SBIR-STTR Award

Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. New findings reveal that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. This SBIR application seeks to develop a novel strategy utilizing a proprietary product already developed by TherapyX, Inc., for intravaginal application to redirect the immune response effectively against N. gonorrhoeae. The product will be evaluated in a mouse model of vaginal gonococcal infection that has become accepted as the only currently available animal model. Phase I aims to establish proof-of- principle that the product can induce anti-gonococcal T-cell and antibody responses against the existing infection and accelerate its clearance, and moreover can be recalled to elicit protection against re-infection. The duration of the recall effect, and its ability to afford protection againt different strains of N. gonorrhoeae, will be determined. Successful completion of Phase I will lead to Phase II in which product dosage will be optimized, toxicity will be tested, and cross-protection against a diversity of naturally occurring strains of N. gonorrhoeae and long-term efficacy will be evaluated in preparation for clinical trial.

Public Health Relevance Statement:


Public Health Relevance:
Gonorrhea is the second-most-frequent, notifiable infectious disease in the United States; the Centers for Disease Control report >300,000 cases annually and world-wide incidence is estimated at over 60 million new infections per year. No vaccine is available and the emergence of multiple-drug-resistant strains now raises serious concerns over future treatment options. This proposal seeks to develop a novel strategy of immune intervention against gonorrhea, by redirecting the host's immune response to generate effective immunity that eliminates an existing infection and protects against re-infection.

Project Terms:
adaptive immunity; Animal Model; Antibiotics; Antibodies; Antibody Formation; Antigenic Variation; base; Biodegradable microsphere; CD4 Positive T Lymphocytes; Centers for Disease Control and Prevention (U.S.); Clinical Trials; Communicable Diseases; Complex; cytokine; design; Disease; dosage; Dose; Drug Kinetics; Encapsulated; Evaluation; Frequencies (time pattern); Future; Generations; genital secretion; Genital system; Goals; Gonorrhea; Immune; Immune response; Immune system; Immunity; Incidence; Infection; Interleukin-12; Intervention; Lead; lymph nodes; Measures; Memory; mouse model; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; novel; novel strategies; Outcome; Phase; Phase I Clinical Trials; Preparation; Prophylactic treatment; public health medicine (field); public health relevance; Reporting; Resistance; resistant strain; response; Schedule; secondary infection; Serum; Small Business Innovation Research Grant; T-Lymphocyte; Testing; Th2 Cells; Tissues; Toxic effect; United States; Vaccines; Vagina; Vaginal Route of Drug Administration; Work

Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. Recent findings have revealed that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. However, this induced immunosuppression can be reversed by treatments that effectively redirect the immune response against N. gonorrhoeae. In a Phase I SBIR project, proof-of-principle has been established for a novel strategy of therapy and prophylaxis against genital gonococcal infection using a mouse model that is accepted as the only currently available animal model. A proprietary product developed by TherapyX, Inc., consisting of interleukin-12 (IL-12) encapsulated in biodegradable microparticles for sustained release is administered intravaginally in mice infected with N. gonorrhoeae. This treatment, termed GenX12, induces anti-gonococcal T-cell and antibody responses against the existing gonococcal infection, both accelerating its clearance and generating protection against re- infection with homologous and heterologous strains for at least several months. In this Phase II application, the dose regimen of GenX12 will be optimized, and initial pharmacokinetics studies on its distribution and uptake after intravaginal administration will be performed, in preparation for subsequent toxicological testing in nonhuman primates. The mechanisms of cross-protection against diverse strains of naturally occurring N. gonorrhoeae will be determined to substantiate the scientific basis for the treatment and to identify parameters of protective immunity that will need to be tested ultimately in humans. In preparation for clinical trials, manufacturing scale-up and product evaluation for batch consistency, purity, uniformity, stability, and other characteristics will be performed. The data obtained in these studies will then be used to create a primate toxicology plan. Along with the preclinical data, this toxicology plan will be incorporated into a briefing package that will b submitted to the FDA in a request for a Type C Meeting.

Thesaurus Terms:
Animal Model;Antibiotic Resistance;Antibiotics;Antibodies;Antibody Formation;Applications Grants;B-Lymphocytes;Base;Cd4 Positive T Lymphocytes;Cd8b1 Gene;Cells;Cellular Immunity;Centers For Disease Control And Prevention (U.S.);Characteristics;Clinical Research;Clinical Trials;Communicable Diseases;Comparative Efficacy;Congenic;Cross Reactivity;Cytokine;Data;Design;Development;Disease;Dose;Drug Kinetics;Drug Or Chemical Tissue Distribution;Encapsulated;Enzyme-Linked Immunosorbent Assay;Evaluation;Frequencies (Time Pattern);Future;Generations;Genital System;Goals;Gonorrhea;High Pressure Liquid Chromatography;Human;Immune;Immune Response;Immune System;Immunity;In Vivo Bioassay;Incidence;Individual;Infection;Interferons;Interleukin 12 Receptor Beta;Interleukin-12;Interleukin-12 Receptor;Interleukin-17;Intervention;Intravaginal Administration;Kinetics;Laboratories;Location;Manufacturing Process;Manufacturing Scale-Up;Measures;Meetings;Mouse Model;Multi-Drug Resistance;Mus;Mutant Strains Mice;Natural Immunosuppression;Neisseria Gonorrhoeae;Nonhuman Primate;Novel;Novel Strategies;Particle;Particle Size;Patients;Phase;Polymers;Pre-Clinical;Preparation;Primates;Process;Prophylactic Treatment;Proteins;Public Health Medicine (Field);Public Health Relevance;Receptor;Regimen;Reporting;Research Design;Research Study;Resistance;Resistant Strain;Response;Rivers;Scale Up;Schedule;Serum;Shapes;Small Business Innovation Research Grant;T-Lymphocyte;Testing;Toxic Effect;Toxicology;United States;Uptake;Vaccines;Vagina;Writing;