Gonorrhea is the second most common bacterial sexually transmitted infection ? the most common is chlamydia, which often coinfects with gonorrhea. About 80 million new cases of gonorrhea occur worldwide annually. Over 555,000 cases were reported in the U.S. in 2017. Serious sequelae of gonorrhea in women include infertility, ectopic pregnancy and chronic pelvic pain. Neisseria gonorrhoeae (Ng), the causative agent of gonorrhea, has become resistant to almost every antibiotic in clinical use. Resistance to ceftriaxone and azithromycin ? the recommended first-line of treatment ? portends an era of untreatable gonorrhea. The CDC has listed Ng as a microorganism with a threat level of ?Urgent.? Development of a safe and effective vaccine against gonorrhea is a public health priority. Our group has shown that a monoclonal antibody (mAb) called 2C7 that targets a widely-expressed Ng lipooligosaccharide (LOS) epitope (the 2C7 epitope) is bactericidal. A peptide mimic (mimitope) of the 2C7 epitope, when configured as a polymer (a ?multiantigen peptide?) elicits bactericidal Abs and attenuates Ng vaginal colonization in mice. Encouraged by the recent retrospective observation that a group B meningococcal vaccine composed of detergent-extracted outer membrane vesicles (MeNZB) designed to curtail a meningococcal epidemic in New Zealand also reduced incident gonococcal disease by 31%, we will incorporate the gonococcal 2C7 epitope into meningococcal outer membrane vesicles to target both meningococci and gonococci. This innovative approach is advantageous because both diseases are highly prevalent in adolescents and young adults. In addition to the economic advantages, a ?pan- Neisseria? vaccine would help address an already crowded vaccination schedule and may mitigate the stigma associated with vaccines against STIs.
In Aim 1, we will develop meningococcal native outer membrane vesicles (NOMVs) containing LOS that displays the 2C7 epitope. Meningococcal FH-binding protein (FHbp) will be mutated to abrogate binding of human FH and thereby elicit higher bactericidal Ab against Nm than wild- type FHbp. We will also delete Rmp and H.8, which may elicit blocking Ab against Ng and Nm, respectively. Elicited Abs will be tested for complement-dependent bactericidal activity against homologous and heterologous Ng strains and tested for efficacy versus Ng in transgenic mice we have developed that express the human complement inhibitors, FH and C4BP, to better simulate the complement environment in humans. We will use mice deficient in C9 (the last step in formation of the bacteriolytic pore) or mice depleted of PMNs to elucidate the mechanism of action of the candidate vaccine, which will also define correlates of protection.
In Aim 2, we will develop detergent-extracted outer membrane vesicle vaccines (dOMVs) that display the 2C7 mimitope peptide in the framework of the major outer membrane protein, PorA. Immunogenicity and efficacy of this vaccine will be evaluated as described in Aim 1.
About 80 million new cases of gonorrhea occur worldwide annually and over 555,000 cases were reported in the U.S. in 2017, making gonorrhea the second most common bacterial sexually transmitted infection ? the most common is chlamydia, which often coinfects with gonorrhea. The objective of this proposal is to improve on the encouraging results of reduced incidence of gonorrhea following use of a meningococcal outer membrane vesicle vaccines by incorporating our promising candidate gonococcal vaccine antigen to design a combination vaccine that effectively targets both Neisseria gonorrhoeae and N. meningitidis.
