Snodgrassella alvi as an attenuated live vaccine against Neisseria gonorrhoeae

点击翻译按钮获取中文摘要

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.