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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的淋病的新病例在全球范围内和美国分别约为80和100万。由于没有针对淋病奈瑟氏菌的疫苗，因此寻求淋球菌疫苗的追求是热烈追求，但是临床试验的不良结果和抗生素治疗的易用性制服了进一步的疫苗研究。目前，N。Gonorrhoeae正在开发抗生素耐药性预计将使它们在不久的将来无法治疗的速度。最近的发现是针对B组Neiserseria Meningitis，Menzb的疫苗，赋予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，分支在奈瑟氏菌科中，是与 Neisseria，Kingella和Eikenella可以被部署为自然减弱的非致病性现场 N.淋病的载体疫苗。 S. alvi不预计会殖民人类，因为它是严重的利基市场限制在其定居的特定蜜蜂上。此外，我们的计算机分析表明S. alvi 实际上缺乏致病性奈瑟氏病的所有主要毒力因素，包括专用从宿主那里取铁的机械。初步数据支持我们的假设1）Alvi S. alvi 高剂量腹膜内腹膜内治疗时，在小鼠中是安全的。 2）S。alvi诱导高IgG滴度对淋病。 3）IgG滴度转化为鲁棒的杀菌活性。这拟议的研究将扩大这些最初的观察结果，以确定Alvi作为淋球菌疫苗。 AIM 1中的研究将优化肠胃外和粘膜接种途径以刺激升高中和抗体和效应T细胞，指示细胞介导的免疫力。研究将评估是否需要佐剂，以及是否粘膜素，肠胃外增强刺激保护性免疫。 AIM 2中的研究将评估S. alvi的效力对阴道N。淋病挑战。