Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

• Published in: mBio 2019-11, Vol.10 (6)
• Main Authors: Gulati, Sunita, Pennington, Michael W, Czerwinski, Andrzej, Carter, Darrick, Zheng, Bo, Nowak, Nancy A, DeOliveira, Rosane B, Shaughnessy, Jutamas, Reed, George W, Ram, Sanjay, Rice, Peter A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bacterial - immunology; Antibodies, Monoclonal - immunology; antibody function; Antigens, Bacterial - immunology; Bacterial Vaccines - immunology; Epitopes - immunology; experimental infection; Female; Gonorrhea - immunology; immunization/vaccine; Immunoglobulin G - immunology; Lipopolysaccharides - immunology; Mice; Mice, Inbred BALB C; Neisseria gonorrhoeae; Neisseria gonorrhoeae - immunology; peptide; Peptides - immunology; Therapeutics and Prevention; vaccine
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.02552-19

The global spread of multidrug-resistant strains of 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 T 1-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. 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 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 T 1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candida