Header Logo

Search Result Details

This page shows the details of why an item matched the keywords from your search.
One or more keywords matched the following properties of Rice, Peter
PropertyValue
overview

Complement

Complement research in the Rice laboratory involves the identification of unique determinants present on bacterial surfaces that may serve as suitable vaccine candidates to protect against infection in humans. In some cases these determinants may also activate or regulate a series of inflammatory mediators called complement (C), which are made up of a group of proteins that are activated sequentially as part of the innate immune response: (1) to combat invading bacteria that infect humans by killing the bacteria and to also enhance their clearance by phagocytes; (2) to facilitate the development of the adaptive immune response to invading bacteria to protect against future infection caused by these organisms and (3) to amplify this immune response once it has developed. Under certain conditions C works to the disadvantage of the host because it is hijacked by microorganisms to down-regulate the activation and binding of C and to also enhance entry into phagocytes (professional and non-professional) where organisms can gain sanctuary; these areas of study are important to consider when vaccines sometimes don’t work. The laboratory examines C interactions with bacteria, particularly the Neisseria species, having been first to report interactions of Neiseria gonorrhoeae with complement (C) down-regulator molecules (factor H; an alternative pathway of C inhibitor) and C4 binding protein (C4BP; a classical pathway of C inhibitor) but also with the only known complement up-regulator, properdin. C down-regulator molecules are important in enabling Neisseria to escape immune surveillance.

Gonococcal vaccine development

As a prelude to identifying suitable vaccine candidates to protect against gonococcal infection, the laboratory first identified and characterized blocking (or subverting) antibody targets on Neisseria species that interfere with productive killing (in vitro ) by complement (C)-dependent bactericidal antibodies. These antibody responses were elicited in a human vaccination trial that used a complex outer membrane structure as an immunogen that had been derived from Neisseria gonorrhoeae. A potentially protective response (C dependent bactericidal antibodies) that was elicited in men by the vaccine was subverted by the accompanying blocking antibody response directed against small amounts of a reduction modifiable protein (Rmp) present in the vaccine, which caused the vaccine to fail when the men who received it were not protected upon subsequent urethral (experimental) challenge with virulent N. gonorrhoeae (experimental urethral gonorrhea in men is safe and an IRB approved method to study this disease). Removal of Rmp-antibody from vaccine serum that has lost baseline bactericidal activity as a result of immunization, restores killing. These experiments were subsequently repeated (and verified) in the mouse experimental model of gonococcal infection. Blocking antibodies are present in normal human serum and are also elicited by gonococcal infection itself. These antibodies may reverse a protective immune antibody response (--a response that may occur with other bacterial infections) and may explain the lack of protective immunity that occurs after gonococcal infection.

In efforts to identify suitable subunit vaccine candidates against gonorrhea devoid of blocking activity, the laboratory examined the chemistry (and immunochemistry) of gonococcal lipopolysaccharide (also known as lipooligosaccharide [LOS]), having reported the first known conserved gonococcal LOS derived oligosaccharide epitope (called 2C7) that is present on almost all wild-type strains of N. gonorrhoeae. This epitope, located in the core of LOS as lactose substitutions on each of the two core heptose molecules of LOS, elicits complement dependent antibody activity in humans both in natural human infection and as a consequence of experimental animal immunization. The Rice laboratory and its collaborators have performed extensive biochemical, structural and genetic analysis of this carbohydrate epitope and the surrounding structure(s) to define their role in complement (C) binding. The 2C7 epitope is: i) broadly expressed as a gonococcal antigenic target in human infection; ii) a critical requirement for gonococcal colonization in the experimental setting and iii) a virulence determinant that is maintained and expressed by gonococci.

To circumvent inherent limitations of carbohydrate antigens as immunogens when they are used as vaccines, the laboratory also “converted” the 2C7 epitope into peptide mimics, first into an anti-idiotope (protein) and then into a complex peptide mimic for testing as vaccine candidates; both have been shown to be the immunologic counterparts (surrogates) of the oligosaccharide epitope. To formulate a prototype vaccine candidate intended for use in humans that represented the 2C7 epitope in antigenicity and immunogenicity, the lab synthesized the candidate compound to >95% purity.  This vaccine candidate, called TMCP2, when administered to BALB/c mice in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1 promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains.

