HepB-CpG Offers Superior Seroprotection in People with HIV, Prior HBV Vaccine Nonresponse

Kristen Marks, MD

Credit: Weill Cornell

The 2- and 3-dose regimens of the HepB-CpG vaccine offer superior seroprotection response compared with 3 doses of the conventional HepB-alum vaccine in people with human immunodeficiency virus (HIV) and prior nonresponse to hepatitis B virus (HBV) vaccination, according to findings from a recent study.1

Results of the phase 3, open-label, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) Network 5379 B-Enhancement of HBV Vaccination in Persons with HIV (BEe-HIVe) randomized clinical trial support a change in practice to use the HepB-CpG vaccine for people with HIV who are vaccine-naive or have prior nonresponse to conventional hepatitis B vaccines.¹

“Risk factors for not achieving seroprotection with a conventional hepatitis B vaccine with an aluminum hydroxide adjuvant include older age, diabetes, obesity, smoking, male sex, and immunocompromising conditions (such as HIV),” Kristen Marks, MD, an associate professor of medicine at Weill Cornell Medicine, and colleagues wrote.¹ “Revaccination is recommended for nonresponders to hepatitis B vaccine, but novel strategies are needed to improve response.”

The development and subsequent availability of a hepatitis B vaccine with a toll-like receptor 9 (TLR-9) agonist adjuvant has enhanced the immune response to HBsAg. Although the HepB-CpG vaccine has demonstrated efficacy in vaccine-naive people with HIV, limited data exist for nonresponders to conventional hepatitis B vaccines.^1,2

To compare the seroprotection response achieved with a 2-dose and a 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant, the HepB-CpG vaccine, versus a conventional 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant, the HepB-alum vaccine, in people with HIV and prior nonresponse to the HepB-alum vaccine, investigators conducted a phase 3, open-label, randomized clinical trial. ¹

They enrolled adult patients ≥18 years of age receiving antiretroviral therapy for HIV who had a CD4 cell count ≥100 cells/μL and HIV RNA <1000 copies/mL. Additionally, patients were required to not have past or present serological evidence of HBV or a response to hepatitis B vaccine, defined as the presence of hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen, or level of antibody titer against HBsAg ≥10 mIU/mL at screening or at any time prior to screening.¹

Participants were randomly assigned to receive 2 doses of HepB-CpG vaccine administered intramuscularly at weeks 0 and 4; 3 doses of HepB-CpG vaccine administered intramuscularly at weeks 0, 4, and 24; or 3 doses of HepB-alum vaccine administered intramuscularly at weeks 0, 4, and 24.¹

The primary outcome was a seroprotection response to hepatitis B vaccine (defined as level of HBsAg ≥10 mIU/mL) at week 12 for the 2-dose regimen (8 weeks after dose 2) and at week 28 for 3-dose regimens (4 weeks after dose 3). Additional secondary outcomes included seroprotection response at additional time points, antibody titer against HBsAg, and adverse events within 4 weeks of hepatitis B vaccination.¹

From December 2020 to February 2023, 561 patients were enrolled and randomized at 41 sites in 10 countries in Africa, Asia, North America, and South America with follow-up for the primary outcome analysis through September 4, 2023. Of these participants, 187 were in the 2-dose HepB-CpG vaccine group, 188 were in the 3-dose HepB-CpG vaccine group, and 186 were in the 3-dose HepB-alum vaccine group.¹

Among the entire study cohort, the median age was 46 (interquartile range [IQR], 31-56) years, 64% of patients were male, and 42% were Black. In total, 96% of participants completed the study vaccine series, with most incompletions attributed to loss of follow-up, study withdrawal, or nonadherence.¹

Investigators noted a seroprotection response was achieved in 93.1% of participants in the 2-dose HepB-CpG vaccine group; 99.4% of participants in the 3-dose HepB-CpG vaccine group; and 80.6% of participants in the 3-dose HepB-alum vaccine group.¹

The stratified difference in seroprotection response between the 2-dose HepB-CpG vaccine group and the 3-dose HepB-alum vaccine group was 12.5% (97.5% CI, 4.1%-20.9%), achieving noninferiority and indicating superiority. Additionally, the 3-dose HepB-CpG vaccine regimen was superior to the 3-dose HepB-alum vaccine regimen (stratified difference in seroprotection response, 18.4%; repeated 97.5% CI, 10.4%-26.2%).¹

Additionally, investigators pointed out the 3-dose regimen of HepB-CpG vaccine achieved a higher proportion of participants with antibody titer against HBsAg greater than 1000 mIU/mL (78.1%) versus the other 2 regimen groups (26.4% for 2 doses of the HepB-CpG vaccine and 35.2% for 3 doses of the HepB-alum vaccine).¹

Adverse events after vaccination were experienced by 33.2% (95% CI, 26.8%-40.2%) of participants in the 2-dose HepB-CpG vaccine group; 44.7% (95% CI, 37.8%-51.8%) of participants in the 3-dose HepB-CpG vaccine group; and 43.5% (95% CI, 36.6%-50.7%) of participants in the 3-dose HepB-alum vaccine group. Injection site pain, headache, fatigue, malaise, and myalgia were the most frequent adverse events related to hepatitis B vaccination.¹

Investigators acknowledged multiple limitations to these findings, including the heterogeneity of past vaccine experiences in the study population; the inclusion of 10 participants who had a level of antibody titer against HBsAg that was ≥ 10 mIU/mL at entry; and the limited representation of patients with a low CD4 cell count and detectable HIV viremia.¹

“​​This phase 3, open-label, randomized clinical trial of people with HIV and prior nonresponse to hepatitis B vaccine demonstrated that both 2 and 3 doses of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine,” investigators concluded.¹ “The current study results support a change in practice to use HepB-CpG vaccine for people with HIV who are vaccine-naive or have prior nonresponse to conventional hepatitis B vaccines.”

References

1. ^{Marks KM, Kang M, Umbleja T, et al. HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial. JAMA. doi:10.1001/jama.2024.24490}
2. ^{Marks KM, Kang M, Umbleja T, et al. Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naïve People With Human Immunodeficiency Virus. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciad201}