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dc.contributor.authorGulati, Sunita
dc.contributor.authorPennington, Michael W.
dc.contributor.authorCzerwinski, Andrzej
dc.contributor.authorCarter, Darrick
dc.contributor.authorZheng, Bo
dc.contributor.authorNowak, Nancy
dc.contributor.authorDeOliveira, Rosane B.
dc.contributor.authorShaughnessy, Jutamas
dc.contributor.authorReed, George W.
dc.contributor.authorRam, Sanjay
dc.contributor.authorRice, Peter A.
dc.date2022-08-11T08:09:54.000
dc.date.accessioned2022-08-23T16:48:29Z
dc.date.available2022-08-23T16:48:29Z
dc.date.issued2019-11-05
dc.date.submitted2019-12-12
dc.identifier.citation<p>MBio. 2019 Nov 5;10(6). pii: mBio.02552-19. doi: 10.1128/mBio.02552-19. <a href="https://doi.org/10.1128/mBio.02552-19">Link to article on publisher's site</a></p>
dc.identifier.issn2150-7511 (Electronic)
dc.identifier.doi10.1128/mBio.02552-19
dc.identifier.pmid31690678
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41281
dc.description.abstractThe global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. 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. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 mug/dose 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. Similarly, a 3-dose biweekly schedule (50 mug TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model. IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31690678&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2019 Gulati et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNeisseria gonorrhoeae
dc.subjectantibody function
dc.subjectexperimental infection
dc.subjectimmunization/vaccine
dc.subjectpeptide
dc.subjectvaccine
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBacterial Infections and Mycoses
dc.subjectImmunology of Infectious Disease
dc.subjectImmunoprophylaxis and Therapy
dc.subjectInfectious Disease
dc.subjectMicrobiology
dc.subjectPublic Health
dc.subjectTherapeutics
dc.titlePreclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
dc.typeJournal Article
dc.source.journaltitlemBio
dc.source.volume10
dc.source.issue6
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5087&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4068
dc.identifier.contextkey15986388
refterms.dateFOA2022-08-23T16:48:29Z
html.description.abstract<p>The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. 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. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 mug/dose 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. Similarly, a 3-dose biweekly schedule (50 mug TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model.</p> <p>IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine.</p>
dc.identifier.submissionpathoapubs/4068
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pagese02552-19


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Copyright © 2019 Gulati et al.  This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's license is described as Copyright © 2019 Gulati et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International license.