Project 1: The impact of innate immune responses on the development of broadly neutralizing antibodies by vaccination

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ABSTRACT - PROJECT 1 The induction of broadly neutralizing antibodies (bNAb) by HIV vaccination remains a major challenge. Rational B-cell-lineage vaccine design with native HIV envelope trimers has emerged as the most promising vaccine strategy. Yet, while HIV Env glycoprotein trimers targeting the respective germline B cell receptor have been successful in inducing autologous tier 2 neutralizing antibodies by vaccination, the induction of antibodies able to neutralize heterologous strains remains limited. Numerous studies have reported that vaccine-induced antibody responses can be enhanced by the inclusion of adjuvants in the vaccine regimen. The potential of adjuvants to impact the induction of bNAb, however, is largely unexplored. The long-term goal of Project 1 is to identify mechanisms by which adjuvants can enhance the induction and maturation of bNAbs. We present preliminary data that immunization of infant rhesus macaques (RM) with the germline targeting BG505 GT1.1 SOSIP mixed with the TLR7,8-based adjuvant 3M-052 in stable emulsion (SE) resulted in the induction of bNAb precursors against the CD4 binding site (CD4bs), indicative of VRC01-like bNAbs, in 3 of 5 animals by 1.5 years. Studies in adult RM have reported that the inclusion of 3M-052 in HIV vaccine regimens promotes the induction of long-lived plasma cells, and HIV vaccines with TLR3- or TLR4-based adjuvants in germline BCR knock-in mice have been associated with increased somatic hypermutation (SHM) and the induction of VRC01-like bNAb precursors. However, the mechanisms by which 3M-052 or other TLR-based adjuvants support germinal center activity, SHM, the induction of HIV bNAb precursors, and/or the development of long-lived plasma cells remain unknown. The objective of Project 1 is to identify the determinants of the initial steps in the induction of bNAb precursors. We hypothesize that adjuvants given in combination with BG505 GT1.1 SOSIP trimers alter the developmental pathway of Env-specific B cells through the induction of specific innate responses that will impact affinity maturation of bNAb precursors. Understanding the complex process of B cell development towards bNAb- producing B cells in response to HIV vaccination and its regulation will require broad omics-based approaches that this Program will apply. Project 1 will thoroughly assess innate immune responses via transcriptomics, single cell (sc) RNA-sequencing, immunome analysis by CyTOF, and proteome analysis of soluble immune mediators in plasma. To determine whether bNAb development can be impacted by the choice of adjuvant, we will ask whether the yield of bNAb precursors after BG505 GT1.1 SOSIP immunization differs dependent on innate responses induced by 3M-052-SE versus a saponin-based adjuvant (Aim 1), and dependent on adjuvant- specific immune cell activation and function in lymph nodes (Aim 2). In collaboration with Project 2, we will define how these innate responses are modulated by commensal bacteria (Aim 3). The results are expected to inform the development of new targeted immunomodulatory approaches of the vaccine prime to optimize the induction of bNAb precursors and provide a framework for bNAb-targeting HIV vaccine evaluation and down-selection.