HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial

Abstract

Importance: Nonresponse to hepatitis B vaccine is common among people with HIV, resulting in vulnerability to infection with hepatitis B virus (HBV).

Objective: To compare the seroprotection response achieved with a 2-dose (noninferiority, 10% margin) and a 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine) vs a conventional 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine) in people with HIV and prior nonresponse to HepB-alum vaccine.

Design, setting, and participants: This phase 3, open-label, randomized clinical trial included people with HIV receiving antiretroviral therapy (CD4 cell count ≥100 cells/μL and HIV RNA <1000 copies/mL) without past or present serological evidence of having HBV or a response to hepatitis B vaccine. From December 2020 to February 2023, 561 adults were enrolled in the study 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.

Interventions: 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.

Main outcomes and measures: The primary outcome was a seroprotection response to hepatitis B vaccine (defined as level of antibody titer against hepatitis B surface antigen [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). Key secondary outcomes included seroprotection response at additional time points, antibody titer against HBsAg, and adverse events within 4 weeks of hepatitis B vaccination.

Results: Of 561 participants included in the analysis (median age, 46 years [IQR, 31-56 years]); 64% were male; 17% of participants were Asian, 42% were Black, and 35% were White), a seroprotection response was achieved in 93.1% who received 2 doses of HepB-CpG vaccine (n = 174), in 99.4% who received 3 doses of HepB-CpG vaccine (n = 169), and in 80.6% who received 3 doses of HepB-alum vaccine (n = 165). 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. 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%]). By week 12, more than 90% of participants who received HepB-CpG vaccine achieved a seroprotection response. 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%) vs the other 2 regimen groups (26.4% for 2 doses of HepB-CpG vaccine and 35.2% for 3 doses of HepB-alum vaccine). No unexpected safety issues were observed.

Conclusions and relevance: Among people with HIV and nonresponse to prior hepatitis B vaccination, both the 2-dose and 3-dose regimens of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine.

Trial registration: ClinicalTrials.gov Identifier: NCT04193189.

Figure 1.. Recruitment, Randomization, and Follow-Up in the Study

^aIndividuals may have met more that 1 ineligibility criteria. Only the first known reason for exclusion was included. ^bThe trial protocol allowed delays in vaccine dose up to 4 weeks after the final scheduled dose. These delays occurred in 6 participants in the group that received 2 doses of hepatitis B vaccine with a cytosine phosphoguanine adjuvant, in 20 participants in the group that received 3 doses of hepatitis B vaccine with a cytosine phosphoguanine adjuvant, and in 16 participants in the group that received 3 doses of conventional hepatitis B vaccine with an aluminum hydroxide adjuvant. ^cFor the primary outcome (study visit with measurement of the seroprotection response to a hepatitis B vaccine). ^dAdditional information appears in the statistical analysis plan in Supplement 2.

Figure 2.. Efficacy Analysis for the Primary Outcome of Seroprotection Response to the Hepatitis B Vaccine

The seroprotection response to the hepatitis B vaccine was defined as a level of antibody titer against hepatitis B surface antigen of 10 mIU/mL or greater. A, Of 174 participants in the group that received 2 doses of HepB-CpG vaccine, 162 (93.1%) had a seroprotection response; of 169 participants in the group that received 3 doses of HepB-CpG vaccine, 168 (99.4%) had a seroprotection response; and of 165 participants in the group that received 3 doses of HepB-alum vaccine, 133 (80.6%) had a seroprotection response. B, The estimated differences included Newcombe 97.5% CIs that were stratified by sex assigned at birth and diabetes status. For the comparison of the 3-dose HepB-CpG vaccine group vs the 3-dose HepB-alum vaccine group, repeated 97.5% CIs were adjusted for group sequential monitoring. The reference line at 0% represents no difference and the reference line at −10% represents the prespecified noninferiority margin.

Figure 3.. Seroprotection Response to the Hepatitis B Vaccine by Scheduled Study Weeks

Vaccine administration occurred at baseline (week 0) and week 4 in all 3 groups and at week 24 in the 2 groups that received 3 doses of hepatitis B vaccine. The seroprotection response to the hepatitis B vaccine was defined as a level of antibody titer against hepatitis B surface antigen of 10 mIU/mL or greater. The trial protocol allowed delays in vaccine dose up to 4 weeks after the final scheduled dose. These delays occurred in 6 participants in the group that received 2 doses of HepB-CpG vaccine, in 20 participants in the group that received 3 doses of HepB-CpG vaccine, and in 16 participants in the group that received 3 doses of HepB-alum vaccine.

Figure 4.. Level of Antibody Against Hepatitis B Surface Antigen at Primary Time Point

A level less than 5 mIU/mL was the assay lower limit of quantitation and a level greater than 1000 mIU/mL was the assay upper limit of quantitation.

Figure 5.. Adverse Events Related to the Hepatitis B Vaccine

The adverse event terms are MedDRA preferred terms (version 26.1). An adverse event receiving grade 1 was mild; grade 2, moderate; grade 3, severe; and grade 4, potentially life-threatening. The grading system is from the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (version 2.1).