These inventions (prototypes and finalized products) have been issued U.S. and foreign patents and are being configured with appropriate adjuvants for use in: (1) humans and (2) experimental models in mice adapted to stimulate the human complement down-regulator system by creating human FH/C4BP transgenic mice.  A gonococcal vaccine candidate has been developed that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a pre-clinical experimental infection model.

One or more keywords matched the following items that are connected to Rice, Peter
Item TypeName
Academic Article Experimental immunization with a monoclonal anti-idiotope antibody that mimics the Neisseria gonorrhoeae lipooligosaccharide epitope 2C7.
Academic Article The pathogenesis of gonococcal urethritis in men: confocal and immunoelectron microscopic analysis of urethral exudates from men infected with Neisseria gonorrhoeae.
Academic Article Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.
Academic Article A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae.
Academic Article T lymphocyte response to Neisseria gonorrhoeae porin in individuals with mucosal gonococcal infections.
Academic Article Immunogenicity of Neisseria gonorrhoeae lipooligosaccharide epitope 2C7, widely expressed in vivo with no immunochemical similarity to human glycosphingolipids.
Academic Article Factors predicting upper genital tract inflammation among women with lower genital tract infection.
Academic Article Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among men with urethritis and their female sex partners.
Academic Article Complement processing and immunoglobulin binding to Neisseria gonorrhoeae determined in vitro simulates in vivo effects.
Academic Article The gonococcal Fur-regulated tbpA and tbpB genes are expressed during natural mucosal gonococcal infection.
Academic Article Bacterial vaginosis (BV) and the risk of incident gonococcal or chlamydial genital infection in a predominantly black population.
Academic Article Expression of the gonococcal global regulatory protein Fur and genes encompassing the Fur and iron regulon during in vitro and in vivo infection in women.
Academic Article Antibody-antigen specificity in the immune response to infection with Neisseria gonorrhoeae.
Academic Article Strategies for mimicking Neisserial saccharide epitopes as vaccines.
Academic Article Characterization of gonococcal antigens responsible for induction of bactericidal antibody in disseminated infection.
Academic Article Implications of phase variation of a gene (pgtA) encoding a pilin galactosyl transferase in gonococcal pathogenesis.
Academic Article Experimental models of bacterial arthritis: a microbiologic and histopathologic characterization of the arthritis after the intraarticular injections of Neisseria gonorrhoeae, Staphylococcus aureus, group A streptococci, and Escherichia coli.
Academic Article Clinical manifestations of disseminated infection caused by Neisseria gonorrhoeae are linked to differences in bactericidal reactivity of infecting strains.
Academic Article Douching, pelvic inflammatory disease, and incident gonococcal and chlamydial genital infection in a cohort of high-risk women.
Academic Article Pathogenesis of pelvic inflammatory disease. What are the questions?
Academic Article por Variable-region typing by DNA probe hybridization is broadly applicable to epidemiologic studies of Neisseria gonorrhoeae.
Academic Article Distinct defensin profiles in Neisseria gonorrhoeae and Chlamydia trachomatis urethritis reveal novel epithelial cell-neutrophil interactions.
Academic Article Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection.
Academic Article Gonococcal arthritis (disseminated gonococcal infection).
Academic Article Phosphoethanolamine substitution of lipid A and resistance of Neisseria gonorrhoeae to cationic antimicrobial peptides and complement-mediated killing by normal human serum.
Academic Article Species-specificity of Neisseria gonorrhoeae infection: do human complement regulators contribute?
Academic Article Specificity of antibodies against Neisseria gonorrhoeae that stimulate neutrophil chemotaxis. Role of antibodies directed against lipooligosaccharides.
Academic Article Bactericidal antibody in genital infection due to Neisseria gonorrhoeae.
Academic Article Immunization against a saccharide epitope accelerates clearance of experimental gonococcal infection.
