Understanding Memory B Cell Formation and Reactivation in HIV Vaccine Strategies

ABSTRACT In 2021, HIV caused 1.5 million new cases and an estimated 650,000 deaths from related illnesses, making it a devastating global health issue. While the discovery of broadly neutralizing antibodies (bnAbs) in HIV-positive individuals has provided hope for the development of an HIV vaccine, the induction of protective bnAb responses through vaccination has yet to be achieved. A new vaccine approach called "germline targeting" (GT) has been developed to target rare naïve B cells with the potential to produce bnAbs. Upon activation by a GT vaccine, these B cells are recruited to germinal centers (GCs) in lymph nodes, where they undergo mutation of their B cell receptors. Over time, B cells that successfully bind antigen are positively selected. These GC reactions give rise to memory B cells (MBCs) that can persist over extended periods. Upon secondary exposure to the antigen, MBCs can be reactivated and recruited back into GCs to undergo further rounds of mutation. HIV GT vaccine strategies may require repeated vaccine doses to elicit progressive rounds of mutation to generate bnAbs. A promising candidate for HIV GT vaccine development are VRC01-class bnAbs which target the region of the virus envelope that binds to CD4 T cells to mediate invasion, known as the CD4 binding site. To activate germline VRC01-class bnAb precursor B cells to GCs, specially designed HIV Env protein structures called engineered outer domain-germline targeting (eOD-GT) immunogens have been developed and have shown promising results in pre-clinical and clinical studies. While the competitive success of VRC01-class B cells in GCs has been shown to be influenced by precursor frequency and antigen avidity, there are still significant gaps in our knowledge regarding how these factors impact the development and subsequent reactivation of MBCs following booster doses. This proposal aims to investigate the central hypothesis that the development, durability, and reactivation of MBCs in response to vaccination are affected by fundamental parameters such as such as antigen avidity, circulating antibody titers, and primary MBC frequency. To investigate this hypothesis, the experiments proposed will use VRC01-class B cell transfer models with validated precursor frequencies and eOD-GT immunogens with defined avidities. Completion of the proposed experiments will determine which MBC subsets should be targeted and identify key parameters that affect the development and reactivation of MBCs. Together the data will support the long-term goal of development towards a vaccine against HIV.