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.

Francisella tolarensis是多态性，革兰氏阴性，辅助细胞内细菌病原体，是 Tularemia的病因学剂，一种潜在的致命人类疾病。 F. tularensis可以轻松 吸入时气燃料及其高度感染性，引起了人们对其在使用潜力的担忧 生物恐怖。 F. tularensis，LVS的经验得出的，仍未使用的疫苗菌株使 几个问题：（i）ft.lvs在某些感染动物模型中仍然具有高度的毒气，（ii）LVS疫苗已有。 与明显的不良副作用相关的（iii）LVS疫苗的受体发展不完整 免疫，（iv）ft.lvs衰减的分子基础尚不清楚。免疫机制 防止f。tularensis，尤其是高毒A型菌株的保护，定义很差。我们的工作， 与其他研究人员一起，提出两种体液免疫（抗O侧的抗体） 脂多糖的链）和细胞免疫对于保护这种生物至关重要。 由于对F. tularensis的免疫不完全理解，我们使用了三种方法 疫苗开发：（1）筛选F. tularensis蛋白质组中的绝大多数蛋白质 潜在的保护性抗原； （2）通过该实时疫苗菌株（FT.LV）明显衰减 O多糖（OPS）生物合理基因座中两个必需基因的突变，以及（3）构建A 由载体蛋白结合的全长OP组成的糖缀合疫苗。我们已经获得了 有关保护性免疫本质的关键信息，并使用此信息来完善我们的 实验策略。目前我们的数据表明，最有效的方法可能会有些 我们原型疫苗的结合。通过将糖缀合物疫苗与衰减突变体相结合 菌株我们使用野生型A型菌株Schu S4引起了防止呼吸挑战的保护。到 我们的知识，此类保护以前仅报告了FT.LVS免疫。组合 我们开发的疫苗比FT.LV在动物模型中的毒气少7个。因此，我们预计 它会更安全。