Immunotherapeutics and vaccines against anthrax, plague and tularemia

炭疽、鼠疫和兔热病的免疫治疗和疫苗

• 批准号: 7653679
• 负责人: Zheng W Chen
• 金额: $ 94.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653679
• 关键词: Anthrax disease; Antibodies; Antigens; Attenuated; Bacillus anthracis; Biological Warfare; Blood; CD4 Positive T Lymphocytes; Categories; Cell physiology; Cells; Clinical; Combined Vaccines; Development; Francisella tularensis; Genus Mycobacterium; Human; Immune; Immune response; Immunity; Immunization; Immunotherapeutic agent; Infection; Listeria; Lung; Lung diseases; Macaca; Mediating; Memory; Monkeys; Mycobacterium Infections; Oral; Plague; Play; Population; Primates; Proteins; Recombinant Vaccines; Recombinants; Research Priority; Role; Route; T-Lymphocyte; Technology; Testing; Treatment Protocols; Tuberculosis; Tularemia; Vaccination; Vaccines; Work; Yersinia pestis; base; biodefense; nonhuman primate; response; vector vaccine

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.

DESCRIPTION (provided by applicant): Biodefense research priorities should include development of immunotherapeutics and effective vaccines against biological warfare agents.细胞和体液免疫反应可能在炭疽、鼠疫和兔热病的免疫中发挥作用。 Vy2V82 T 细胞仅存在于灵长类动物中，占血液中人类 y5 T 细胞总数的 60-95%。 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.重要的是，对猴子进行磷酸抗原 HMBPP 治疗可以将 Vy2V52 T 细胞在总循环 T 细胞中的比例从 <1% 扩大到 > 70%。 HMBPP 激活的 Vy2V82 T 细胞很容易迁移到肺部，并为猕猴提供针对肺部分枝杆菌感染的保护。 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.二. Construct and characterize recombinant BCG and recombinant attenuated Listeria vaccine vectors expressing B. anthrax PA, Y. pestis F1 or F. tularensis Ag.三． 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.四． 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.