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.

土拉弗朗西斯菌（Francisella tularensis）是一种多形性、革兰氏阴性、兼性细胞内细菌病原体。 兔热病的病原体，一种潜在致命的人类疾病。 F. tularensis 可以轻松地 雾化及其吸入时的高度传染性引起了人们对其在以下领域的潜在用途的担忧： 生物恐怖主义。一种根据经验衍生的、尚未获得许可的土拉弗朗西斯疫苗株 LVS 的复杂性在于 几个问题：(i) Ft.LVS 在某些感染动物模型中仍然具有高毒力，(ii) LVS 疫苗已被采用 与显着的不良副作用相关，(iii) LVS 疫苗接种者发育不完全 (iv) Ft.LVS 减弱的分子基础尚不清楚。免疫机制 针对土拉弗朗西斯菌（尤其是高毒力 A 型菌株）的保护作用尚不明确。我们的工作， 与其他研究人员一起表明，体液免疫（O 侧抗体） 脂多糖链）和细胞免疫对于预防这种生物体至关重要。 由于对土拉弗拉菌免疫的了解不完全，我们使用了三种方法 疫苗开发：（1）筛选土拉弗拉菌蛋白质组中的绝大多数蛋白质 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，以及（3）构建 由与载体蛋白缀合的全长 OPS 组成的糖缀合疫苗。我们已经获得了 关于保护性免疫性质的关键信息，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。通过将糖复合物疫苗与减毒突变体相结合 我们已经用野生型 A 菌株 Schu S4 诱导了针对呼吸道挑战的保护作用。到 据我们所知，此前仅针对 Ft.LVS 免疫报道了这种保护作用。组合 我们开发的疫苗在动物模型中的毒性比 Ft.LVS 低 7 个对数；因此，我们预计 它将更加安全。