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, and resistance even to the latest generations of antibiotics continues to emerge. There is no vaccine available, and none appears to be on the horizon of development. It has recently been demonstrated 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 intravaginal treatment with the cytokine interleukin-12 encapsulated in sustained release microspheres (IL-12/ms), a proprietary product developed by TherapyX, Inc., to elicit effective immune responses against existing infection with N. gonorrhoeae and thereby promote therapeutic clearance of the infection. In this SBIR application, a novel experimental gonococcal vaccine will be evaluated in a mouse model of vaginal gonococcal infection that is accepted as the only currently available animal model. Phase I aims to establish Proof-of-Principle that a vaccine consisting of gonococcal outer- membrane vesicles plus IL-12/ms given intravaginally can induce protective immunity against genital gonococcal infection, and generate recallable T-cell and antibody responses to N. gonorrhoeae. The duration of immunity, and protection against different strains of N. gonorrhoeae, will be determined. Successful completion of Phase I will lead to Phase II in which the vaccine components, dosage, and immunization regimen will be optimized, cross-protection and long-term efficacy against a diversity of naturally occurring strains of N. gonorrhoeae, and toxicity 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 100 million new infections per year. The emergence of multiple-drug-resistant strains of Neisseria gonorrhoeae now raises serious concerns over future treatment options, and both US and international authorities have called for renewed efforts at vaccine development. This proposal seeks to develop a vaccine against gonorrhea, based on intravaginal immunization with gonococcal antigen plus a proprietary microencapsulated adjuvant which counteracts the ability of N. gonorrhoeae to interfere with the normal course of an immune response.

Project Terms:
adaptive immunity; Adjuvant; Animal Model; Antibiotics; Antibodies; Antibody Formation; Antigens; authority; base; Biodegradable microsphere; CD8B1 gene; Centers for Disease Control and Prevention (U.S.); Cervical; Clinical Trials; Communicable Diseases; cytokine; design; Development; Disease; dosage; Dose; Drug Kinetics; Encapsulated; Future; Generations; genital secretion; Genital system; Goals; Gonorrhea; Immune; Immune response; Immune system; Immunity; Immunization; Incidence; Infection; Interleukin-12; International; Lead; lymph nodes; Measures; Membrane; Memory; Microspheres; mouse model; Multi-Drug Resistance; Mus; Natural immunosuppression; Neisseria gonorrhoeae; novel; novel strategies; Outcome; Phase; Phase I Clinical Trials; Preparation; Production; public health medicine (field); public health relevance; Regimen; Reporting; Research; resistant strain; response; Route; Serum; Small Business Innovation Research Grant; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; United States; Vaccination; vaccine development; Vaccines; Vagina; Vesicle; Woman; Work

Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and it 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. Proof-of-principle has been established for a novel strategy of prophylaxis against genital gonococcal infection using a mouse model that is accepted as the only currently available animal model. The current vaccine prototype, GvaX12® (a combinatorial formulation of our proprietary sustained-release nanoparticulate interleukin-12 and gonococcal outer membrane vesicles) induces anti-gonococcal T-cell and antibody responses, and generates protection against homologous and heterologous strains for up to 6 months. In this Phase II application, we will define, optimize, and validate a vaccination regimen including route, aiming for intranasal administration. We will determine the basis of cross-protection against diverse strains of naturally occurring N. gonorrhoeae, and begin preliminary pharmacokinetics and toxicology studies in preparation for subsequent toxicological testing in nonhuman primates. Along with the preclinical data, toxicology results and future plans will be incorporated into a briefing package that will be submitted to the FDA in a request for a Type C Meeting.

Public Health Relevance Statement:
NARRATIVE (PUBLIC HEALTH RELEVANCE STATEMENT) Gonorrhea is the second-most-frequent, notifiable infectious disease in the United States; the Centers for Disease Control report ~350,000 cases annually, and world-wide incidence is estimated at 78 million new infections per year. No vaccine is available and the emergence of multiple-drug-resistant strains now raises serious and urgent concerns over future treatment options. This proposal seeks to develop a novel strategy for prophylactic vaccination against gonorrhea by directing the immune response to generate lasting protective immunity.

Project Terms:
adaptive immune response; Animal Model; Antibiotics; Antibodies; Antibody Response; Antibody Specificity; Antibody titer measurement; Antigens; Applications Grants; Biological Availability; Centers for Disease Control and Prevention (U.S.); Clinical; clinical toxicology; combinatorial; Communicable Diseases; cytokine; Data; Detergents; Development; Disease; Drug Kinetics; Embryonic and Fetal Development; Formulation; Frequencies; Future; Generations; Genital system; Gonorrhea; Human; Immune response; Immune system; Immunity; Immunization; Incidence; Infection; Interferons; Interleukin-12; Intranasal Administration; Intravaginal Administration; male; Measures; meetings; Membrane; mouse model; Multi-Drug Resistance; Mus; nanoparticulate; Natural immunosuppression; Neisseria gonorrhoeae; nonhuman primate; Nose; novel strategies; Particulate; Phase; pre-clinical; Preparation; Preventive vaccine; Progress Reports; prophylactic; Prophylactic treatment; prototype; Public Health; public health relevance; Rattus; Regimen; Reporting; reproductive; reproductive toxicity; reproductive tract; Research Design; Resistance; resistant strain; response; Rodent; Route; S-Adenosylmethionine; Serum; Shapes; Small Business Innovation Research Grant; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Th1 Cells; Toxic effect; Toxicology; Vaccination; vaccine delivery; Vaccines; Vagina; Vesicle