Assessing the effects of oral pre-exposure prophylaxis on pharmacokinetics of monoclonal and vaccine-induced antibodies among women vulnerable to HIV-1

About This Grant

Abstract In this proposal, we will determine the influence of oral pre-exposure prophylaxis (PrEP) on the pharmacokinetics (PK) of passively administered monoclonal antibodies (mAbs) and vaccine-induced polyclonal antibodies (Abs) in females vulnerable to HIV-1, using data and specimens from past HIV-1 prevention trials. This research will have a significant impact on global health because oral PrEP is currently the most accessible pharmaceutical HIV-1 prevention option, and Abs are critical for immune protection and therapeutic efficacy. Aim 1 focuses on determining whether oral PrEP affects the PK of VRC01, a broadly neutralizing HIV-1 mAb, in female participants from the recently completed Antibody Mediated Prevention (AMP) study. We will identify biomarkers of PrEP use that correlate with increased mAb clearance, with a specific emphasis on assessing PrEP’s effects on two intestinal Ab clearance mechanisms: disruption of the epithelial barrier and increased Fc receptor (FcR) mediated Ab degradation. Aim 2 extends this investigation by examining the impact of oral PrEP on the magnitude and durability of HIV-1 vaccine-induced antibodies (Abs) in female participants from two completed HIV-1 vaccine efficacy trials. To extend beyond HIV-1, we will also assess durability of Hepatitis B (HB) vaccine-induced Abs in female and male participants from AMP and the vaccine trials. Consistent with what was observed for VRC01 PK in males from the AMP trial, our preliminary data in two pre-efficacy vaccine trials suggest an association between PrEP use and faster decay of HIV-1 vaccine-induced Abs. We plan to identify PrEP biomarkers associated with vaccine Ab kinetics. In biopsy donors, we will also determine the association between HB vaccine Ab kinetics and identified biomarkers with the two potential intestinal mechanisms of Ab clearance. Characterizing any PrEP effects on Abs is crucial for people who take oral PrEP and rely on mAb immunotherapies and/or Ab-inducing vaccines for protection against pathogens. Aim 3 focuses on developing a pharmacokinetic and statistical modeling framework to rank and select mAb regimens for efficacy testing. This framework will account for PrEP use and mAb PK biomarkers identified in Aim 1. It will also incorporate mAb levels in serum and rectal tissue from both males and females, recognizing the importance of tissue levels in predicting protection against HIV-1 and intestinal PrEP effects on mAb PK. By building and validating advanced PK models and statistical methods for bridging differences in study populations, we seek to enhance the accuracy of selecting the most promising mAb regimens for future clinical trials, ultimately contributing to more effective HIV-1 prevention strategies.