Novel Adjuvant Stimulates Greater Response to HBV Vaccination in Older Adults

October 11, 2007 (San Diego) — Vaccination with 1018 immunostimulatory sequence (1018 ISS) combined with hepatitis B surface antigen (HBsAg) generated a greater immune response in older adults than did traditional vaccine using an alum adjuvant. The data were presented here at the Infectious Diseases Society of America 45th Annual Meeting.
Traditional HBV vaccination generates protective titers of antibodies in only 75% of adults aged 60 years or older. Edwardo B. Martins, MD, from Dynavax Technologies, San Francisco, California, explained that the company developed 1018 ISS, an immunostimulatory phosphorotioate oligonucleotide, as an antagonist to Toll-like receptor 9 to overcome this issue.
Dr. Martins said the 3000-µg 1018 ISS molecule primarily activates plasmacytoid cells and B cells in human peripheral blood. It is a potent adjuvant for stimulating antibody and Th1 T-cell responses.
The phase 3 clinical trial enrolled 412 subjects aged 40 to 70 years in multiple centers in Singapore, the Philippines, and Korea. It randomly assigned them in a 1:1 ratio to receiveHBsAg + 1018 ISS or the commercially available Engerix-B vaccine made by GlaxoSmithKline.
A placebo was administered to each group at differing time points so that the schedule of intramuscular inoculations was the same in both. HBsAg + 1018 ISS was administered at weeks 0, 8, and 24 (placebo at week 4), and Engerix-B was administered at weeks 0, 4, and 24 (placebo at week 8).
Seroprotective levels of anti-HBsAg (≥ 10 mU/L) were measured 4 weeks after every inoculation and at week 50 in this study of older adults. The trial found superior protection in the ISS-containing group compared with the Engerix-B group at every time point (week 4, 14% vs 3%; week 8, 30% vs 24%; week 12, 97% vs 23%; week 24, 99% vs 25%; week 28, 100% vs 73%; and week 50, 100% vs 69%).
To factor out any possible confounding of results from administering the placebo dose at different time points in each group, the study also looked at the geometric mean concentration (GMC) of antibody 4 weeks after administration of the second dose of true vaccine and found the same superiority (539 vs 2 GMC). The differential persisted at week 24 (1753 vs 94 GMC) and week 50 (379 vs 34 GMC). At each time point, P was less than .0001.
A subgroup analysis of those aged 56 to 70 years showed seroprotection of 100% vs 56% at week 28 — an even greater differential than that seen in the younger group of subjects.
Overall adverse events were mild to moderate and comparable in both groups.
Dr. Martins said that HBsAG + 1018 ISS generates "a faster, more durable immune response, and higher rates of seroprotection compared to alum-adjuvant vaccine." The data from the control group of this trial are consistent with response rates seen in the literature.
He also believes that the clinical impact of HBsAG + 1018 ISS will be most broadly seen in vaccinating adults, particularly older adults, where it will provide broader, more durable protection from infection with HBV.
Richard Sterling, MD, a hepatologist at the Virginia Commonwealth University School of Medicine, Richmond, called the results "thoroughly encouraging, because currently available vaccines for hepatitis B are not effective 100% of the time."
He was surprised to see rates of protection among the control group that are lower than what is commonly seen in the literature for the approved HBV vaccines. However, part of that might be attributed to differing ages of the study populations. And although the titers of antibody generated by HBsAG + 1018 ISS are impressive, complete protection is seen with levels of 10 — or possibly even as low as 8 — so the elevated levels of antibody are likely to have little clinical relevance for most patients.
Dr. Sterling would be most interested in seeing data in traditionally hard-to-vaccinate populations such as patients with cirrhosis and compromised immune systems and healthcare workers, in whom multiple vaccinations have failed to produce protective titers of antibodies. He also would like to see safety data in children to assuage concerns about possible broader use of the vaccine.
Dr. Martins is an employee of Dynavax, which is developing the product. Dr. Sterling has disclosed no relevant financial relationships.
Infectious Diseases Society of America 45th Annual Meeting: Abstract 1148. Presented October 6, 2007.