Mucosal or Parenteral Administration of Microsphere-Associated Bacillus anthracis Protective Antigen Protects against Anthrax Infection in Mice

Abstract

Existing licensed anthrax vaccines are administered parenterally and require multiple doses to induce protective immunity. This requires trained personnel and is not the optimum route for stimulating a mucosal immune response. Microencapsulation of vaccine antigens offers a number of advantages over traditional vaccine formulations, including stability without refrigeration and the potential for utilizing less invasive routes of administration. Recombinant protective antigen (rPA), the dominant antigen for protection against anthrax infection, was encapsulated in poly-L-lactide 100-kDa microspheres. Alternatively, rPA was loosely attached to the surfaces of microspheres by lyophilization. All of the microspheric formulations were administered to A/J mice with a two-dose schedule by either the intramuscular route, the intranasal route, or a combination of these two routes, and immunogenicity and protective efficacy were assessed. An intramuscular priming immunization followed by either an intramuscular or intranasal boost gave optimum anti-rPA immunoglobulin G titers. Despite differences in rPA-specific antibody titers, all immunized mice survived an injected challenge consisting of 10 3 median lethal doses of Bacillus anthracis STI spores. Immunization with microencapsulated and microsphere-associated formulations of rPA also protected against aerosol challenge with 30 median lethal doses of STI spores. These results show that rPA can be encapsulated and surface bound to polymeric microspheres without impairing its immunogenicity and also that mucosal or parenteral administration of microspheric formulations of rPA efficiently protects mice against both injected and aerosol challenges with B. anthracis spores. Microspheric formulations of rPA could represent the next generation of anthrax vaccines, which could require fewer doses because they are more potent, are less reactogenic than currently available human anthrax vaccines, and could be self-administered without injection.Anthrax, the disease caused by the spore-forming bacterium Bacillus anthracis, occurs in three distinct forms, cutaneous, gastrointestinal, and pulmonary, depending upon the route of infection. Cutaneous anthrax, in which the spores infect a lesion in the skin, produces a characteristic black eschar and edema at the site of infection and can be effectively treated with antibiotics. Gastrointestinal and pulmonary anthrax infections, caused by ingestion and inhalation of spores, respectively, are more difficult to diagnose and treat successfully as the symptoms of infection are not always apparent in time for antibiotic treatment to be effective (21), so vaccination is essential to protect individuals who are likely to be exposed. There are currently two licensed anthrax vaccines available for human use. The current United Kingdom-licensed anthrax vaccine is an alum-precipitated filtrate of a B. anthracis Sterne strain culture which is administered by the intramuscular (i.m.) route and occasionally causes some transient reactogenicity. It als...

Effect of aluminum hydroxide adjuvant and formaldehyde in the formulation of rPA anthrax vaccine

“…Various formulations have been tested in preparing anthrax vaccines based upon rPA for its ability to elicit optimal immunological responses. Recent examples include Toll-like receptor ligands CpG ODN and Resiquimod R-848 [35,36], pluronic F127, a non-ionic, hydrophilic polyoxyethylenepolyoxypropylene block copolymer [37], additional vaccine antigens such as capsule [38] or EF [39,40], DNA vaccines [41], and mucosal vaccine strategies [42,43]. That antibodies have been recognized as important in protection is demonstrated by the number of immunotherapeutic reagents that have been recently suggested [44][45][46][47][48][49].…”

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits

“…Several candidate vaccines based on rPA have been described [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and have been shown to be highly protective against lethal aerosol or parenteral B. anthracis spore challenge.…”

Carbunco. Prevención de la enfermedad

“…También ha resultado exitosa la utilización de una vacuna a base de esporos de la cepa ΔSterne pXO1-, pXO2-, con posibilidad de expresar AP e inducir una respuesta anti AP mediada por IgG e IgAs cuando se la aplica por vía oral a cobayos, siendo capaz de proteger animales vacunados cuando se desafían con 20 DL 50 de B. anthracis. Las ventaja de estas vacunas orales reside en la facilidad de aplicación de las mismas, teniendo en cuenta el plan básico de inmunización que consta, como mí-nimo, de 6 aplicaciones (Aloni-Gristein et al, 2005;Flick-Smith et al, 2002;Mikszta et al, 2005;Sloat et al, 2005).…”