Trial offers hope for shortening anthrax-shot series

Oct 6, 2008 (CIDRAP News) – An interim report from a major study of the US's only licensed anthrax vaccine suggests it may be possible to reduce local side effects without sacrificing effectiveness by changing the injection route and using fewer doses.

The standard regimen for the vaccine—required for US military personnel deployed in the Middle East—is six subcutaneous doses over an 18-month period, followed by annual boosters. Many military members have complained of side effects over the years. The vaccine, called anthrax vaccine adsorbed (AVA), or BioThrax, is made by Emergent BioSolutions Inc.

In the study, volunteers who received three or four intramuscular (IM), instead of subcutaneous, doses over 6 months had about the same antibody responses at 7 months as did volunteers who received the standard regimen, involving four subcutaneous doses in the first 6 months. In addition, those who received four IM doses had fewer negative effects at the injection site than did those who received four subcutaneous doses.

"Changing the injection route from SQ [subcutaneous] to IM may increase vaccine acceptability," says the report, published in the Oct 1 Journal of the American Medical Association. "Reducing the number of doses in the AVA regimen would have the added benefit of increasing the number of doses available for prophylactic use."

Study design and approach
The study is part of the Centers for Disease Control and Prevention's (CDC's) Anthrax Vaccine Research Program, established by Congress in 1999, the report says. The authors include investigators from the CDC and five other centers around the country. They report their analysis of data collected from the first 1,005 participants during the first 7 months of a 43-month trial.

Healthy volunteers between the ages of 18 and 61 were randomly assigned to one of six groups. The first group (the 4-SQ group) received the first four AVA doses subcutaneously on the standard schedule: at 0, 2, and 4 weeks and at 6 months. The second group (the 4-IM group) received the first four doses on the same schedule but by the IM route.

Groups 3, 4, and 5 received the vaccine intramuscularly at weeks 0 and 4 and at 6 months, getting a placebo vaccine at 2 weeks. The groups were to go on different regimens later in the study but were combined for the interim analysis and designated the 3-IM group. Group 6 received placebo vaccines on the same four-dose schedule.

The investigators assessed injection-site reactions and the levels of immunoglobulin-G (IgG) antibodies to anthrax protective antigen (PA), as indicated by geometric mean concentration (GMC), geometric mean titer (GMT), and the proportion of responders with a fourfold rise in titer.

Promising results
After 8 weeks, the 4-IM group was statistically "noninferior" to the 4-SQ by all the measures of antibody response, but the 3-IM group was noninferior to the 4-SQ group only for the percent showing a fourfold rise in titer. After 7 months, however, both of the IM groups were noninferior to the 4-SQ group. For example, 98.8% of the 4-IM group and 98.2% of the 3-IM group had a fourfold rise in antibody titer, versus 99.4% in the standard-regimen (4-SQ) group.

Comparing rates of injection-site reactions in the 4-SQ and 4-IM groups, the authors found that the 4-IM group had significant reductions in the incidence of warmth, tenderness, itching, erythema, induration, edema, and nodules, though not in pain, arm stiffness, or bruising. For example, edema was 64% less common in the 4-IM group than in the other group (odds ratio, 0.36; 95% confidence interval, 0.25 to 0.51). The data also showed that reactions in the 4-IM group resolved faster.

However, the route of vaccine administration made no significant difference in the rates of systemic adverse events, such as fatigue, muscle aches, headache, and fever, the report says.

Results also showed that in all treatment groups, women were almost twice as likely as men to experience any injection-site reactions, but the differences for several of the reactions were largest in the 4-SQ group.

The report says that the rise in antibody levels in the 3-IM group after two doses and 8 weeks was significant in comparison with the controls but was 50% lower than that seen in the 4-IM group at the same time point (after three doses). In light of results in animal studies, the authors write, "It is nonetheless highly probable that the antibody levels elicited by 2 doses of AVA (weeks 0, 4) would confer protection against anthrax in humans."

They add that this interpretation is supported by the immune responses observed after 7 months, "which clearly demonstrate that a 3-IM schedule provides immunological priming equivalent to the 4-SQ and 4-IM schedules."

Marano N, Plikaytis BD, Martin SW, et al. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months. JAMA 2008 Oct 1;300(13):1532-43 [Abstract]

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