Advancing Multi-bNAbs Microneedle Patch Technology For HIV-1 Prevention in Breastfeeding Infants. - PROJECT SUMMARY / ABSTRACT Despite significant progress made in preventing perinatal mother-to-child-transmission of HIV, 2022 saw about 130,000 new HIV infections in children globally, a vulnerable group that also accounts for 13% of AIDS-related deaths. Postnatal infection through breastfeeding remains a significant contributing factor for mother-to-child transmission of HIV, and often derives from untreated/undiagnosed mothers living with HIV or poor adherence to antiretrovirals (ARVs). Currently available prophylaxis options for newborns with the potential for perinatal exposure to HIV is ARV therapy. However, ARV formulations (oral and injectable) and regimens meant for pediatric use are limited, difficult to adhere to, and potentially accompanied by multiple undesirable side effects. Broadly neutralizing antibodies (bnAbs), currently under investigation in clinical trials, represent an innovative and safer way to deliver perinatal HIV prophylaxis by directly engaging and reinforcing host immunity. Despite the promise, these highly potent Abs have demonstrated in adults and children, in their current form, they often require multiple injections and cold chain storage and transportation, which is burdensome to health care systems and a considerable expense in low-resource settings. A user-friendly transdermal microneedle (MN) patch containing thermally stabilized bnAbs would circumvent these problems through the safe and easy delivery of these potent Abs for protection against HIV-1, even outside of a clinic setting. The MN patch design proposed here is aimed to accomplish co-delivery of a cocktail of long-acting bnAbs offering long-lasting protection without the burden of frequent and adverse-effect laden pediatric ARV formulations or potentially painful and cumbersome antibody infusions for newborns. In this proposal, we will test this innovative delivery platform for the co-delivery of three different bnAbs currently in advanced clinical development (VRC07-523LS, PDGM1400LS and PGT-121LS). Rigorous design and fabrication of MN patches with in vitro and ex vivo characterization of formulated bnAbs will precede their in vivo preclinical assessment of safety in young rabbits, pharmacokinetics (PK) in rats, and subsequent testing in neonate Rhesus macaques to characterize the PK profile and efficacy against oral challenges with SHIVSF162P3. Together, these findings will inform the characteristics and viability of an innovative bnAb delivery platform that could significantly curtail the persistent health crisis of pediatric HIV infections.
