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Principal Investigator: Paola Massari
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2022
Award: $580,195
Funding agency: National Institute of Allergy and Infectious Diseases
Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease
with high morbidity worldwide, estimated at 87 million cases annually, and severe reproductive tract
complications in women. Current treatment approaches against gonorrhea are compromised by recent onset of
antibiotic resistance. There is a pressing need for an effective vaccine against N. gonorrhoeae, but protective
antigens have been limited, so far. Our previous work on the gonococcal transcriptome during human natural
infection has described differences in mRNA expression of gonococcal genes in urethral and vaginal lavage
samples fromnaturally-infected subjects as compared to mRNA expression when the correspondinggonococcal
strains were cultured in vitro. We termed those genes “in vivo-expressed factors” (IVEFs). We also reported that
~30% of the gonococcal genes expressed during infection are hypothetical proteins. We hypothesized that
gonococcal hypothetical proteins expressed and regulated during infection include new candidate antigens for a
vaccine against N. gonorrhoeae. Through a bioinformatics-based candidate antigen selection strategy (CASS)
that examined predicted immunogenicity, cellular localization, conservation in N. gonorrhoeae and structure
features of the gonococcal hypothetical proteins, we identified 36 new potential targets (ongoing R21AI131004).
We investigated an initial group of 6 antigens, confirming 3 as surface-exposed proteins (NGO0690, NGO0948
and NGO1701) that induced cross-reactive antibodies with complement-mediated serum bactericidal activity
(SBA) against diverse N. gonorrhoeae strains. In preliminary studies, a combination of these antigens showed
promise as protective vaccine candidates in a mouse model of gonococcal infection. Correlates of protection
against gonorrhea in humans are not known but SBA and reduced vaginal colonization in mice are stepping-
stones in preclinical gonococcal vaccine evaluation. An example is the (currently most advanced) N.
gonorrhoeae vaccine candidate, the 2C7 LOS epitope (and its mimotope TCMP2). Other cited mechanisms of
protection include antibody-dependent inhibition of bacterial adhesion or invasion of host cells at the colonization
site, but these have yet to be confirmed in human studies. The goal of this project is to validate and improve
the efficacy of our three candidates as gonococcal vaccine antigens. In Aim 1, we propose antigen dosing
and adjuvant studies to achieve optimal immune responses to our candidates and SBA; in Aim 2 we will validate
protection in the available female mouse model of gonococcal vaginal colonization, broaden strain coverage by
including TMCP2, and correlate immune effector mechanisms and protection; in Aim 3, we will define the
function of the hypothetical protein candidates and their impact on N. gonorrhoeae virulence, fitness and
Immunity, a necessary complement for their selection as vaccine candidates. Our studies will provide new tools
and knowledge towards the unmet goal of a successful vaccine against N. gonorrhoeae.
