Immunological characterization of rationally-designed vaccines against plague in mice and non-human primate models

合理设计的鼠疫疫苗和非人灵长类动物模型的免疫学特征

基本信息

批准号：
10335231
负责人：
ASHOK K CHOPRA
金额：
$ 57.49万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10335231
关键词：
Acyltransferase African Green Monkey Animals Antibiotic Resistance Antibodies Antibody Formation Antibody Response Antibody titer measurement Antigens Attenuated Attenuated Vaccines Bacteria Bacterial Antigens Binding Bite Bubonic Plague Calcium Case Fatality Rates Categories Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Cessation of life China Clinical Clinical Research Clinical Trials Congo Coronavirus Country Data Democratic Republic of the Congo Disease Disease Outbreaks Dose Engineering Etiology Exposure to FDA approved Fatality rate Fleas Fright Future Generations Genes Genetic Engineering Goals Human Immune response Immunity Immunization Immunize Immunoglobulin A Immunoglobulin G Immunologics Infection Injections Interferon Type II Interleukin-17 Intramuscular Iron Laboratories Lauric Acids Left Legal patent Lesion Link Lipopolysaccharides Lipoproteins Macaca Macaca fascicularis Madagascar Military Personnel Modeling Mucosal Immunity Mus Nature Nepal Neutrophil Infiltration Patient-Focused Outcomes Patients Peptide Hydrolases Plague Plague Vaccine Plasminogen Activator Pneumonic Plague Quarantine Rattus Reporting Resistance Rodent Rodent Model Role Serum Signal Transduction Site Subunit Vaccines Symptoms T cell response TLR2 gene TLR4 gene Testing Th1 Cells Toxicology Type III Secretion System Pathway Vaccinated Vaccine Design Vaccines Variant Virulence Yersinia pestis Zoonoses arm base bioweapon climate change co-infection combat cytokine design emerging human pathogen immunogenicity innovation mouse model mutant nonhuman primate novel novel coronavirus pandemic disease pathogen pre-clinical resistant strain respiratory response translational approach vaccine access vaccine candidate vaccine efficacy

项目摘要

ABSTRACT The increasing number of bubonic/pneumonic plague cases globally (2010-2018), including the U.S., with a ~18% case fatality rate may reflect climate changes and a rodent carrier range shift. The 2017-18 plague outbreak in Madagascar with ~2400 cases (>75% pneumonic) and ~9% causalities has led WHO (April 2018) to intensify the need for developing new generation subunit and live-attenuated plague vaccines. This need is exemplified by deadly plague cases in China (2019) and Congo (2020 with a 35% fatality rate). Y. pestis’ (Yp) ability to persist in dead hosts to resurge after years of silence, existence of antibiotic-resistant strains that occur naturally or have been intentionally developed, and no FDA-approved plague vaccine, is fearsome. Two- component subunit vaccines composed of capsular antigen F1 and a T3SS component and effector LcrV (low calcium response V antigen), which only generate a humoral immune response, provide variable protection in African green monkeys (AGM) and generate poor T cell responses in humans. Such vaccines will not be effective against Yp strains lacking F1 or possessing LcrV variants. Since the cellular immunity is also critical for protection, we focused first on identifying new virulence genes of Yp and then to delete them in combination to develop novel live-attenuated vaccine (LAV) strains. Two such LAVs were 100% attenuated in inducing bubonic/pneumonic plague in mice/rats and generated long-term humoral and cellular immune responses to provide 100% protection to rodents against developing plague. No clinical symptoms of the disease or histopathological lesions were noted either during immunization or when the vaccinated animals were subsequently exposed to Yp CO92 in a more stringent pneumonic plague model. Therefore, further immunological characterization of these mutants and their testing in higher animals, such as cynomolgus macaques (CM) and AGM, will provide a rationale for future clinical studies. There is a precedent for using a LAV against plague (EV76 strain) in humans. However, this vaccine is reactogenic, represents a spontaneous mutant, and causes disease in patients with over iron load. In Aim 1, we will demonstrate efficacy and immune responses of two vaccine candidates generated from Yp CO92 (biovar Orientalis) against other Yp biovars (Antiqua and Medievalis), the F1-minus mutant of CO92, and Yp CO92 with LcrV variants, in bubonic and pneumonic mouse models. Our data with the mutants indicated a role of IL-17 (a Th17 cytokine), Th1-IFN-γ, and antibodies, in protection. In Aim 2, we will study the mechanistic basis of this protection (one chosen mutant) by using RORt-/- mice, which lack Th17 cells, as well as IFN-γ and IgA k/o mice, to discern their links to neutrophil recruitment and mucosal immunity, to combat Yp infection in bubonic/pneumonic plague models. In Aim 3, CM and AGM will be used with one mutant to demonstrate its short- and long-term efficacy in causing bubonic and/or pneumonic plague as well as reactogenicity. The correlates of protective immunity will then be established. These innovative mechanistic/translational approaches will result in effective new generation plague vaccines.

