HIV- 1 in adults established the Predicted serum neutralization 80% inhibitory dilution titer (PT80) as an excellent predictor of the level of prevention efficacy conferred by that bnAb. Moreover, this biomarker that combines the concentration of the bnAb with its in vitro potency was highly correlated with the serum neutralization in the adult trials. The overall goal of this study is to determine if HIV-1 exposed infants passively immunized with CD4-bs bnAbs in the IMPAACT P1112 trial attained high serum neutralization titers against HIV-1 viruses transmitted through breastmilk and if the level of infant serum neutralization can be predicted by a biomarker. Identifying a biomarker that predicts serum neutralization will guide the down selection of bnAb regimens and their evaluation in pediatric clinical trials. Because HIV-1 exposed infants have preexisting maternal antibodies, whether the tight correlation observed between the PT80 and the measured 80% neutralization titer (ID80) seen in adults will hold in HIV-1 exposed infants, or if another biomarker will better predict serum neutralization, remains unknown. We hypothesize that the PT80 predicts the serum neutralization in HIV-1 exposed infants passively immunized with a bnAb, but that this correlation is strong only after maternal antibodies have waned. Leveraging existing samples from P1112 participants, we will test our hypothesis by 1) Defining the serum antiviral functional profile of HIV-1 exposed infants passively administered a bnAb; and 2) Evaluating the PT80 as a predictor of serum neutralization in bnAb passively immunized HIV-1 exposed infants. Our proposal to thoroughly characterize the antiviral responses elicited in P1112 participants and develop methodology for predicting the neutralization function of bnAb regimens will fill critical gaps for identifying the most promising bnAb regimens to advance in the clinical pipeline and designing clinical trials for their evaluation.