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  Conference on Retroviruses
and Opportunistic Infections
Denver, Colorado
March 3-6 2024
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HepB-CpG Vaccine Superior to HepB-alum in HIV Group With Prior Nonresponse
  CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver
Mark Mascolini
Two or 3 doses of a HepB-CpG vaccine achieved a seroprotection response (SPR) superior to 3 doses of a standard HepB-alum vaccine in people with HIV infection and prior nonresponse to conventional hepatitis B vaccines [1]. No unexpected safety concerns arose in this international trial involving 561 people with HIV infection, ACTG study A5379 (the BEe-HIVe study).
Kristen Marks (Weill Cornell Medicine, New York) and colleagues on 4 continents explained that conventional hepatitis B vaccines combine recombinant hepatitis B surface antigen (HBsAg) and an alum adjuvant. (Alum has seen duty as a vaccine adjuvant since the 1930s.[2]) These standard vaccines attain seroprotection (anti-HBs 10 mIU/mL or greater) in 35% to 80% of people with HIV infection. Older age, low CD4 count, and a detectable viral load predict nonresponse to HepB-alum vaccines.
HepB-CpG vaccines such as HEPLISAV-B combine 20 mcg of recombinant HBsAg with CpG 1018 adjuvant. HepB-CpG’s novel adjuvant binds to TLR9, a toll-like receptor agonist that provokes innate immune responses. The FDA approved 2 doses of this vaccine for people 18 and older. But recent work by Kristen Marks and coworkers showed that 3 doses of the HepB-CpG vaccine provide 100% seroprotection in people with HIV and no previous hepatitis B vaccination [3].
Aims of the new study were (1) to compare seroprotection between 2 doses of HepB-CpG and 3 doses of HepB-alum after 28 weeks in a noninferiority comparison, (2) to compare seroprotection between 3 doses of HepB-CpG and 3 doses of HepB-alum after 28 weeks in a superiority comparison, and (3) to assess safety.
Participants had to be 18 to 70 years old and have an HBsAg level below 10 mIU/mL or be “negative” of indeterminant within 45 days of entering the study. They had to have documented HBV vaccination and an HIV load below 1000 copies and CD4 count above 100 while taking antiretroviral therapy (ART) for 45 days before study entry. Their hemoglobin A1c had to be below 9.0% and they had to use contraception if they could bear children. The trial excluded people with (1) HBsAg above 10 mIU/mL at any time, (2) current infection or prior exposure to HBV defined as being HBsAg or HBcAg positive, (3) a history of clinical hepatic decompensation, chronic kidney disease stage G4 or G5, a cancer diagnosis, or various immunosuppressive conditions or (4) breastfeeding or pregnant women.
The primary SPR endpoint was anti-HBs at or above 10 mIU/mL at week 28 in 3-dose arms and at week 12 in the 2-dose arm. The researchers used the Newcombe method stratified by sex at birth and screening diabetes status to determine differences in SPR proportions with a 2-sided 97.5% confidence interval (CI).
The A5379 trial accrued participants at 41 sites in 10 countries (the US, Brazil, and multiple countries in Africa and Asia) from December 2020 to February 2023. Participants received the 2-dose HepB-CpG vaccine at weeks 0 and 4 and either of the 3-dose vaccines at weeks 0, 4, and 24. The 187 people in the HepB-CpG 2-dose arm, the 188 in the HepB-CpG 3-dose arm, and the 186 in the HepB-alum arm had median ages of 46, 46, and 47. Females made up 36% of each arm and proportions of blacks were 45%, 40%, and 40%, whites 34%, 33%, and 39%, and Hispanics 21%, 22%, and 22%. Respective proportions of non-US residents were 45%, 46%, and 42%. Current median CD4 counts for the three groups were in the 600s, 94% in each arm had an HIV load below 40 copies, and median body mass index for the three groups lay around 26.5 kg/m2.
Proportions who met the primary SPR endpoint were 93.1% in the 2-dose HepB-CpG arm, 99.4% in the 3-dose HepB-CpG arm, and 80.6% in the 3-dose HepB-alum arm. Sensitivity analysis including participants with imputed results registered respective SPRs of 92.3%, 99.4%, and 77.8%.
SPR difference between the 2-dose HepB-CpG arm the 3-dose HepB-alum arm was 12.5% (97.5% CI 4.1 to 20.9), a result confirming noninferiority of the 2-dose CpG vaccine to the alum vaccine and indicating superiority over the alum vaccine. SPR difference between the 3-dose HepB-CpG vaccine and the HepB-alum vaccine was 18.4% (97.5% CI 10.4 to 26.2), meaning the CpG vaccine was superior to the alum vaccine in attaining SPR. The SPR proportion of the two CpG vaccines virtually overlapped and diverged from the alum SPR after 4 injections. From that point CpG vaccine SPR proportions remained about 20% higher than the alum vaccine SPR proportion through 24 injections.
The researchers recorded anti-HBs titers above 1000 mIU/mL in 78% getting 3 doses of the HepB-CpG vaccine, 25% getting 2 doses of that vaccine, and 35% getting the HepB-alum vaccine.
Three shots of the CpG vaccine yielded SPR for 100% of everyone under 60 years old and for 94% of those 60 and older. Three injections of that vaccine elicited a seroprotective response for 100% with a CD4 count below 200, 100% with a count between 200 and 350, 96% with a count between 350 and 500, and 100% with a count above 500. HIV load below or above 40 copies did not affect SPR with the CpG vaccine (99% below 40 copies and 100% above); nor did years since previous vaccination: 0 to less than 5 years, 99% SPR; 5 to less than 10 years, 100% SPR; 10 or more years, 100% SPR.
Grade 2 or worse adverse events within 4 weeks of vaccination affected 33% of people in the 2-dose HepB-CpG group, 45% in the 3-dose HepB-CpG group, and 43% in the 3-dose HepB-alum group. Grade 2 or 3 adverse events that affected 5% or more participants included injection site pain, fatigue, headache, malaise, and myalgia. One or more vaccine-related adverse events of any grade affected 33% in the 2-dose HepB-CpG arm, 46% in the 3-dose HepB-CpG arm, and 36% in the HepB-alum arm.
CROI: HepB-CpG vaccine is superior to HepB-alum in people with HIV and prior vaccine non-response (A5379) - (03/15/24)
1. Marks K, Kang M, Umbleja T, et al. HepB-CpG vaccine is superior to HepB-alum in people with HIV and prior vaccine nonresponse: A5379. CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver. Abstract 209. 2, Centers for Disease Control and Prevention. Adjuvants and vaccines.
3. 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-naive people with human immunodeficiency virus. Clin Infect Dis. 2023;77:414-418. doi: 10.1093/cid/ciad201. https://pubmed.ncbi.nlm.nih.gov/37017075/