One of the difficulties in developing countermeasures to biothreat agents is the challenge inherent in demonstrating their efficacy in man. Since the first publication of the Animal Rule by the FDA, there has been increased discussion of potential correlates of protection in animal models and their use to establish surrogate markers of efficacy in man. The latter need to be relatively easy to measure in assays that are at least qualified, if not validated, in order to derive a quantitative assessment of the clinical benefit conferred. The demonstration of safety and clinical benefit is essential to achieve regulatory approval for countermeasures for which clinical efficacy cannot be tested directly, as is the case for example, for biodefence vaccines. Plague is an ancient, serious infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses potential immune correlates of protection for plague, from which it may be possible to derive surrogate markers of efficacy, in order to predict the clinical efficacy of candidate prophylaxes and therapies. 1. Plague The ancient disease of plague is still present in endemic regions of the modern world and results in approximately 3,000 reported cases each year [1]. Plague is a flea-vectored infection caused by the Gram-negative bacterium Yersinia pestis, a potential biothreat agent. Originally an enteric pathogen, Y. pestis is thought to have evolved from the enteropathogen Y. pseudotuberculosis [2] as a flea-vectored, enzootic infection. Fleas feed on infected rodents and then transmit bacteria to a susceptible mammal by flea bite. Man is an accidental host in this cycle, but if bitten can contract bubonic plague, a serious infection if not treated promptly before the individual becomes symptomatic. A secondary pneumonic plague can develop in an individual suffering from bubonic plague, and this is of even greater concern, since Y. pestis bacteria are highly transmissible in aerosolised form between unprotected individuals in close contact, with the potential for epidemic spread [3]. 2. Virulence Factors in Yersinia pestis Y. pestis produces a range of antigens and virulence factors, three of which have known protective efficacy as candidate subunit vaccines: F1-antigen [4], V-antigen [5], and Yersinia secretory factor F (YscF) [6]. These three proteins are virulence factors when secreted by Y. pestis during infection. F1 antigen is a capsular protein with antiphagocytic properties [7], whilst the V-antigen is a regulatory protein in the type three
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