Milestones in Progression of Primary Pneumonic Plague in Cynomolgus Macaques

Abstract

Vaccines against primary pneumonic plague, a potential bioweapon, must be tested for efficacy in well-characterized nonhuman primate models. Telemetered cynomolgus macaques (Macaca fascicularis) were challenged by the aerosol route with doses equivalent to approximately 100 50% effective doses of Yersinia pestis strain CO92 and necropsied at 24-h intervals postexposure (p.e.). Data for telemetered heart rates, respiratory rates, and increases in the temperature greater than the diurnal baseline values identified the onset of the systemic response at 55 to 60 h p.e. in all animals observed for at least 70 h p.e. Bacteremia was detected at 72 h p.e. by a Yersinia 16S rRNA-specific quantitative reverse transcription-PCR and was detected later by the culture method at the time of moribund necropsy. By 72 h p.e. multilobar pneumonia with diffuse septal inflammation consistent with early bacteremia was established, and all lung tissues had a high bacterial burden. The levels of cytokines or chemokines in serum were not significantly elevated at any time, and only the interleukin-1␤, CCL2, and CCL3 levels were elevated in lung tissue. Inhalational plague in the cynomolgus macaque inoculated by the aerosol route produces most clinical features of the human disease, and in addition the disease progression mimics the disease progression from the anti-inflammatory phase to the proinflammatory phase described for the murine model. Defined milestones of disease progression, particularly the onset of fever, tachypnea, and bacteremia, should be useful for evaluating the efficacy of candidate vaccines.Primary pneumonic plague is rarely acquired under natural conditions (5, 9, 22), but the virulence and ease of aerosolization make Yersinia pestis a potential aerosolized bioweapon (13). The FDA "animal rule" allows the use of large animal models to substitute for human testing if the disease in the model mimics human disease and is well characterized (11). Adequate characterization should include the cause of death, phases of disease progression, and definition of secondary endpoints of success in addition to the primary endpoint of a reduction in mortality.Primary pneumonic plague in the murine model following intranasal inoculation has been described well (3,14,20). The murine model mimics the human infection with respect to high mortality, focal consolidation in the lung, and high levels of bacteremia and dissemination to the liver and the spleen. The murine infection is described as a two-phase disease with an initial anti-inflammatory phase lasting 36 to 48 h after intranasal inoculation, followed by a rapidly progressing proinflammatory phase until death occurs at 4 days postinfection (3,14).Nonhuman primates (NHP) are susceptible to aerosolized Y. pestis, which produces a rapidly fatal disease similar to that seen in humans with primary pneumonic plague. Different species of NHP may display different susceptibilities and disease progressions after exposure to Y. pestis in an aerosol form (7,8,10,16), and a workshop has rec...

Yersinia pestisbiovarMicrotusstrain 201, an avirulent strain to humans, provides protection against bubonic plague in rhesus macaques

“…This result seems to be consistent with a previous report, in which no elevated levels of MCP-1, MIP-1α, RANTES, MIP-1β, and IL-8 were found in sera of Indonesian-origin cynomolgus macaques within 96 h after aerosol infection with Y. pestis CO92, but the elevated concentration of MCP-1, MIP-1α or IL-8 was observed in some lung tissue 72 h after aerosol infection with Y. pestis CO92. 57 No elevated levels of MCP-1 and IL-8 were observed in sera of the animals infected with Y. pestis CO92, which may be attributed to short-term of observation. However, in some lung tissue, the elevated concentration of MCP-1 and IL-8, not RANTES was observed, indicating that MCP-1 and IL-8 secreted earlier than RANTES or Y. pestis CO92 does not induce elevated level of RANTES in Indonesian-origin cynomolgus macaques.…”

Pulmonary infection by Yersinia pestis rapidly establishes a permissive environment for microbial proliferation

“…This process allows the organisms to multiply rapidly before the inflammatory response is fully activated, typically too late to control the infection. Thus, disease progression for primary pneumonic plague can be subdivided into two distinct phases: an initial preinflammatory phase followed by a proinflammatory phase, which is recapitulated in both mouse and nonhuman primate models of infection (1)(2)(3)(4). The absence of early pulmonary inflammation in response to Y. pestis could be because of the organisms avoiding detection by the immune system, a strategy used by many pathogens, including Y. pestis (5-7); or, it could be because of the organisms completely suppressing early innate immune responses, which has never been observed for bacterial pathogens.…”

A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates

“…However, the current recommendations from FDA and the National Institute of Allergy and Infectious Disease to support plague therapeutic and vaccine studies involve a cynomolgus macaque (Macaca fascicularis) (CM) pneumonic plague model (63). In addition, the lethal dose of Y. pestis has been established for aerosol challenge of CMs with the standard CO92 strain, and this model was utilized in protection studies including F1-V-based subunit vaccines for the past several years as well as in most recent studies (7,8,(63)(64)(65)(66)(67)(68). Importantly, CMs exhibit a clinical course of the disease similar to that described in humans (69).…”