FDA Rejects Novel Hepatitis B Vaccine

Miriam E. Tucker

February 25, 2013

The US Food and Drug Administration (FDA) is withholding licensure of a new type of adult hepatitis B vaccine, citing safety concerns.

In a complete response letter issued to Dynavax Technologies Corporation regarding its biologic license application for Heplisav, the FDA specified that more safety data would be required for adults aged 18 to 70 years because it is such a broad population. The agency also expressed concern that the vaccine's novel adjuvant, intended to boost immunogenicity, might cause rare autoimmune problems.

This concern had been discussed at a November 15, 2012, meeting of the FDA's Vaccines and Related Biological Products Advisory Committee. There, the panel had voted 13 to 1 in favor of the immunogenicity data supporting the effectiveness of the vaccine but also voted 8 to 5 with 1 abstention that the safety data presented by the company were inadequate to support safety of the product.

Heplisav differs from currently licensed hepatitis B vaccines in its adjuvant, a toll-like receptor 9 agonist that elicits hepatitis B surface antigen–specific antibodies against the hepatitis B virus. Current hepatitis vaccines use the less-specific adjuvant alum, which stimulates a more general inflammatory response.

Because of its adjuvant, Heplisav provides improved seroprotection with 2 doses given 1 month apart as opposed to the 3 doses given at 0, 1, and 6 months that current hepatitis vaccines require. Heplisav was also designed to overcome the problem of the reduced immunogenicity seen with current hepatitis B vaccines among several groups of high-risk adults for whom the vaccine is recommended, including older adults, men, obese individuals, smokers, people with diabetes, and those who are immunocompromised.

However, although safety analyses showed no statistically significant differences between Heplisav and the currently licensed hepatitis B vaccine Engerix-B (GlaxoSmithKline) in local and systemic solicited adverse events or deaths, there were numerically greater numbers of patients receiving Heplisav who had evidence of autoimmunity disorders, including thyroid disorders.

The increases were not statistically significant, but advisory panel members said the safety database was too small to detect rare adverse events.

At the November hearing, Melinda Wharton, deputy director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, Atlanta, Georgia, voted yes for efficacy but no for safety. She said she was "glad to see work being done" on a hepatitis B vaccine that is more immunogenic in populations that do not respond optimally to current vaccines.

"That said, I don't think the safety database is sufficiently large to support a recommendation for use in the general adult population, given that this vaccine contains a new adjuvant," she explained.

In a statement released today, Dynavax said that the FDA expressed willingness to discuss a more restricted use of Heplisav and that the company plans to discuss with the FDA plans to "identify the most expeditious path to approval" of the vaccine, particularly for high-risk adults. Dynavax "currently believes the meeting can take place within 6 weeks."

The vaccine is currently under review in Europe.