A Novel Sublingual Vaccine to Prevent Neisseria Gonorrhoeae Infection

Project Summary Our goal is to advance a novel, safe and effective sublingual (SL) vaccine against Neisseria gonorrhoeae (Ng) infection. Antibiotic resistant Ng is an interconnected global threat to people, animals, and the environment. Furthermore, approximately 50% of all annual Ng infections in the US are drug-resistant1. The emergence of drug-resistant Ng is accelerating, and previous antibiotic treatments such as penicillin, tetracycline, ciprofloxacin, and cefixime are no longer recommended1, 2. A single recommended treatment remains – ceftriaxone. Current research suggests that it is the suppression of Th1 and Th2 responses by Ng, modulated by increased Th17 responses, which drives Ng infection and re-infection3-5. Protection from Ng is thought to benefit from a robust Th1 response or balanced Th1/Th2 response3, 6, 7. However, current Ng vaccination approaches mainly using aluminum salt do not induce appropriate Th1/2 responses, limiting vaccine efficacy4, 8, 9. A vaccine that generates a strong Th1, or a more balanced Th1/Th2 response, with robust mucosal immunity, would significantly enhance Ng vaccine efficacy. Current Ng vaccine approaches are mainly focused on developing novel parenteral vaccines4, 8. Parenteral vaccines are generally effective at stimulating systemic antibody-mediated immune responses but are less effective at inducing mucosal immunity10-12. Parenteral vaccines require significant resources for cold-chain management and administration, which translate into slow global vaccination. Since low- and middle-income countries have the highest Ng burden, new vaccines must support global delivery. Our project team brings together three innovative aspects and areas of expertise that will make a novel SL Ng vaccine a reality. First, we have identified novel Ng antigens expressed during natural mucosal infection that generate cross-reactive antibody responses. Second, our novel TLR4 agonist, INI-2005, induces robust systemic and mucosal immune response following SL administration. Third, INI-2005 demonstrates good synthesis and thermostability properties and appears safe. Building from this work, this application is designed to validate a SL Ng vaccine consisting of a novel SL adjuvant, INI-2005, and three unique Ng antigens identified from a reverse vaccinology-like approach. The specific aims of this Phase I SBIR application are to: 1) Produce and benchmark the TLR agonist and Ng antigens; 2) Determine the optimal SL formulation to maximize immune responses in mice; and 3) Demonstrate that the SL formulation effectively protects mice against Ng infection. Funding of this application will validate a SL vaccine to prevent Ng infection, designed for robust Th1 immune responses and mucosal immunity, administered easily, and thermostable for rapid, global distribution.