Translating germline-targeting HIV Env SOSIP immunization of infants: targeting bnAbs in early life - ABSTRACT – OVERALL Despite decades of research and millions of global infections and deaths, we remain without an effective vaccine against HIV. Traditional vaccine approaches have failed to induce broadly neutralizing antibodies (bnAbs), crucial for protection against diverse HIV strains. The primary goal of next-generation HIV vaccines is to stimulate B cell lineages capable of producing bnAbs. Recent successes in this realm involve structurally designed immunogens, such as the BG505 Germline-Targeting (GT1.1) HIV Envelope SOSIP trimer, which mimics native viral envelope structures and engages bnAb precursor lineages. While promising, achieving bnAb responses in plasma, even at low levels, remains unachieved in the adult populations where it has been tested. Children living with HIV exhibit faster development and more polyclonal bnAb responses compared to adults, suggesting the potential success of early-life vaccination strategies targeting bnAb responses. Our preclinical studies in nonhuman primates have indicated that infant rhesus macaques more frequently develop bnAb precursor responses following BG505 GT1.1 SOSIP trimer immunization, with robust autologous virus neutralization and early evidence of heterologous virus neutralization in plasma. This vaccine has also shown promise in adult human clinical trials in eliciting “on target” vaccine responses, without any safety concerns. While the early life immune system may offer benefits to this vaccine regimen for achieving its immunologic goals, the dosing, intervals, and potential interactions with pre-existing antibodies and other childhood vaccines is unknown, limiting the development of an optimal infant phase 1 trial. Thus, this Program aims to design and systematically test the optimal regimen of BG505 GT1.1 SOSIP trimer vaccine series as a safe and effective pediatric immunogen for eliciting lifelong bnAb responses. Specific aims include: Aim 1: Determining the optimal pediatric formulation and dose, Aim 2: Aligning immunization intervals with childhood vaccine schedules and assessment of persistence of responses into adolescence, and Aim 3: Assessing the impact of maternal antibodies and passive immunization with bnAbs on vaccine immunogenicity and efficacy. By leveraging preclinical models to assess safety, regimen, and persistence into adulthood, this Program seeks to overcome regulatory hurdles that will pave the way for optimized infant HIV vaccine trials. Successful induction of bnAbs via early-life vaccination could revolutionize HIV prevention efforts, offering hope for a future without the burden of the HIV epidemic.
