Given the challenges of maternal and child access and adherence to antiretroviral therapy in high HIV-prevalence settings, innovative biomedical solutions, including long-acting, injectable formulations, offer a paradigm shift in the pediatric HIV/AIDS epidemic. Modified HIV-1 broadly neutralizing antibodies (bNAbs) are highly potent and long-acting, and therefore have indisputable potential for protection from HIV-1 peri- and post-natal transmission.
PedMAb’s FIRST OBJECTIVE is a multi-step approach phase I (dose finding) study followed by a phase II study to test the safety, tolerability and pharmacokinetic (PK) profile of bNAbs administered subcutaneously (SC) alone or in combinations to breastfeeding, HIV-exposed, uninfected (HEU) neonates (within 72h of birth) alongside standard-of-care ARVs, and repeated (at 4 or 6 months) in infants.
Our goal is to define the optimal dose(s), timing, and the ideal combination(s) of bNAbs to prevent HIV breast-milk transmission in high-incidence regions.
The long-acting (LS) version of the bNAb CAP256, never tested in pediatric populations, and VRC07-523, were chosen for 1) epitope complementarity (CD4bs and V1V2-glycan); 2) breadth for subtype C (dominant in South Africa) and other subtypes; 3) half-life >3-4 months in adults (VRC07-523LS), allowing large administration intervals; 4) potency and availability of the formulation for SC administration, which in children is preferable to intravenous administration; 5) availability through non-profit partnerships.
The trials will be implemented at the South African Medical Research Council’s Chatsworth accredited Clinical Research site, located within the premises of the RK Khan regional hospital, Durban. It accounts for 2000-2300 deliveries by HIV-infected women/year. Antenatal HIV-prevalence in this district is approximately 46%, and exclusive breastfeeding prevalence is 64% among HEU aged 0-14 weeks.
The primary outcome will be the number of participants who experience severe adverse events to bNAbs, administered alone or in combination, within 28 days of each administration. The secondary outcome is elimination half-life of bNAbs, alone or in combination, within 6 months of each administration. Exploratory studies will provide additional information on persistence and distribution of functional bNAbs in infants, and on immunemodulation driven by bNAbs. Viral phenotyping will provide essential information on the sensitivity of circulating maternal and pediatric viruses to clinically relevant bNAbs.
The clinical trials and associated research questions will form an excellent basis for knowledge, technology transfer, quality assurance programs and training between consortium partners and contribute to capacity building (SECOND OBJECTIVE).
Overall, PedMAb will provide critical new information for future large-scale efficacy studies of bNAbs in infants, who continue to be infected with HIV-1 through breastfeeding.