CpG-Adjuvanted Heplisav-B Induces Strong Th1-Biased Innate Responses Compared to Alum-Adjuvanted HBV Vaccines in PLWH 2308661

Abstract Introduction Alum-adjuvanted HBV vaccines such as Engerix-B offer limited protection for people living with HIV (PLWH), achieving only 35—70% seroprotection (as defined by HBsAb titers ≥10 mIU/mL). While Heplisav-B’s CpG 1018 adjuvant improves immunogenicity in PLWH, its mechanisms for overcoming HIV-related immune dysfunction are not yet defined. Methods We performed multiplex cytokine/chemokine profiling assays and high-dimensional flow cytometry, including markers to interrogate cellular metabolism, to characterize early innate responses 24 hours after the first dose of Engerix-B or Heplisav-B in PLWH who were non-responders to prior HBV vaccination. Results Heplisav-B induced robust early innate activation, characterized by significantly elevated IP-10, MCP-2, and IFN-γ versus baseline, consistent with Th1-skewed inflammatory profile that was not observed following Engerix-B vaccination. Heplisav-B produced an increased frequency of B cells following vaccination, but the cellular immunometabolic expression profiles were otherwise not significantly different between the two vaccines 24 hours after vaccination. This suggests that global immune cell proportions were largely maintained despite differences in cytokine induction. However, 24-hour cytokine levels predictive of seroprotection were distinct between vaccines, with low IL-17A production following Heplisav-B and low IL-2 and IL-4 production following Engerix-B being the strongest predictors of antibody responses. Conclusion Heplisav-B induces stronger Th1-skewed innate responses and increased B cell frequency than Engerix-B in PLWH within the first 24 hours of vaccination, while overall cellular composition and activation remain largely preserved. These findings provide mechanistic insight into how TLR9-targeting adjuvants can enhance vaccine immunogenicity in immunocompromised populations and suggest that response to the two vaccines may be driven through different innate immune pathways. Funding Source NIH/NIAID R01AI186730 Topic Categories Vaccines and Immunotherapy (VAC)