Multiple Imputation in the Anthrax Vaccine Research Program

Anthrax, caused by the bacterium Bacillus anthracis, can be a highly lethal acute disease in humans and animals. Prior to the 20th century, it led to thousands of deaths each year. Anthrax infection became extremely rare in the United States in the 20th century, thanks to extensive animal vaccination and anthrax eradication programs. The 2001 anthrax attacks in the United States drew this formidable disease back into the public spotlight. Anthrax spores have not long been used in biological warfare or as a terrorism weapon, but anthrax has been on the bioterrorism (BT) agent list for a long time. U.S. military personnel are now routinely vaccinated against anthrax prior to active service in places where biological attacks are considered a threat. The current FDA-licensed vaccine, anthrax vaccine adsorbed (AVA), is produced from a nonvirulent strain of the anthrax bacterium. The licensed regimen for AVA is subcutaneous administration of a series of six primary doses (zero, two, and four weeks and six, 12, and 18 months), followed by annual booster doses. In 1998, a pilot study conducted by the U.S. Department of Defense provided preliminary data suggesting AVA could be given intramuscularly and without the two-week dose, reducing adverse events and not adversely impacting immunogenicity. Since 2000, the CDC has been planning and conducting a clinical trial, the Anthrax Vaccine Research Program (AVRP), to evaluate a reduced AVA schedule and a change in the route of administration in humans. The AVA trial is a 43-month prospective, randomized, double-blind, placebo-controlled trial for the comparison of immunogenicity (i.e., immunity) and reactogenicity (i.e., side effect) elicited by AVA given by different routes of administration and dosing regimens. Administration is subcutaneous (SQ) versus intramuscular (IM). Dosing regimens require as many as eight doses versus as few as four doses. In the AVRP, sterile saline is used as the placebo when a dose is not actually administered. The trial is being conducted among 1,005 healthy adult men and women (18–61 years of age) at five U.S. sites. Participants were randomized into one of seven study groups. One group receives AVA as currently licensed (SQ with six doses followed by annual boosters). Another group receives saline IM or SQ at the same time points as the currently licensed regimen. The five other groups receive AVA IM: one group at the same time points as the currently licensed regimen and the remaining groups in modified dosing regimens. Placebo is given when a dose of AVA is omitted from the licensed dosing regimen. There are 25 required visits over 42 months, during which all participants receive an injection of vaccine or placebo (eight injections total), have a blood sample drawn (16 total), and have an in-clinic examination for adverse events (22 total). Total anti-protective antigen IgG antibody (anti-PA IgG levels) is measured using a standardized and validated enzyme-linked immunosorbent assay (ELISA). The primary study endpoints are four-fold rise in antibody titer, geometric mean antibody concentration, and titer. All adverse events, Multiple Imputation in the Anthrax Vaccine Research Program