抽象的包括美国在内的全球（2010-2018 年）腺鼠疫/肺鼠疫病例数量不断增加，约 18% 的病死率可能反映了气候变化和啮齿动物携带者范围的变化 2017-18 年鼠疫。马达加斯加爆发约 2400 例病例（>75% 为肺炎病例），约 9% 的死亡人数导致世界卫生组织（2018 年 4 月）加强了开发新一代亚单位和减毒鼠疫疫苗的需求。以中国（2019 年）和刚果（2020 年，死亡率为 35%）的致命鼠疫病例为例。死亡宿主在多年沉寂后复活的能力，出现抗生素抗性菌株的存在自然或有意开发的，并且没有 FDA 批准的鼠疫疫苗，是可怕的二-。由荚膜抗原 F1 和 T3SS 成分以及效应子 LcrV（低钙反应 V 抗原），仅产生体液免疫反应，在非洲绿猴（AGM）和人类 T 细胞反应较差，此类疫苗不会有效。由于细胞免疫对于缺乏 F1 或具有 LcrV 变体的 Yp 菌株也至关重要。为了保护，我们首先关注于识别Yp的新毒力基因，然后将它们组合删除以开发新型减毒活疫苗（LAV）毒株，其中两种 LAV 在诱导时已 100% 减毒。小鼠/大鼠体内的腺鼠疫/肺鼠疫，并产生长期的体液和细胞免疫反应为啮齿类动物提供 100% 的保护，预防鼠疫的发生没有疾病的临床症状或症状。在免疫期间或当肺炎动物被感染时，注意到组织病理学损伤。随后在更严格的肺鼠疫模型中暴露于Yp CO92，因此进一步进行。这些突变体的免疫学特征及其在高等动物（例如食蟹猴）中的测试猕猴（CM）和 AGM，将为未来的临床研究提供依据有使用先例。 LAV 对抗人类鼠疫（EV76 株），但这种疫苗具有反应性，代表一种自发性。突变体，并导致铁负荷过高的患者患病。在目标 1 中，我们将证明其功效和免疫能力。 Yp CO92（东方生物变种）产生的两种候选疫苗对其他 Yp 生物变种的反应（Antiqua 和 Medievalis），CO92 的 F1 减突变体，以及带有 LcrV 变体的 Yp CO92，在腺鼠疫和我们对突变体的数据表明了IL-17（Th17细胞因子）、Th1-IFN-γ和Th1-IFN-γ的作用。在目标 2 中，我们将研究这种保护的机制基础（一种选定的突变体）。使用缺乏 Th17 细胞的 RORt-/- 小鼠以及 IFN-γ 和 IgA k/o 小鼠来辨别它们与中性粒细胞的联系募集和粘膜免疫，以对抗鼠疫/肺鼠疫模型中的 Yp 感染，目标 3，CM。 AGM 将与一种突变体一起使用，以证明其在引起腺鼠疫和/或然后将确定肺鼠疫和反应原性的相关性。这些创新的机械/转化方法将产生有效的新一代鼠疫疫苗。