Snodgrassella alvi as an attenuated live vaccine against Neisseria gonorrhoeae

Snodgrassella alvi 作为针对淋病奈瑟菌的减毒活疫苗

• 批准号: 10263891
• 负责人: David W Pascual
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263891
• 关键词: Adjuvant; Alleles; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antibody-mediated protection; Antigens; Apis; Attenuated; Attenuated Vaccines; Bacteria; Bees; Cells; Cellular Immunity; Clinical Trials; Data; Development; Disease; Dose; Eikenella; Family; Female; Future; Genetic Recombination; Genital; Genitalia; Genome; Goals; Gonorrhea; Health; Honey; Human; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunologic Memory; Immunologic Surveillance; Incidence; Infection; Insecta; Interleukin-12; Investigation; Iron; Kingella; Link; Mammals; Membrane; Meningococcal vaccine; Modeling; Mucous Membrane; Mus; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Neisseriaceae; Outcome; Pathogenicity; Pathologic; Phase; Proteome; Regimen; Research; Route; Serum; Serum Bactericidal Test; Sexually Transmitted Diseases; Subunit Vaccines; Testing; Translating; Vaccination; Vaccine Research; Vaccines; Vagina; Variant; Vesicle; Virulence Factors; Work; bactericide; base; cross reactivity; effector T cell; efficacy testing; experimental study; gonorrhea vaccine; human disease; immunogenicity; in silico; in vivo; intraperitoneal; member; men; mucosal vaccination; neutralizing antibody; novel; pathogen; pressure; prevent; reproductive tract; response; universal vaccine; vaccine candidate; vaccinology; vector vaccine; virtual

ABSTRACT New cases of gonorrhea are approximately 80 and 1 million worldwide and in the US, respectively. Since no vaccine against Neisseria gonorrhoeae exists, the quest for a gonococcal vaccine was hotly pursued, but the poor outcomes from clinical trials and the ease of antibiotic treatment subdued further vaccine research. Currently, N. gonorrhoeae is developing antibiotic resistance at a pace that is projected to make them untreatable in the near future. The recent finding that the vaccine against Group B Neisseria meningitidis, MeNZB, confers partial protection against gonorrhea, suggests that a gonococcal vaccine is feasible. Given this finding, we hypothesize that Snodgrassella alvi, which branches within the family Neisseriaceae, and is a related genus to Neisseria, Kingella, and Eikenella, can be deployed as a naturally attenuated, nonpathogenic live vector vaccine for N. gonorrhoeae. S. alvi is not expected to colonize humans because it is severely niche-restricted to the specific bees it colonizes. Moreover, our in silico analysis shows that S. alvi virtually lack all major virulence factors of pathogenic Neisseriaceae, including a dedicated machinery to retrieve iron from the host. Preliminary data support our hypothesis in that 1) S. alvi is safe in mice when administered intraperitoneally at high doses; 2) S. alvi induces high IgG titers that cross-react to N. gonorrhoeae; and 3) IgG titers translate into robust bactericidal activity. The proposed research will expand these initial observations to ascertain S. alvi as a gonococcal vaccine. Studies in Aim 1 will optimize parenteral and mucosal routes of vaccination to stimulate elevated neutralizing antibodies and effector T cells indicative of cell-mediated immunity. Studies will assess if adjuvants are required, and whether a mucosal prime, parenteral boost best stimulates protective immunity. Studies in Aim 2 will assess S. alvi `s efficacy against vaginal N. gonorrhoeae challenge.

抽象的 全球和美国新增淋病病例分别约为 80 例和 100 万例。 由于没有针对淋病奈瑟氏菌的疫苗，因此寻求淋球菌疫苗 受到热烈追捧，但临床试验结果不佳以及抗生素治疗的难易程度 抑制了进一步的疫苗研究。目前，淋病奈瑟菌正在产生抗生素耐药性 预计在不久的将来它们将无法治愈。最近的发现表明 针对 B 组脑膜炎奈瑟菌 (MeNZB) 的疫苗可提供部分保护 淋病，表明淋球菌疫苗是可行的。鉴于这一发现，我们假设 Snodgrassella alvi，属于奈瑟菌科 (Neisseriaceae) 的分支，是与 奈瑟氏菌、金氏菌和艾肯氏菌可作为自然减毒、非致病性活菌使用 淋病奈瑟菌载体疫苗。 S. alvi 预计不会在人类中定殖，因为它严重危害人类健康。 生态位仅限于它所聚居的特定蜜蜂。此外，我们的计算机分析表明 S. alvi 实际上缺乏致病性奈瑟菌科的所有主要毒力因子，包括专门的毒力因子 从宿主中回收铁的机械。初步数据支持我们的假设：1) S. alvi 高剂量腹腔注射对小鼠是安全的； 2) S. alvi 诱导高 IgG 滴度 与淋病奈瑟菌发生交叉反应； 3) IgG 滴度转化为强大的杀菌活性。这 拟议的研究将扩大这些初步观察结果，以确定沙门氏菌是否为淋球菌 疫苗。目标 1 的研究将优化胃肠外和粘膜疫苗接种途径，以刺激 中和抗体和效应 T 细胞升高表明细胞介导的免疫。研究 将评估是否需要佐剂，以及粘膜初免、肠外加强是否最好 刺激保护性免疫力。目标 2 中的研究将评估 S. alvi 对阴道奈瑟菌的功效。 淋病挑战。