Combined Hepatitis B and HIV-1 envelope vaccination to augment T cell help via linked recognition of unrelated antigens

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PROJECT SUMMARY There is a critical need for an effective HIV vaccine to prevent new infections and to end the global AIDS epidemic. Studies conducted to date have not yet identified a safe, highly efficacious, and durable prophylactic HIV vaccine. Increasing CD4+ T cell help from T follicular helper (TFH) cells is one potential strategy for improving the antibody response elicited by candidate HIV vaccines. TFH cells are essential for development of long-lived affinity-matured B cells and have recently been identified as a key component of immune responses that generate antibodies with the ability to neutralize diverse HIV isolates. However, there is presently a gap in knowledge on the best approaches to increase vaccine-induced TFH responses. To address this limitation, the applicant will gain the skills and experience required to lead the development of novel vaccine strategies with tenable paths from preclinical studies in non-human primates (NHP) to human clinical trials. Expertise will be provided by a highly experienced mentorship team, and with additional didactic and practical training. The applicant’s career goal is to lead a research program dedicated to the development of immune interventions for prevention and cure of infectious diseases in infants, children, and adolescents. The overall objective of the proposal is to develop an HIV envelope (Env) vaccine regimen that is able to maximize T cell help by recruiting memory TFH cells elicited by childhood immunizations in addition to those specific for HIV Env. Novel Hepatitis B surface antigen (HBsAg) and HIV Env conjugate vaccines will be used to augment the TFH response to HIV Env in Hepatitis B immune rhesus macaques. The hypothesis is that a vaccine regimen able to recruit both HIV-Env-specific and non-HIV-Env-specific TFH cells for providing help to Env-specific B cells will improve the quantity and quality of the HIV-Env antibody response. The vaccine regimen will be initiated in neonatal macaques as a surrogate of human infancy, and will model a childhood immunization schedule that allows for completion of the regimen and induction of mature antibodies pre- adolescence, prior to sexual debut. The proposed study will demonstrate the proof of concept that conjugate vaccines can leverage pre-existing memory T cell help from childhood vaccines to augment the response to an HIV-Env vaccine, resulting in higher magnitude, quality, and maturation of Env-specific antibodies. In addition, this award will provide essential training to an early career investigator interested in identifying effective and implementable prophylactic vaccines for use in vulnerable and underserved pediatric populations.