Terms: <(TNF)-α><3-10C><7S Gamma Globulin><AMCF-I><Ab response><Adjuvant><Adjuvant Study><Adjuvant Trials><Alum Adjuvant><Amino Acid Sequence><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antibodies><Antibody Formation><Antibody Production><Antibody Specificity><Antigenic Determinants><Antigens><Apoptosis Response Protein><Avidity><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BALB C Mouse><BALB/c><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Bacteria><Bacterial Adhesion><Beta Proprotein Interleukin 1><Binding><Binding Determinants><Binetrakin><Bio-Informatics><Bioinformatics><Blood Serum><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CDC><CTLA-8><CTLA8><CXCL8><Cachectin><Cannot achieve a pregnancy><Cefatriaxone><Ceftriaxone><Cell Body><Cells><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><China><Clinical><Clinical Treatment Moab><Combination Vaccines><Combined Vaccines><Complement><Complement Proteins><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Detection><Difficulty conceiving><Disease><Disorder><Dose><Douching><Epithelial Cells><Epitopes><FDA approved><Female><GCP1><Gamma interferon><Gene Proteins><Generalized Growth><Genes><Goals><Gonococcal Infection><Gonococcus><Gonorrhea><Growth><H2O2><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><Hydrogen Peroxide><Hydroperoxide><Hypothetical Protein><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-1 beta><IL-1 β><IL-1-b><IL-17><IL-17A><IL-1β><IL-4><IL-6><IL-8><IL1-Beta><IL1-β><IL17 Protein><IL17A><IL1B Protein><IL1F2><IL1β><IL4 Protein><IL6 Protein><IL8><IL8 gene><IgA><IgG><Immune><Immune Interferon><Immune response><Immunes><Immunity><Immunize><Immunoglobulin A><Immunoglobulin G><Immunological response><In Vitro><Inbred BALB C Mice><Individual><Infection><Infertility><Inflammatory><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin 1beta><Interleukin-1 beta><Interleukin-17><Interleukin-1β><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Irrigation><K60><Knowledge><Lavage><Lead><Lipid A><Lymphocyte Stimulatory Factor 1><MCGF-2><MGI-2><Macrophage-Derived TNF><Mainland China><Mast Cell Growth Factor-2><Measures><Mediating><Membrane><Messenger RNA><Metals><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Molecular Interaction><Monoclonal Antibodies><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Myeloid Differentiation-Inducing Protein><N gonorrhea><N gonorrhoeae><N. gonorrhea><N. gonorrhoeae><Neisseria gonorrhea><Neisseria gonorrhoeae><Nonvaginal irrigation><Nonvaginal lavage><Nutrient Depletion><O element><O2 element><Oxygen><PAWR protein><PRKC, Apoptosis, WT1, Regulator><Pb element><Pharmacology><Phylogenetic Analysis><Phylogenetics><Plasmacytoma Growth Factor><Preinterleukin 1 Beta><Primary Protein Structure><Probability><Production><Property><Prostate Apoptosis Response Protein 4><Protein Gene Products><Proteins><RNA Seq><RNA sequencing><RNAseq><Reporting><Research Design><Research Specimen><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antibiotics><Resistant to Multiple Drug><Resistant to antibiotics><Resistant to multi-drug><Resistant to multidrug><SCYB8><Sampling><Serum><Sexually Transmitted Agents><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Site><Specimen><Splenocyte><Structure><Study Type><Subgroup><Surface><T-Cell Growth Factor 2><T-Cell Proliferation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Therapeutic><Time><Tissue Growth><Transcriptional Repressor PAR4><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Urethra><Vaccine Antigen><Vaccines><Vagina><Vaginal><Vaginal Douching><Vaginal Irrigation><Vaginal Lavage><Venereal Diseases><Venereal Disorders><Venereal Infections><Vesicle><Virulence><WT1-Interacting Protein><Woman><Work><adjuvant protocol><alum><aluminum sulfate><anti-microbial peptide><antibiotic drug resistance><antibiotic resistant><antibody biosynthesis><antimicrobial peptide><b-ENAP><bacterial fitness><bactericidal><bactericide><base><cervicovaginal><cohort><cross reactivity><cytokine><design><designing><evaluate vaccines><fertility cessation><fertility loss><fitness><genital tract><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><infertile><interferon beta 2><irrigation therapy><lFN-Gamma><lavage therapy><lipid-linked oligosaccharides><lipooligosaccharide><mAbs><mRNA><mRNA Expression><male><membrane structure><mouse model><multi-drug resistant><multidrug resistant><murine model><mutant><new vaccines><next generation vaccines><novel><novel vaccines><ontogeny><other than vaginal Douching><other than vaginal Irrigation><par-4 protein><peptide mimetic><peptide mimic><peptidomimetics><pre-clinical><preclinical><protein sequence><reproductive tract><response><study design><thymus derived lymphocyte><tool><transcriptome><transcriptome sequencing><urethral><vaccine candidate><vaccine evaluation><vaccine formulation><vaccine screening><vaccine testing>