SALISBURY, UK—Approved anthrax vaccines require multiple intramuscular (IM) doses and poorly stimulate mucosal immunity. By binding anthrax recombinant protective antigen (rPA) to microspheres, researchers have created an experimental vaccine that can be administered via either an IM or intranasal (IN) route; in a recent study, only two doses protected mice against both inhaled and injected anthrax spores.[1] The approach could lead to human vaccines employing microsphere-bound rPA; these might better promote mucosal immunity than approved vaccines and could simplify immunization by allowing longer storage and self-administration.

The study shows that “nasal immunization against anthrax has the potential to be as effective as parenteral immunization,” E. Diane Williamson, BSc, PhD, told PULMONARY REVIEWS. Thus, her findings suggest alternatives to current anthrax vaccines.

APPROVED VERSUS EXPERIMENTAL

A vaccine licensed in the United Kingdom which contains PA protein from Bacillus anthracis filtrate precipitated with alum requires four IM doses in a six-month period, and it has unknown efficacy against inhalational anthrax. A vaccine used in the United States, anthrax vaccine adsorbed (AVA), employs adsorbed PA. AVA entails six subcutaneous doses in 18 months and has been shown to protect monkeys from experimentally induced inhalational anthrax. Both vaccines can cause local reactions and require annual booster doses.

Like AVA, Dr. Williamson’s vaccine is based on PA, but in recombinant form. “If a potent immune response can be achieved to PA, then this is likely to be protective, because PA is the key toxin secreted by the bacterium,” emphasized Dr. Williamson, a group leader in microbiology at the UK’s Defence Science and Technology Laboratory. But conjugating rPA to polymeric microspheres confers advantages. “Encapsulation not only protects the PA from degradation by host enzymes, it also presents the PA in a highly immunogenic, particulate form,” which allows application to the nasal mucosa instead of injection. Nasal immunization, already used for influenza vaccines, confers protective immunity, particularly in the lung mucosa.

PROTECTION OPTIMIZED

While free rPA administered IN was ineffectual, free rPA combined with a mucosal adjuvant induced anti-PA immunoglobulin G (IgG). Free and various microsphere-bound rPA formulations injected IM also induced substantial IgG titers and protected all mice from an otherwise-lethal intraperitoneal dose of 1 X 106 anthrax spores.

Two formulations of rPA weakly bound to microspheres induced optimal IgG titers, the researchers found. Two IM doses produced higher titers than did two IN doses or an IN priming dose combined with an IM booster. However, immunization by any route protected mice from intraperitoneal challenge with 7 X 106 spores, about 103 median lethal doses (MLDs). Inoculation with one formulation by any route also saved all mice challenged with an inhaled aerosol dose of 1.57 X 104 spores (30 MLDs). Although one of six mice (17%) inoculated only by the IN route with a second formulation died, priming/booster combinations including at least one IM injection protected all.

Because mucosal immunization induces potent local protective immunity and does not require injection, it may improve upon current human IM vaccines, Dr. Williamson argued. However, based on her findings, she envisions optimizing anthrax prophylaxis by combining IM and IN routes.

—Mimi Zucker, PhD

Reference
1. Flick-Smith HC, Eyles JE, Hebdon R, et al. Mucosal or parenteral administration of microsphere-associated Bacillus anthracis protective antigen protects against anthrax infection in mice. Infect Immun. 2002;70:2022-2028.

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