Comparison of virulence between theYersinia pestis Microtus201, an avirulent strain to humans, and the vaccine strain EV in rhesus macaques,Macaca mulatta

Abstract

Our previous study has demonstrated that Yersinia pestis Microtus 201 is a low virulent strain to the Chinese-origin rhesus macaques, Macaca mulatta, and can protect it against high dose of virulent Y. pestis challenge by subcutaneous route. To investigate whether the Y. pestis Microtus 201 can be used as a live attenuated vaccine candidate, in this study its intravenous virulence was determined and compared with the live attenuated vaccine strain EV in the Chinese-origin rhesus macaque model. The results showed that the Chinese-origin rhesus macaques can survive intravenous infection with approximately 10(9) CFU of the Y. pestis Microtus 201, but all the animals succumbed to 10(10) CFU of intravenous infection. By contrast, all the animals survive intravenous infection with 10(10) CFU of the vaccine EV. Post-mortem examination showed multiple areas of severe abscess in the lungs of the dead animals infected with 10(10) CFU of the Y. pestis Microtus 201, whereas histopathology observation, microbiological examination and immunohistochemistry staining showed that the Y. pestis Microtus 201 also invaded hearts, livers, spleens, kidneys and lymph nodes and caused different degrees of pathological changes in these organs. These results indicated that the Y. pestis Microtus 201 is indeed low virulent to monkeys, but it is more virulent than the vaccine EV when administered by intravenous route. The Y. pestis Microtus 201 mainly attack the lungs when administered by intravenous infection, which may be the leading cause of animal death.

Animal Models of Type III Secretion System-Mediated Pathogenesis

“…Non-human primates are the best and most accurate animal model of human infection [85][86][87][88][89][90][91][92][93] and are often used in preclinical trials [122]. Similar to companion animals, non-human primates are also USDA protected, although the approvals and protocol requirements differ.…”

“…Vaccination studies are commonly done in mice [40,42,49], rabbits [65,66], cattle [81], and primates [86,91,93]. These studies can demonstrate the power of inhibiting the T3SS by using antibodies that recognize T3SS effectors or structural components.…”

Complete Protection Against Yersinia pestis in BALB/c Mouse Model Elicited by Immunization With Inhalable Formulations of rF1-V10 Fusion Protein via Aerosolized Intratracheal Inoculation

“…Y. pestis strain 201, which is avirulent to humans ( 53 ), is maintained in our laboratory. It was cultivated in Brain Heart Infusion broth (BHI; BD, Voigt Global Distribution Inc., Lawrence, KS).…”

Plague vaccines: new developments in an ongoing search

“…rhesus macaque infection model revealed that both strains were well tolerated in NHPs at high doses. However, the microtus strain infected the lungs and led to 100% mortality in 10 10 i.v.-challenged animals; none of the EV-challenged animals died at that same dose (Tian et al 2014 ). The side effects associated with the EV strain in humans as well as the ability of the pigmentation locus (pgm) minus strains of Y. pestis to cause a fatal disease in patients with hemochromatosis suggest that the EV mutant strain could be further attenuated through specific gene knockouts to generate live-attenuated plague vaccine candidates, as has been recently reported (Tiner et al 2015A &B; Tiner et al 2016 ; van Lier et al 2014 ).…”