Development of a conjugate vaccine for the prevention of tularemia

开发预防兔热病的结合疫苗

• 批准号: 8233446
• 负责人: Dennis L. Kasper
• 金额: $ 47.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233446
• 关键词: Adverse effects; Animal Model; Antibodies; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Bioterrorism; Breathing; Carrier Proteins; Categories; Cellular Immunity; Combined Vaccines; Conjugate Vaccines; Data; Development; Disease; Essential Genes; Francisella; Francisella tularensis; Glycoconjugates; Humoral Immunities; Immune; Immunity; Immunization; Infection; Infection prevention; Length; Lipopolysaccharides; Molecular; Mutation; Nature; New England; Organism; Polysaccharides; Prevention; Proteins; Proteome; Reporting; Research Personnel; Screening procedure; Side; Subunit Vaccines; Tularemia; Vaccines; Virulent; Work; aerosolized; attenuation; base; biodefense; cell type; human disease; mortality; mutant; pathogen; prevent; prototype; respiratory; vaccine development

Francisella tularensis, a pleomorphic, gram-negative, facultative intracellular bacterial pathogen, is the etiologic agent of tularemia, a potentially fatal human disease. The ease with which F. tularensis can be aerosolized and its high degree of infectivity when inhaled have raised concerns about its potential for use in bioterrorism. An empirically derived, still-unlicensed vaccine strain of F. tularensis, LVS, is complicated by several issues: (i) Ft.LVS is still highly virulent in some animal models of infection, (ii) LVS vaccine has.been associated with significant undesirable side effects, (iii) Recipients of LVS vaccine develop incomplete immunity, (iv) The molecular basis for the attenuation of Ft.LVS is unknown. The mechanisms of immune protection against F. tularensis, particularly the highly virulent type A strains, are poorly defined. Our work, along with that of other investigators, has suggested that both humoral immunity (antibody to the O side chain of the lipopolysaccharide) and cellular immunity are critical for protection against this organism. Because of the incomplete understanding of immunity to F. tularensis, we have used three approaches to vaccine development: (1) screening of the vast majority of proteins in the F. tularensis proteome for potentially protective antigens; (2) marked attenuation of the live vaccine strain (Ft.LVS) through the mutation of two essential genes in the O polysaccharide (OPS) biosythesis locus, and (3) construction of a glycoconjugate vaccine composed of the full-length OPS conjugated to a carrier protein. We have obtained critical information on the nature of protective immunity and have used this information to refine our experimental strategy. Our data at this point indicate that the most effective approach will likely be some combination of our prototype vaccines. By combining the glycoconjugate vaccine with an attenuated mutant strain we have elicited protection against respiratory challenge with the wild-type type A strain Schu S4. To our knowledge, such protection has previously been reported only for Ft.LVS immunization. The combination vaccine we have developed is 7 logs less virulent in animal models than Ft.LVS; therefore, we anticipate that it will be considerably safer.

土拉热弗朗西丝菌是一种多形、革兰氏阴性、兼性胞内细菌病原体， 土拉菌病是一种潜在的致命性人类疾病。F的容易程度。土拉热可以是 雾化和吸入时的高度感染性引起了对其用于治疗 生物恐怖主义一个经验性的，仍然未经许可的疫苗株的F。土拉热，LVS，是复杂的， 几个问题：（i）Ft.LVS在一些感染的动物模型中仍然是高毒力的，（ii）LVS疫苗已经 与显著的不良副作用相关，（iii）LVS疫苗的接受者发生不完全的 免疫力，（iv）Ft.LVS衰减的分子基础是未知的。免疫机制 对F.土拉热，特别是高毒力的A型菌株，定义不明确。我们的工作， 沿着其他研究者的研究表明，体液免疫（O侧抗体） 脂多糖链）和细胞免疫对于保护免受这种生物体的侵害至关重要。 由于对F. tularensis，我们使用了三种方法， 疫苗研制：（1）筛选出F.土拉热菌蛋白质组 潜在的保护性抗原;（2）活疫苗株（Ft.LVS）通过 O多糖（OPS）生物合成基因座中两个必需基因的突变，和（3）构建一个 在一个实施方案中，本发明提供了由缀合至载体蛋白的全长OPS组成的糖缀合物疫苗。我们所获得 保护性免疫的本质的关键信息，并利用这些信息来完善我们的 实验策略我们目前的数据表明，最有效的方法可能是一些 我们的原型疫苗的组合。通过将糖缀合物疫苗与减毒突变体结合， 菌株，我们已经引发了对野生型A菌株Schu S4的呼吸攻击的保护。到 据我们所知，这种保护以前仅报道用于Ft.LVS免疫。相结合 我们开发的疫苗在动物模型中的毒力比Ft.LVS低7个对数;因此，我们预计， 会安全得多