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Principal Investigator: Lisa Ann Lewis
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2022
Award: $251,250
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Gonorrhea affects over 87 million people annually globally. In 2019, over 600,000 cases of gonorrhea were
reported to the CDC, a 92% increase since the historic low in the US in 2009. However, the true incidence of
cases annually in the US is estimated to be ~1.5 million. The spread of antimicrobial resistance has severely
limited treatment options – currently, ceftriaxone is the only approved first line of treatment. A safe and effective
vaccine against gonorrhea is urgently needed. Lipooligosaccharide (LOS) is the most abundant molecule on the
gonococcal surface and plays multifaceted roles in bacterial virulence. A LOS epitope recognized by mAb 2C7
(therefore called the 2C7 epitope) is expressed by >95% of Ng in vivo; Ng mutants that do not express the 2C7
epitope are attenuated in mice. Our group has developed a peptide mimic (mimitope) of the 2C7 epitope, which
when configured as a multi-antigen peptide (MAP) elicits bactericidal Abs and attenuates Ng colonization in
mice. Further, we have elucidated the mechanism of action of MAP as complement-mediated killing (killing
through membrane attack complex), strongly suggesting serum bactericidal activity as a mechanistic correlate
of protection. In a collaborative venture with Evaxion Biotech, we screened 30 antigens that were identified by
EDEN, Evaxion’s proprietary in silico platform, for immunogenicity, bactericidal activity and efficacy in the mouse
vaginal colonization model. These studies identified two cell division proteins as promising candidates based on
efficacy in vivo. When configured as a fusion protein (chimera), the cell division proteins showed improved ac-
tivity in vivo compared to individual proteins and currently is our lead protein vaccine candidate. DNA and mRNA
vaccines have proven very successful in the fight against the Covid-19 pandemic. These platforms elicit high
levels of protection, have proven safe, are rapidly adaptable and economical. Here, we will leverage these two
newer vaccine platforms to deliver the protective gonococcal antigens. A multivalent vaccine has the advantage
of broader strain coverage, improved efficacy and would also raise the barrier for development of resistance. In
Aim 1, we will evaluate DNA vaccine constructs that contain the 2C7 LOS mimitope (PEP1) configured as an
octameric concatemer (PEP1_OCT), the cell division protein chimera, or a combination of the two. Serum will
be assessed for antibody titers and complement-dependent bactericidal activity, as well durability of responses.
Comparisons will be made with the protein versions of these vaccines currently under development. Mucosal
(vaginal) Ab responses will also be measured. T cell responses will be measured by ELISpot. Based on data in
vitro, the lead DNA vaccine formulation(s) will be assessed for efficacy in the mouse vaginal colonization model.
In Aim 2 the constructs described in Aim 1 will be expressed using an mRNA vaccine delivery platform. As in
Aim 1, we will evaluate Ab titers in serum and vaginal fluid, measure serum bactericidal activity, T cell responses
and efficacy of the lead mRNA vaccine formulation(s) in the mouse model of gonorrhea. Successful completion
of the work in this proposal will identify a lead gonococcal DNA and/or mRNA vaccine for further pre-clinical
development.
Terms: <7S Gamma Globulin><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antibodies><Antibody Formation><Antibody Production><Antibody titer measurement><Antigen Targeting><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Antimicrobial Resistance><Antimicrobial resistant><Attenuated><Binding Determinants><Biology><Biotech><Biotechnology><Blood Serum><C 5b-9><C5b-9><CDC><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><Cannot achieve a pregnancy><Cefatriaxone><Ceftriaxone><Cell Nucleus><Cell division><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Chimera><Chimera Protein><Chimera organism><Chimeric Proteins><Chlamydia><Clinical><Clinical Treatment Moab><Complement><Complement Complex C5b-9><Complement Membrane Attack Complex><Complement Proteins><Country><Cryofixation><Cryopreservation><Cytolytic Terminal Complement Complex><Cytoplasm><DNA Vaccines><Data><Development><Difficulty conceiving><Disease><Disorder><Ectopic Pregnancy><Epitopes><FPLC><Formulation><Fusion Protein><Gonococcal Infection><Gonococcus><Gonorrhea><HIV><Human Immunodeficiency Viruses><IgA><IgG><Immune response><Immunize><Immunoglobulin A><Immunoglobulin G><Immunological response><Immunology><In Vitro><Incidence><Individual><Infection><Infertility><Inflammation><LAV-HTLV-III><Lead><Link><Lymphadenopathy-Associated Virus><Measures><Mediating><Membrane Attack Complex><Messenger RNA><Mice><Mice Mammals><Microbe><Miscellaneous Antibiotic><Miyagawanella><Modeling><Monoclonal Antibodies><Mucosa><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><N gonorrhea><N gonorrhoeae><N-Acetylneuraminic Acids><N. gonorrhea><N. gonorrhoeae><Naked DNA Vaccines><Neisseria gonorrhea><Neisseria gonorrhoeae><Nucleic Acid Vaccines><Nucleic Acids><Nucleus><Pathogenicity Factors><Pb element><Peptides><Persons><Phase I Study><Play><Proteins><RNA vaccine><RNA-based vaccine><Receptor Protein><Recombinant DNA Vaccines><Reporting><Research Resources><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistance to antimicrobial><Resistant development><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><Resources><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Serum><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Sialic Acids><Surface><T cell response><TM Pharmacia Fast Protein Liquid Chromatography><Technology><Terminal Complement Complex><Testing><Transmission><United States><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Vaccine Antigen><Vaccines><Vagina><Vaginal><Venereal Diseases><Venereal Disorders><Venereal Infections><Virulence><Virulence Factors><Virus-HIV><Woman><Work><accessory cell><anti-microbial resistance><anti-microbial resistant><antibiotic drug resistance><antibiotic resistant><antibody biosynthesis><antibody titering><bactericidal><bactericide><base><bedsonia><burden of infection><cervicovaginal><chronic pelvic pain><chronic pelvic pain syndrome><cold preservation><cold storage><combat><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cost><deliver vaccines><density><develop a vaccine><develop vaccines><developing resistance><development of a vaccine><developmental><evaluate vaccines><extrauterine pregnancy><fast protein liquid chromatography><fertility cessation><fertility loss><fight against><genital tract><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in silico><in vivo><infection burden><infertile><lipid based nanoparticle><lipid nanoparticle><lipid-linked oligosaccharides><lipooligosaccharide><low income country><mAbs><mRNA><mRNA Stability><mRNA delivery><mRNA vaccine><mRNA-based vaccine><model of animal><model organism><mouse model><multi-drug resistant><multidrug resistant><murine model><mutant><nano particle delivery><nanoparticle delivered><nanoparticle delivery><new vaccines><next generation vaccines><novel vaccines><nucleic acid-based vaccine><optimism><peptide mimetic><peptide mimic><peptidomimetics><phase 1 study><plasmid DNA><postiive attitude><pre-clinical><pre-clinical development><preclinical><preclinical development><public health priorities><receptor><reproductive tract><resistance 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