Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

ABSTRACT 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 vacci...

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Autores principales:	Sunita Gulati, Michael W. Pennington, Andrzej Czerwinski, Darrick Carter, Bo Zheng, Nancy A. Nowak, Rosane B. DeOliveira, Jutamas Shaughnessy, George W. Reed, Sanjay Ram, Peter A. Rice
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Neisseria gonorrhoeae vaccine peptide antibody function experimental infection immunization/vaccine Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4b8aef151fe64987bab230d38ff5f4fa
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spelling	oai:doaj.org-article:4b8aef151fe64987bab230d38ff5f4fa2021-11-15T15:54:46ZPreclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine10.1128/mBio.02552-192150-7511https://doaj.org/article/4b8aef151fe64987bab230d38ff5f4fa2019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02552-19https://doaj.org/toc/2150-7511ABSTRACT 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 μg/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 μg 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.Sunita GulatiMichael W. PenningtonAndrzej CzerwinskiDarrick CarterBo ZhengNancy A. NowakRosane B. DeOliveiraJutamas ShaughnessyGeorge W. ReedSanjay RamPeter A. RiceAmerican Society for MicrobiologyarticleNeisseria gonorrhoeaevaccinepeptideantibody functionexperimental infectionimmunization/vaccineMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neisseria gonorrhoeae vaccine peptide antibody function experimental infection immunization/vaccine Microbiology QR1-502
spellingShingle	Neisseria gonorrhoeae vaccine peptide antibody function experimental infection immunization/vaccine Microbiology QR1-502 Sunita Gulati Michael W. Pennington Andrzej Czerwinski Darrick Carter Bo Zheng Nancy A. Nowak Rosane B. DeOliveira Jutamas Shaughnessy George W. Reed Sanjay Ram Peter A. Rice Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
description	ABSTRACT 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 μg/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 μg 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.
format	article
author	Sunita Gulati Michael W. Pennington Andrzej Czerwinski Darrick Carter Bo Zheng Nancy A. Nowak Rosane B. DeOliveira Jutamas Shaughnessy George W. Reed Sanjay Ram Peter A. Rice
author_facet	Sunita Gulati Michael W. Pennington Andrzej Czerwinski Darrick Carter Bo Zheng Nancy A. Nowak Rosane B. DeOliveira Jutamas Shaughnessy George W. Reed Sanjay Ram Peter A. Rice
author_sort	Sunita Gulati
title	Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
title_short	Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
title_full	Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
title_fullStr	Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
title_full_unstemmed	Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
title_sort	preclinical efficacy of a lipooligosaccharide peptide mimic candidate gonococcal vaccine
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/4b8aef151fe64987bab230d38ff5f4fa
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Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

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