title: A nonhuman primate scrub typhus model: protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques.
abstract: 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.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom; parigi@tropmedres.ac.
authors.forename: Daniel H
authors.identifier: http://orcid.org/0000-0003-4743-5987
authors.initials: DH
authors.lastname: Paris
authors.affiliation: Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, MD 20910;
authors.forename: Suchismita
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, MD 20910;
authors.forename: Ju
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Pruksa
authors.initials: P
authors.lastname: Nawtaisong
authors.affiliation: Division of Entomology, Walter Reed Army Institute of Research, Silver Spring, MD 20910;
authors.forename: John S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Leonard Wood Memorial Institute, Cebu 6000, Philippines;
authors.forename: Esterlina
authors.initials: E
authors.lastname: Tan
authors.affiliation: Leonard Wood Memorial Institute, Cebu 6000, Philippines;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Dela Cruz
authors.affiliation: Leonard Wood Memorial Institute, Cebu 6000, Philippines;
authors.forename: Jasmin
authors.initials: J
authors.lastname: Burgos
authors.affiliation: Leonard Wood Memorial Institute, Cebu 6000, Philippines;
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Abalos
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom;
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Blacksell
authors.affiliation: Veterinary Medicine Department, Armed Forces Medical Research Institute of Science, Thanon Yothi, 10400 Bangkok; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Lombardini
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom;
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Turner
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom;
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, MD 20910; Preventive Medicine and Biometrics Department, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
authors.forename: Allen L
authors.initials: AL
authors.lastname: Richards
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008252:Macaca fascicularis; D008297:Male; D012612:Scrub Typhus / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000942:Antigens, Bacterial; D019444:Vaccines, DNA