Hepatitis B Virus Vaccines Underperform in People Living With HIV

Standard hepatitis B virus (HBV) vaccination leaves many people living with HIV (PLWH) unprotected, with seroconversion rates as low as 34% compared with 90% to 95% in the general population, according to a review published in Vaccines.¹ The gap stems from HIV-driven immune dysfunction that blunts vaccine-induced antibody responses, and it has renewed attention on intensified dosing schedules and newer adjuvanted formulations as ways to close it.

The findings arrive as managed care organizations and HIV specialty clinics face growing calls to systematize postvaccination serologic testing and revaccination pathways rather than treating HBV vaccination as a 1-time, 1-size-fits-all intervention.

Why Do PLWH Respond Poorly to Standard Vaccines?

HIV disrupts several steps required for durable antibody production. CD4+ helper T cells, which support germinal center formation and antibody maturation, are depleted and functionally impaired. Antigen-presenting cells, such as dendritic cells, show reduced costimulatory signaling, and chronic immune activation creates an inflammatory environment that is active but poorly coordinated for vaccine priming. B cells are similarly affected, with HIV driving loss of memory B-cell pools and expansion of exhausted, atypical B-cell subsets, changes linked to weaker anti–hepatitis B surface antibody responses.²

Antiretroviral therapy (ART) helps: viral suppression and higher CD4+ counts are consistently associated with better seroconversion, and one Ugandan cohort with a median CD4+ count of 426 cells/µL saw 92% of participants achieve protective titers after a standard 3-dose series. However, ART does not fully normalize responses, and antibody titers often wane faster in PLWH than in the general population, even after initial seroconversion.

Which Vaccination Strategies Improve Response Rates?

A 2021 meta-analysis of 17 studies and 1821 PLWH found that doubling the antigen dose (40 µg) raised seroconversion to 75.2% vs 65.5% at the standard dose, and a 4-dose schedule reached 89.7% vs 63.3% for the conventional 3-dose series. A separate systematic review of 9 trials and 970 PLWH confirmed that double-dose regimens improve both the magnitude and durability of response.

CpG-adjuvanted vaccination (Heplisav-B; Dynavax) has emerged as a particularly promising option. It activates TLR9, driving stronger dendritic cell and B-cell activation than aluminum-adjuvanted vaccines. In PLWH with documented prior vaccine nonresponse, 2-dose and 3-dose hepatitis B–CpG regimens achieved significantly higher seroprotection than repeating a standard aluminum-adjuvanted series, and a phase 3 trial in vaccine-naive PLWH reported 100% seroprotection after 3 CpG-adjuvanted doses with no serious safety signals.¹

This mirrors prior research showing Heplisav-B’s superiority in the general population; in head-to-head trials, the vaccine achieved a 95.1% seroprotection rate 8 weeks after the second dose vs 81.1% for Engerix-B 4 weeks after the third dose, a difference that held up as both noninferior and statistically superior.³ The new review extends that immunogenicity advantage specifically to PLWH, a population the original Heplisav-B trials excluded.¹

Accelerated schedules and intradermal delivery have been studied as well, with mixed results. An accelerated 0-, 1-, and 3-week regimen improved series completion (91.8% vs 82.7%) but did not improve seroprotection; the series produced a 20.8% lower response among patients with CD4+ counts of 200 to 500 cells/mm³. Intradermal delivery has shown inconsistent results across trials, making it a biologically plausible but less standardized alternative to optimized intramuscular dosing.

Current guidance from the National Institutes of Health calls for postvaccination serologic testing 1 to 2 months after the final dose, with revaccination, preferably using hepatitis B–CpG or an intensified schedule, for anyone who fails to reach an anti–hepatitis B surface antibody level of 10 mIU/mL or higher. The review also flags isolated hepatitis B core antibody, a pattern seen in 7% to 19% of PLWH, as clinically ambiguous: a single challenge dose followed by anti-hepatitis B surface antibody testing can distinguish an anamnestic memory response from primary nonresponse, guiding whether a full series is needed.

What Stands in the Way of Better Coverage?

Even where optimized regimens exist, delivery gaps persist. One specialty HIV clinic cohort found 59% of 502 PLWH were missing at least 1 CDC-recommended vaccine. Globally, HBV birth-dose coverage remains at just 45%, and HIV- and HBV-related stigma continue to suppress screening, disclosure, and follow-through on vaccination.

Real-world catch-up vaccination efforts can move the needle: expanded HBV vaccination recommendations in Germany were associated with declining HBV prevalence among PLWH between 1996 and 2019, even though 14% of that population remained unvaccinated as of the study’s close.⁴ Combined with newer adjuvant and dosing options, the current review’s authors argue that closing the remaining implementation gaps, not just improving the vaccines themselves, will be essential to protecting PLWH from HBV-related liver disease going forward.¹

“Based on these considerations, a pragmatic, stepwise approach to HBV vaccination in PLWH is proposed to guide clinical decision-making and implementation in routine care,” they concluded.

References

1. Radi C, Faraj JA, Idriss J, et al. Hepatitis B vaccination in people living with HIV: bridging the immunological gap. Vaccines (Basel). 2026;14(7):623. doi:10.3390/vaccines14070623
2. Tian Y, Hua W, Wu Y, et al. Immune response to hepatitis B virus vaccine among people living with HIV: a meta-analysis. Front Immunol. 2021;12:745541. doi:10.3389/fimmu.2021.745541
3. Surofchy DD, Shieh N, Tam I. Evolving considerations for choice of hepatitis B vaccine. AJMC^®. February 14, 2023. Accessed July 29, 2026. https://www.ajmc.com/view/evolving-considerations-for-choice-of-hepatitis-b-vaccine
4. Bonavitacola J. HBV vaccine recommendations, catch-up efforts decreased infection rate in patients with HIV. AJMC. October 4, 2023. Accessed July 29, 2026. https://www.ajmc.com/view/hbv-vaccine-recommendations-catch-up-efforts-decreased-infection-rate-in-patients-with-hiv