Paris Daniel H, Chattopadhyay Suchismita, Jiang Ju, Nawtaisong Pruksa, Lee John S, Tan Esterlina, Dela Cruz Eduardo, Burgos Jasmin, Abalos Rodolfo, Blacksell Stuart D, Lombardini Eric, Turner Gareth D, Day Nicholas P J, Richards Allen L
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;
Viral and Rickettsial Diseases Department, Naval Medical Research Center, Silver Spring, MD 20910;
J Immunol. 2015 Feb 15;194(4):1702-16. doi: 10.4049/jimmunol.1402244. Epub 2015 Jan 19.
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.
我们建立了一种恙虫病东方体皮内（ID）激发食蟹猴（猕猴）模型，恙虫病东方体是热带亚洲可治疗的未分化发热性疾病的主要病因，由专性细胞内细菌恙虫病东方体引起。开发临床相关诊断检测方法以及评估治疗药物和候选疫苗需要一个特征明确的动物模型。我们研究了恙虫病的疾病病理生理学，并评估了两种基于恙虫病东方体47-kDa抗原的候选疫苗，一种DNA质粒疫苗（pKarp47）和一种病毒载体疫苗（Kp47/47-委内瑞拉马脑炎病毒复制子颗粒），以检测其安全性、免疫原性以及针对恙虫病东方体Karp同源ID激发的效力。对照食蟹猴出现发热、典型焦痂、淋巴结病、菌血症、肝功能改变、白细胞计数增加、病原体特异性抗体（IgM和IgG）以及细胞介导的免疫反应。接种DNA质粒pKarp47疫苗的猕猴，其恙虫病东方体特异性、产生干扰素-γ的外周血单个核细胞显著增加（p = 0.04），焦痂频率和菌血症持续时间降低（p≤0.01），菌血症发作延迟（p < 0.05），循环细菌生物量减少（p = 0.01），肝转氨酶水平降低幅度更大（p < 0.03）。本研究证明了在非人灵长类动物模型中，疫苗诱导的免疫反应能够赋予针对高剂量恙虫病东方体同源ID激发的无菌免疫力，并且提供了对恙虫病东方体细胞介导免疫控制和传播动力学的见解，强调了菌血症指标在评估自然免疫反应和疫苗诱导免疫反应中的重要性，重要的是，据我们所知，确定了恙虫病免疫保护的首个表型相关性。我们得出结论，该模型适用于对恙虫病疫苗诱导的免疫反应和免疫相关性进行详细研究。