Academic Article Infections of the genitourinary tract in women: selected aspects.
Academic Article Risk of acquiring gonorrhea and prevalence of abnormal adnexal findings among women recently exposed to gonorrhea.
Academic Article Arthritis in rabbits induced by killed Neisseria gonorrhoeae and gonococcal lipopolysaccharide.
Academic Article Natural serum bactericidal activity against Neisseria gonorrhoeae isolates from disseminated, locally invasive, and uncomplicated disease.
Academic Article Characterization of serum resistance of Neisseria gonorrhoeae that disseminate. Roles of blocking antibody and gonococcal outer membrane proteins.
Academic Article Serum resistance of Neisseria gonorrhoeae. Does it thwart the inflammatory response and facilitate the transmission of infection?
Concept Gonorrhea
Academic Article Antimicrobial susceptibility of Neisseria gonorrhoeae isolates from symptomatic men attending the Nanjing sexually transmitted diseases clinic (2011-2012): genetic characteristics of isolates with reduced sensitivity to ceftriaxone.
Academic Article Antibody to reduction modifiable protein increases the bacterial burden and the duration of gonococcal infection in a mouse model.
Academic Article a-2,3-sialyltransferase expression level impacts the kinetics of lipooligosaccharide sialylation, complement resistance, and the ability of Neisseria gonorrhoeae to colonize the murine genital tract.
Academic Article The Gonococcal Transcriptome during Infection of the Lower Genital Tract in Women.
Academic Article Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914).
Academic Article Utilizing CMP-Sialic Acid Analogs to Unravel Neisseria gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance and Design Novel Therapeutics.
Academic Article A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae.
Academic Article Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop "Gonorrhea Vaccines: the Way Forward".
Academic Article Desialylation of Neisseria gonorrhoeae Lipooligosaccharide by Cervicovaginal Microbiome Sialidases: The Potential for Enhancing Infectivity in Men.
Academic Article Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics.
Academic Article Neisseria gonorrhoeae: Drug Resistance, Mouse Models, and Vaccine Development.
Academic Article A Novel Sialylation Site on Neisseria gonorrhoeae Lipooligosaccharide Links Heptose II Lactose Expression with Pathogenicity.
Academic Article Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women.
Academic Article Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae.
Academic Article Antimicrobial Resistance in Neisseria gonorrhoeae: Proceedings of the STAR Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting.
Academic Article Role of Gonococcal Neisserial Surface Protein A (NspA) in Serum Resistance and Comparison of Its Factor H Binding Properties with Those of Its Meningococcal Counterpart.
Academic Article Targeting Lipooligosaccharide (LOS) for a Gonococcal Vaccine.
Academic Article Biology of the Gonococcus: Disease and Pathogenesis.
Academic Article Complement-Dependent Serum Bactericidal Assays for Neisseria gonorrhoeae.
Academic Article Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody.
Academic Article Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine.
Academic Article Bypassing Phase Variation of Lipooligosaccharide (LOS): Using Heptose 1 Glycan Mutants To Establish Widespread Efficacy of Gonococcal Anti-LOS Monoclonal Antibody 2C7.
Academic Article Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins.
Academic Article Susceptibility Trends of Zoliflodacin against Multidrug-Resistant Neisseria gonorrhoeae Clinical Isolates in Nanjing, China, 2014 to 2018.
Academic Article Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection.
Academic Article In Vitro Efficacy of Gentamicin Alone and in Combination with Ceftriaxone, Ertapenem, and Azithromycin against Multidrug-Resistant Neisseria gonorrhoeae.
Academic Article Efficacy of an Experimental Gonococcal Lipooligosaccharide Mimitope Vaccine Requires Terminal Complement.
Academic Article In Vitro Activity of Ertapenem against Neisseria gonorrhoeae Clinical Isolates with Decreased Susceptibility or Resistance to Extended-Spectrum Cephalosporins in Nanjing, China (2013 to 2019).
Academic Article Neisseria gonorrhoeae Infection in Women Increases With Rising Gonococcal Burdens in Partners: Chlamydia Coinfection in Women Increases Gonococcal Burden.
Search Criteria
  • Gonorrhea