Dissecting Hepatitis B Vaccine Adjuvant Effects on Immune Responses and the HIV Reservoir in PLWH

Project Summary Hepatitis B virus (HBV) is a leading cause of cirrhosis and liver cancer globally, resulting in over 800,000 deaths annually. Approximately 10% of people living with HIV (PLWH) worldwide are infected with HBV and prevention of HBV infection remains a critical goal in PLWH. Vaccination with ENGERIX-B and other alum

adjuvanted hepatitis B surface antigen (HBsAg) vaccines has been the cornerstone of HBV prevention, but the response to current standard vaccination is suboptimal in PLWH. HEPLISAV-B vaccine is HBsAg combined with CpG 1018 adjuvant, a Toll-like receptor 9 (TLR9) agonist. A Phase III trial, A5379, randomized PLWH

with a prior history of HBV vaccination who do not achieve protective HBsAb levels to receive three doses of HEPLISAV-B or ENGERIX-B. Preliminary analysis demonstrates significantly higher response rates with HEPLISAV-B. To explore the immunologic mechanisms associated with increased rates of response, we plan

to compare innate and adaptive immune responses induced by HEPLISAV-B to those of ENGERIX-B vaccination. In Aim 1, we define the innate immune signatures of CpG 1018 and alum adjuvated HBsAg vaccination, including plasma chemokine and cytokine and transcriptomic profiles that are associated with response to vaccination and with adaptive cell phenotypes defined in Aim 2. In Aim 2, we compare HBsAg-

specific B- and T-cell responses following three doses of HEPLISAV-B to those induced with a standard three- dose regimen of ENGERIX-B, using high dimensional flow cytometry and single cell RNAseq to define the immunologic and metabolic profiles of HBV-specific T and B cells associated with vaccine response. Previous

studies have shown that TLR9 activation in HIV infection increases HIV-1 transcription and reduces proviral DNA, key outcomes in HIV-1 cure strategies. Thus, Aim 3 will assess the HIV reservoir and HIV-specific immune responses before and after vaccination with HEPLISAV-B. With these three complementary but

independent aims, we will define innate and cellular characteristics associated with superior antibody production, with broad implications regarding the use of TLR9 agonist vaccine adjuvants in populations with suboptimal vaccine responses and improved understanding of dysregulation of immune responses in PLWH.

Additionally, this research leverages a large and diverse participant group to explore the dynamics of HIV reservoir maintenance after TLR9 agonist exposure with the potential to inform development of HIV curative strategies.