A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: A need for more robust study designs and results

BACKGROUND: B. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax outbreak an approved anti-toxin agent was administered in, survival did not differ comparing recipients and non-recipients, although recipients appeared sicker. OBJECTIVE: Employ a systematic review and meta-analysis to investigate preclinical studies supporting anthrax anti-toxin agents. DATA SOURCE: PubMed, EMBASE, and Scopus. STUDY ELIGIBILITY: Compared survival with an anti-toxin agent versus control in B. anthracis challenged, antibiotic treated animals. STUDY METHODS: Examine model and study design and the effect of anti-toxin agents on relative risk of death(95%CI) (RR). RESULTS: From 9 studies, 29 experiments were analyzed which included 4 species (748 animals) and 5 agents; LFI, AIG, AVP-21D9, Raxibacumab, and ETI-204. Only five experiments were blinded and no experiment included the cardiopulmonary support sick B. anthracis patients receive. Only one agent in a single un-blinded experiment reduced RR significantly [0.45(0.22,0.940]. However, in six studies testing an agent in more than one experiment in the same species, agents had consistent survival effects across experiments [I(2) = 0, p≥0.55 in five and I(2) = 42%, p = 0.16 in one]. Within each species, agents had effects on the side of benefit; in one study testing AVP-21D9 in mice [0.11(0.01,1.82)] or guinea pigs [0.70(0.48,1.03)]; across eight rabbit studies testing LFI, Raxibacumab, AIG or ETI-204 [0.62(0.45,0.87); I(2) = 17.4%, p = 0.29]; and across three monkey studies testing Raxibacumab, AIG or ETI-204 [0.66(0.34,1.27); I(2) = 25.3%, p = 0.26]. Across all agents and species, agents decreased RR [0.64(0.52,0.79); I(2) = 5.3%, p = 0.39]. LIMITATIONS: Incidence of selective reporting not identifiable. CONCLUSIONS: Although overall significant, individually anti-toxin agents had weak beneficial effects. Lack of study blinding and relevant clinical therapies further weakened studies. Although difficult, preclinical studies with more robust designs and results are warranted to justify the resources necessary to maintain anti-toxin agents in national stockpiles.