Dose, interval, and adjuvant optimization of HIV Env SOSIP GT1.1 for administration in early life

ABSTRACT – PROJECT 1 Despite more than four decades of efforts, the HIV epidemic persists without an effective vaccine. With annual infections surpassing 1.3 million, and a significant burden in adolescents and young women, urgent action is required. Induction of broadly neutralizing antibodies (bnAbs) in childhood prior to sexual debut will be key to ending the HIV epidemic and can leverage the advantages of the early life immune system for induction of bnAb responses. Building on promising preclinical and adult trials employing the BG505 Germline-targeting (GT1.1) HIV Envelope native-like SOSIP trimer immunogen for induction of bnAb lineages, we aim to optimize a pediatric vaccine regimen that will inform and derisk a human infant vaccine trial. Our overarching goal is to define the optimal adjuvant formulation, doses, and intervals of an infant BG505 GT1.1-based vaccine regimen in infant non-human primate (NHP) models to inform the design an infant HIV vaccine protocol with clinical trial partners at the HIV Vaccine Trials Network (HVTN). We hypothesize that low doses of the BG505 GT1.1 immunogen and 3M-052 TLR 7/8 agonist adjuvant spaced along childhood vaccine schedules will be safe and will induce bnAb precursor responses in plasma that can be boosted in later life. Aim 1 focuses on defining the optimal formulation of the 3M-052 adjuvant for infant BG505 GT1.1 SOSIP immunization. Aim 2 aims to establish the safe and immunogenic minimal dose of infant BG505 GT1.1 SOSIP and 3M-052 adjuvant using a matrixed immunogenicity assessment approach. Aim 3 seeks to define optimal infant BG505 GT1.1 SOSIP immunization intervals aligned with the Expanded Program on Immunization (EPI) schedule. By extending intervals and aligning doses with routine childhood vaccines, we aim to maximize bnAb precursor induction, potentially leading to heterologous virus neutralizing responses. Collaboration between Project 1 and 2 ensures design of an EPI-aligned infant vaccine schedule that circumvents interference by maternal antibodies or passive bnAb administration and will not interfere with standard vaccine immunity. Leveraging preclinical models and immunogenicity assessments, our project seeks to establish a vaccine regimen for a human infant vaccine trial led by HVTN. Ultimately, this Project will pave the way for a pediatric HIV vaccine that can be seamlessly integrated into routine immunization programs, offering hope for ending the HIV pandemic.