Attenuated Nontoxinogenic and Nonencapsulated Recombinant Bacillus anthracis Spore Vaccines Protect against Anthrax

摘要: The etiological agent of anthrax disease in animals and humans is the spore-forming bacterium Bacillus anthracis. major factors virulence B. anthracis are located on two plasmids, pXO1 pXO2. pXO2 encodes a poly-d-glutamic acid capsule (19, 41), while binary exotoxins, lethal toxin (LT) edema (ET) (43, 46, 61). These toxins composed three different proteins: protective antigen (PA), factor (EF), (LF) (for review, see reference 36). PA common receptor binding domain can interact with effector domains, EF LF, to mediate their entry into target cells (14). calmodulin-dependent adenylate cyclase (37) responsible for seen at site infection experimental (17). LF metalloprotease (34) recently shown cleave amino termini mitogen-activated protein kinase kinases 1 2, which results inactivation (13). It remains be determined whether these main physiological substrates LT activity vivo (5, 22). Two types vaccines licensed use humans: spores toxigenic, nonencapsulated STI-1 strain (55) cell-free PA-based consisting aluminum hydroxide-adsorbed supernatant material from cultures V770-NPI-R (49) or alum-precipitated culture filtrate Sterne (6). live attenuated occasionally general local adverse responses, observed both after primary application revaccination, frequency responses increases number vaccinations (58). Furthermore, it was reported that vaccine has relatively low immunogenicity (reviewed by Stepanov et al. 58). To increase immunogenicity, combined supplemented formulation evaluated proposed veterinary (1). While appear safer, they require numerous boosters (8) were have reduced ability protect laboratory against certain virulent strains (39, 60). In addition, contain variable amounts PA, as well undefined quantities EF, adsorbed hydroxide (4, 21, 49, 59). appears, therefore, there need safe more efficient could generate stable prolonged immunity (59). conclusions led evaluation various adjuvants purified (2, 16, 29, 59) creation vaccines: based nonvirulent (pXO1+) mutated (31, 47) expressing cloned pagA gene using heterologous hosts such vaccinia virus, subtilis, Salmonella typhimurium (10, 27, 28, 30, 31, 64), nontoxinogenic (4). pioneering studies suggest recombinant may potential future vaccine. We report here construction several recombinant, nonencapsulated, levels PA. We demonstrate one strains, containing under potent constitutive promoter, safely used provide efficacious long-lasting following single immunization dose.