Immunotherapeutics and vaccines against anthrax, plague and tularemia

描述（由申请人提供）：生物防御研究的重点应包括开发免疫疗法和针对生物战剂的有效疫苗。细胞和体液免疫反应都可能在对炭疽、鼠疫和土拉菌病的免疫中发挥作用。Vy2V82 T细胞仅存在于灵长类动物中，占人类血液中y5 T细胞总数的60-95%。我们和其他人已经证明，磷抗原特异性Vy2V82 T细胞可以作为先天性和适应性免疫细胞，并有助于对急性致死性结核病的适应性免疫。我们的新研究表明，炭疽芽孢杆菌确实可以产生刺激Vy2V52 T细胞的磷抗原，并在随后感染产生磷抗原的分枝杆菌后，使这些细胞产生交叉反应记忆型反应。重要的是，磷酸抗原HMBPP处理猴子可以使Vy2V52 T细胞在总循环T细胞中的比例从<1%增加到bbb70 %。hmbpp激活的Vy2V82 T细胞很容易迁移到肺部，并赋予猕猴抵抗肺分枝杆菌感染的保护作用。我们假设磷酸抗原hmbpp介导的Vy2V52 T细胞活化可以极大地增强对炭疽杆菌、鼠疫杆菌和土拉菌的先天和适应性免疫反应，并赋予对致命的吸入性炭疽、鼠疫和土拉菌病的保护。我们进一步假设，由磷抗原和蛋白抗原组成的联合疫苗可以靶向4种免疫成分：Vy2V52 T细胞、CD4 T辅助细胞、CDS T杀伤细胞和抗体，因此可以更有效地免疫和疫苗诱导的对炭疽、鼠疫和土拉菌病的保护。为了便于验证这些假设，我们制定了HMBPP治疗方案的临床和免疫学方面，并开发了构建重组卡介苗和李斯特菌疫苗载体的疫苗平台技术。为了验证我们的假设并最终开发针对炭疽、鼠疫和土拉菌病的重组疫苗，我们将：1 .评估HMBPP方案对非人灵长类动物致命吸入性炭疽、鼠疫和土拉菌病的免疫治疗效果。2。构建重组卡介苗和重组减毒李斯特菌疫苗载体，表达炭疽芽孢杆菌PA、鼠疫杆菌F1和土拉杆菌Ag。3。比较口服和皮内免疫途径在接受重组卡介苗和李斯特菌疫苗载体表达炭疽芽孢杆菌PA、鼠疫杆菌F1或土拉菌F. Ag的异源强化疫苗接种的猴子中引起的免疫反应。IV.确定用表达PA、F1或兔热病抗原的重组卡介苗和李斯特菌疫苗载体口服异源强化免疫是否能在非人灵长类动物中获得对致命吸入性炭疽、鼠疫和兔热病的保护性免疫。

DESCRIPTION (provided by applicant): Biodefense research priorities should include development of immunotherapeutics and effective vaccines against biological warfare agents. Both cellular and humoral immune responses may play a role in immunity to anthrax, plague and tularemia. Vy2V82 T cells exist only in primates and constitute 60-95% of total human y5 T cell population in the blood. We and others have demonstrated that phosphoantigen-specific Vy2V82 T cells can function as both innate and adaptive immune cells, and contribute to adaptive immunity to acutely fatal form of tuberculosis. Our new studies indicate that B. anthracis can indeed produce phosphoantigen stimulating Vy2V52 T cells and prime these cells for cross-reactive memory-type response after subsequent infection with phosphoantigen-producing mycobacteria. Importantly, phosphoantigen HMBPP treatment of monkeys can expand Vy2V52 T cells from <1% to > 70% in total circulating T cells. HMBPP-activated Vy2V82 T cells readily migrate to the lung and confer protection against pulmonary mycobacterial infection in macaques. We hypothesize that phosphoantigen HMBPP-mediated activation of Vy2V52 T cells can greatly boost innate and adaptive immune responses to B. anthracis, Y. pestis and F. tularensis, and confer protection against fatal inhalational anthrax, plague and tularemia. We further hypothesize that a combined vaccine comprised of both phosphoantigen and protein antigen can target 4 immune components: Vy2V52 T cells, CD4 T helpers, CDS T killers, and antibodies, and therefore can be more efficient for immunization and vaccine-induced protection against anthrax, plague and tularemia. To facilitate testing these hypotheses, we have worked out clinical and immunological aspects of HMBPP treatment regimens, and developed vaccine platform technology for constructing recombinant BCG and Listeria vaccine vectors. To test our hypothesis and ultimately develop recombinant vaccines against anthrax, plague and tularemia, we will: I. Assess HMBPP regimens for immunotherapeutic effects on fatal inhalational anthrax, plague, and tularemia in nonhuman primates. II. Construct and characterize recombinant BCG and recombinant attenuated Listeria vaccine vectors expressing B. anthrax PA, Y. pestis F1 or F. tularensis Ag. III. Compare oral and intradermal immunization routes for vaccine-elicited immune responses in monkeys that receive heterologous prime-boost vaccination with recombinant BCG and Listeria vaccine vectors expressing B. anthracis PA, Y. pestis F1, or F. tularensis Ag. IV. Determine whether oral heterologous prime-boost vaccination with recombinant BCG and Listeria vaccine vectors expressing PA, F1, or tularemia Ag can confer protective immunity against fatal inhalational anthrax, plague and tularemia in nonhuman primates.