AAV-delivery of broadly neutralizing antibodies to augment ART-free control of HIV-1 in children - AAV-Delivery of Broadly Neutralizing Antibodies to Augment ART-Free Post-Treatment Control of HIV-1 in Children Initiation of antiretroviral therapy (ART) to infants with HIV-1 within 3 months of birth can durably suppress HIV-1 replication, preserve immune function, limit the establishment and persistence of viral reservoirs, and reduce HIV-related morbidity and mortality. However, rates of viral suppression in early childhood are low due to the many challenges inherent in delivering lifetime, daily ART. There is thus a critical need for new therapeutic approaches to achieve durable HIV-1 control off ART in young children. This clinical trial planning grant, submitted in response to PAR-23-206, addresses key barriers to the efficient translation of promising pre- clinical data from infant macaque studies into a proof-of-concept POC Phase I clinical trial that will evaluate whether a single administration of two AAV9-vectored broadly-neutralizing antibodies (AAV9-VRC07-523LS; AAV9-10-1074LS) to children on ART will be safe, tolerable, and lead to sustained production of bNAbs at levels that will allow control of HIV-1 replication after ART discontinuation. Intramuscular AAV9 administration will selectively target long-lived muscle cells using a dose likely to provide sustained in vivo production of antibodies with minimal off-target effects and immunogenicity. Administration to young children capitalizes on the relative tolerogenic immune milieu in early life to circumvent ADA, a major barrier to this approach in adults. Primary trial outcomes include safety, pharmacokinetics (bNAb levels), and the proportion of children who maintain HIV control (plasma HIV-1 RNA < LOD) off ART. To enable efficient POC clinical trial development and implementation, we will coordinate multiple partners to: 1) develop a full regulatory strategy; 2) complete a full clinical trial protocol and associated documents; and 3) engage communities and ethics committees to inform clinical trial development and implementation. Enabling the timely design and completion of the POC trial will be an important step to advancing broadly accessible, safe, durable, and effective therapies to achieve control of HIV-1 replication off ART in children.
