Cross-Protective Vaccines Against Emerging Infectious Agents

针对新出现的传染病的交叉保护疫苗

• 批准号: 7148093
• 负责人: MICHAEL J MAHAN
• 金额: $ 44.27万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148093
• 关键词: Animals; Antigen-Presenting Cells; Antigens; Attenuated; Bacteremia; Bacterial Vaccines; Biological Warfare; Birds; Bos taurus; CD8B1 gene; Cattle; Cells; Clinical; Data; Development; Disease; Emerging Communicable Diseases; Epithelial Cells; Evaluation; Gastroenteritis; Genes; Goals; Heat shock proteins; Immune response; Immunity; Immunization; Immunocompromised Host; Individual; Infection; Infectious Agent; Life; Mediating; Modeling; Mus; Mutation; National Institute of Allergy and Infectious Disease; Nature; Oral; Organism; Pasteurella pseudotuberculosis; Pathway interactions; Property; Proteins; Range; Regulator Genes; Reporting; Risk; Safety; Salmonella; Salmonella Vaccines; Salmonella enterica; Salmonella typhimurium; Site-Specific DNA-Methyltransferase (Adenine-Specific); Surface; T-Lymphocyte; Testing; Therapeutic Index; Toxic effect; Treatment Efficacy; Typhoid Fever; Vaccinated; Vaccination; Vaccine Design; Vaccines; Variant; Virulence; Virulence Factors; Virulent; Virus; Yersinia; base; cost effective; expression vector; immunogenic; macrophage; microbial; microorganism antigen; mouse model; mutant; pathogen; pathogenic bacteria; response; stress protein; success; tumor; vaccine development; vaccine efficacy; vaccine evaluation; vector

DESCRIPTION (provided by applicant): The development of vaccines that protect against more than one strain is paramount to the defense against biowarfare agents and emerging infectious diseases as infection with several different strains may override the immunity elicited by a single vaccine, and pathogenic strains can develop in vaccinated individuals that make our current vaccines ineffective. The long-range objective of this proposal is to develop vaccines that are safe, and confer a potent state of cross-protective immunity against a variety of infectious agents. It has recently been established by us and others that S. typhimurium lacking a functional DNA adenine methylase (Dam) are significantly attenuated for virulence and elicit a potent state of protective immunity against challenge with the parental dam+ strain. (AIM 1) We plan to evaluate how attenuated strains of S. typhimurium influence innate defenses of naive hosts, and how they influence professional antigen-presenting cells to present antigens to naive CD4+ and CD8+ T cells. We will also analyze whether oral vaccination with aroA, dam, aroA dam, Dam overproducing (DamOP), or aroA DamOP mutants of S. typhimurium will induce in naive hosts the presence of long lasting cell-mediated and humoral immune responses, both systemically and at the mucosal surfaces. (AIM 2) The therapeutic index, or the ratio of the efficacy of the therapy over the toxicity, determines the success of Salmonella based vaccines. Currently, the most promising candidates include strains harboring mutations in genes whose products are involved in key biosynthetic pathways (aroA aroD), regulatory genes (cya crp and phoP phoQ), and genes encoding stress proteins (htrA) and combinations of these mutations. Here we propose to evaluate the safety and efficacy of dam mutant strains in combination with one or more of these attenuating mutations. (AIM 3) Our data show that a single oral immunization of dam- or DamOP S. typhimurium elicits significant but incomplete cross-protective immunity to more than one Salmonella strain in murine and avian models of typhoid fever. We propose to determine if multiple immunizations of dam- or DamOP mutants, alone and in combination, can confer strong cross-protective immune responses against multiple Salmonella clinical isolates. (AIM 4) The heightened immunity elicited by Salmonella dam mutant strains raises the possibility that passenger antigens from microbial infectious agents, when expressed by dam mutant vaccines, will elicit a protective immune response against the cognate pathogens. We will focus on the LcrV passenger antigen from Yersinia pseudotuberculosis since it is a known immunogen, and a virulence factor required for secretion of effector proteins into target cells and elicitation of pro-inhibitory responses. We propose to express Y. pseudotuberculosis LcrV in Salmonella dam mutant vaccines, and test whether vaccinated animals are protected against Y. pseudotuberculosis infection in a mouse model for Yersinia bacteremia.

描述（由申请人提供）：开发针对一种以上毒株的疫苗对于防御生物战剂和新出现的传染病至关重要，因为几种不同毒株的感染可能会推翻单一疫苗引起的免疫力，并且致病毒株可能会在接种疫苗的个体中产生，从而使我们当前的疫苗失效。该提案的长期目标是开发安全的疫苗，并赋予针对多种传染源的有效交叉保护性免疫力。我们和其他人最近已经确定，缺乏功能性 DNA 腺嘌呤甲基化酶 (Dam) 的鼠伤寒沙门氏菌的毒力显着减弱，并引发针对亲本 dam+ 菌株攻击的有效保护性免疫状态。 (目标 1) 我们计划评估鼠伤寒沙门氏菌减毒株如何影响幼稚宿主的先天防御，以及它们如何影响专业抗原呈递细胞将抗原呈递给幼稚 CD4+ 和 CD8+ T 细胞。我们还将分析口服接种鼠伤寒沙门氏菌的aroA、dam、aroA dam、Dam过量产生（DamOP）或aroA DamOP突变体是否会在初始宿主体内诱导全身和粘膜表面出现持久的细胞介导和体液免疫反应。 (目标 2) 治疗指数，或治疗功效与毒性的比率，决定了基于沙门氏菌的疫苗的成功。目前，最有希望的候选菌株包括含有基因突变的菌株，其产物涉及关键生物合成途径（aroA aroD）、调节基因（cya crp 和 phoP phoQ）、编码应激蛋白（htrA）的基因以及这些突变的组合。在这里，我们建议评估 dam 突变株与这些减毒突变中的一种或多种组合的安全性和有效性。 (AIM 3) 我们的数据显示，在伤寒鼠和禽类模型中，单次口服 dam- 或 DamOP 鼠伤寒沙门氏菌可引发对一种以上沙门氏菌菌株的显着但不完全的交叉保护性免疫。我们建议确定 dam- 或 DamOP 突变体的多次免疫（单独或组合）是否可以针对多种沙门氏菌临床分离株产生强烈的交叉保护性免疫反应。 (AIM 4) 沙门氏菌 dam 突变株引起的增强免疫力提出了一种可能性，即来自微生物感染因子的过客抗原，当通过 dam 突变疫苗表达时，将引发针对同源病原体的保护性免疫反应。我们将重点关注来自假结核耶尔森氏菌的 LcrV 过客抗原，因为它是一种已知的免疫原，也是将效应蛋白分泌到靶细胞中并引发促抑制反应所需的毒力因子。我们建议在沙门氏菌坝突变疫苗中表达假结核菌 LcrV，并在耶尔森氏菌菌血症小鼠模型中测试接种疫苗的动物是否能免受假结核菌感染。