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.

摘要 淋病的新病例在全球和美国分别约为8000万和100万。 由于没有针对淋病奈瑟菌的疫苗存在，寻求淋球菌疫苗是 但临床试验的结果不佳，抗生素治疗也很容易， 抑制了进一步的疫苗研究目前，N。淋病正在产生抗生素耐药性 预计在不久的将来，这种疾病将无法治愈。最近的研究发现， 抗B群脑膜炎奈瑟菌疫苗MeNZ B可部分保护 淋病，表明淋球菌疫苗是可行的。鉴于这一发现，我们假设， Alvi，其分支于奈瑟氏菌科，并且是与Neisseriaceae相关的属。 奈瑟氏菌属、金氏菌属和艾肯氏菌属，可以作为天然减毒的非致病性活疫苗部署。 N.的载体疫苗。淋病S.预计alvi不会殖民人类，因为它严重 只限于它所殖民的特定蜜蜂。此外，我们的计算机分析表明，S。Alvi 几乎缺乏致病性奈瑟氏球菌科的所有主要毒力因子，包括一个专门的 从宿主体内回收铁的机器。初步数据支持我们的假设：1）S。Alvi 高剂量腹腔给药安全; 2）S. alvi诱导高IgG滴度 对N有交叉反应淋病;和3）IgG滴度转化为稳健的杀菌活性。的 拟议的研究将扩大这些初步观察，以确定S。alvi作为淋球菌 疫苗目标1中的研究将优化胃肠外和粘膜接种途径，以刺激 升高的中和抗体和效应T细胞指示细胞介导的免疫。研究 将评估是否需要佐剂，以及粘膜预充、胃肠外加强是否最佳 刺激保护性免疫力。目标2中的研究将评估S。alvi对阴道奈瑟菌的有效性。 淋病攻毒