Publication: A nonhuman primate scrub typhus model: Protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques
Issued Date
2015-02-15
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15506606
00221767
00221767
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2-s2.0-84922496495
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Immunology. Vol.194, No.4 (2015), 1702-1716
Suggested Citation
Daniel H. Paris, Suchismita Chattopadhyay, Ju Jiang, Pruksa Nawtaisong, John S. Lee, Esterlina Tan, Eduardo Dela Cruz, Jasmin Burgos, Rodolfo Abalos, Stuart D. Blacksell, Eric Lombardini, Gareth D. Turner, Nicholas P.J. Day, Allen L. Richards A nonhuman primate scrub typhus model: Protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques. Journal of Immunology. Vol.194, No.4 (2015), 1702-1716. doi:10.4049/jimmunol.1402244 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/36125
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Title
A nonhuman primate scrub typhus model: Protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques
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Abstract
Copyright © 2015 by The American Association of Immunologists, Inc. We developed an intradermal (ID) challenge cynomolgus macaque (Macaca fascicularis) model of scrub typhus, the leading cause of treatable undifferentiated febrile illness in tropical Asia, caused by the obligate intracellular bacterium, Orientia tsutsugamushi. A well-characterized animal model is required for the development of clinically relevant diagnostic assays and evaluation of therapeutic agents and candidate vaccines. We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp. Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses. Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi-specific, IFN-γ-producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls. This study demonstrates a vaccine-induced immune response capable of conferring sterile immunity against high-dose homologous ID challenge of O. tsutsugamushi in a nonhuman primate model, and it provides insight into cell-mediated immune control of O. tsutsugamushi and dissemination dynamics, highlights the importance of bacteremia indices for evaluation of both natural and vaccine-induced immune responses, and importantly, to our knowledge, has determined the first phenotypic correlates of immune protection in scrub typhus. We conclude that this model is suitable for detailed investigations into vaccine-induced immune responses and correlates of immunity for scrub typhus.