Successful development of a vaccine against HIV will require the induction of neutralizing antibody sufficient to prevent infection. Recent work analyzing HIV specific antibody responses from infected individuals has shown that broadly neutralizing antibodies are directed at several sites on the HIV Env. Moreover, several of these antibodies have unique characteristics such as a high rate of somatic mutation and/or long CDRH3 regions. Thus, improving antigen design and understanding the in vivo mechanisms that control the maturation of the B cell response with various vaccines should facilitate development of a successful HIV vaccine. The data obtained over this past year have shown the following; 1. A comparative analysis of adjuvants and formulation was recently completed in NHP using HIV Env protein. This study focused on two clinically approved adjuvants ( alum and MF-59) with or without TLR 4 or TLR 7 ligands as additional immune stimulators. The data generated so far show that MF-59 induces more potent humoral and cellular immunity than alum when given with HIV Env protein. Combining alum with a TLR 7 ligand strongly enhanced immunity compared to alum alone. By contrast, adding TLR 4 or TLR 7 ligands to MF 59 did increase immunity compared to alum alone. In terms of T cell immunity, MF 59 induced a mixed Th1 and Th2 cytokine response. HIV Env specific B cells were isolated from all NHP that had been immunized with these 8 different adjuvants and next generation sequencing performed. Data was analyzed for the extent of somatic mutation, length of CDRH3 regions and Vh gene family usage and this was published. 2. In collaboration with Dr. Malcolm Martin, we analyzed the extent of somatic mutation, length of CDRH3 regions and Vh gene family usage. of the HIV Env B cell response following infection with SHIV Ad8 in NHP. This is a pathogenic virus that causes several characteristics associated with HIV infection in humans and provides a model for understanding how broadly neutralizing antibodies are developed. 3. Adjuvant Development: A key feature of adjuvants are to optimize the immune response by providing innate stimulation at the site of T and B cell priming ( draining lymph node) and limit systemic innate activation to prevent inflammation and toxicity. Moreover, by improving the formulation of adjuvants to persist longer at the site of immune priming, this will lead to improved generation of T cell and antibody responses. Using novel synthetic polymers and agonists which activate toll like receptor 7 and 8 ligands we performed a series of studies in mice that assessed the physiochemical parameters of the adjuvant delivery system and defined the in vivo immune mechanisms by which they influenced innate and adaptive immunity. 4. A critical scientific hurdle in developing protective vaccine responses for HIV is to induce long lived antibody responses that may have binding activity against the Envelope and effector function mediated by characteristics of the antibody in terms of mediating cytolytic activity. Recent studies are aimed at understanding the innate pathways which influence the magnitude, quality and durability of antibodies.
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