Cross-Protective Vaccines vs. Emerging Infectious Agents

交叉保护疫苗与新出现的传染性病原体

• 批准号: 6984818
• 负责人: MICHAEL J MAHAN
• 金额: $ 45.64万
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984818
• 关键词: Salmonella typhimurium; Salmonella vaccines; T lymphocyte; Yersinia; active immunization; antigen presentation; antigen presenting cell; attenuated microorganism; bacterial antigens; biotechnology; bioterrorism /chemical warfare; cellular immunity; combination chemotherapy; cross immunity; emerging infectious disease; gene mutation; genetic strain; humoral immunity; hyperimmunization; laboratory mouse; nonhuman therapy evaluation; regulatory gene; stress proteins; vaccine development; vaccine evaluation

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）：预防多种菌株的疫苗的开发对于防御生物劳资剂和新兴的感染性疾病至关重要，因为具有几种不同菌株的感染可能会覆盖单一疫苗引起的免疫力，而病原体可能会在疫苗接种的个体中发展出我们当前疫苗不适的疫苗。该提案的远距离目标是开发安全的疫苗，并赋予对各种传染药的有效跨保护免疫的状态。最近，美国和其他人确定了缺乏功能性DNA腺嘌呤甲基酶（DAM）的伤寒链霉菌因毒力而显着衰减，并引发了一种有效的保护性免疫状态，以防止父母大坝+菌株挑战。 （目标1）我们计划评估鼠伤伤小链球菌的减毒菌株如何影响天真的宿主的先天防御，以及它们如何影响专业的抗原呈递细胞以向天真的CD4+和CD8+ T细胞呈现抗原。我们还将分析用AROA，DAM，AROA大坝，大坝产生过度产生（Damop）或Aroa Typhimurium的Aroa Damop突变体是否会在天真的宿主中诱导持续持续的细胞介导的持续性和体液免疫反应，无论是系统地和粘膜表面。 （AIM 2）治疗指数或治疗与毒性的疗效之比，决定了基于沙门氏菌的疫苗的成功。当前，最有希望的候选者包括携带突变的菌株，其产物与关键的生物合成途径（AROA AROD），调节基因（CYA CRP和PHOP PHOQ）以及编码应激蛋白（HTRA）的基因及其组合以及这些突变的组合。在这里，我们建议评估大坝突变菌株与其中一个或多个衰减突变的安全性和功效。 （AIM 3）我们的数据表明，在鼠和伤寒的禽类模型中，鼠伤寒的单一口服免疫引起了对多种沙门氏菌菌株的显着但不完全的交叉保护免疫。我们建议确定单独和组合的多种坝或DAMOP突变体的免疫免疫可以赋予强烈的交叉保护免疫反应，以针对多种沙门氏菌临床分离株进行。 （AIM 4）沙门氏菌大坝突变菌株引起的增强免疫力增加了以下可能是，当通过大坝突变疫苗表达微生物传染剂的乘客抗原会引起针对认知病原体的保护性免疫反应。我们将重点关注耶尔森氏菌的LCRV乘客抗原，因为它是已知的免疫原，并且将效应蛋白分泌为靶细胞和促抑制性反应所需的毒力因子所需的毒力因子。我们建议在沙门氏菌大坝突变体疫苗中表达Y型假结核LCRV，并测试在小鼠模型中，耶尔森氏菌菌血症模型中是否保护了疫苗的动物。