In vivo conjugated multivalent toxoid-polysaccharide vaccine for S. aureus

DESCRIPTION provided by applicant Staphylococcus aureus is a Gram positive human pathogen that causes a wide range of infections from skin and soft tissue infections SSTI to life threatening sepsis and pneumonia The pathogenicity of S aureus is dependent on numerous virulence factors including cell surface proteins and polysaccharides as well as secreted toxins An important group of these toxins includes pore forming toxins such as hemolysins and leukocidins as well as small peptidic toxins with lytic activity towards erythrocytes and leukocytes particularly the neutrophils that represent the major line of defense against S aureus These toxins cause tissue damage promote bacterial dissemination and growth in distant organs and enable the pathogen to evade the host innate immune response Furthermore capsular polysaccharide CP are known to protect bacteria from phagocytic activity of polymorphonuclear leukocytes and have been validated as important vaccine targets Integrated BioTherapeutics IBT is pursuing development of toxin based vaccines in combination with CPs against S aureus infections The pore forming hemolysin Hla also known as toxin AT is produced by nearly all strains and is implicated in several S aureus invasive diseases Recent microbiological and serological studies in humans with S aureus bacteremia also show the importance of toxin and phenol soluble modulins PSM for S aureus pathogenicity Based on our recent study pre existing antibodies against Hla toxin and PSM significantly reduce the risk of sepsis in adults with S aureus bacteremia The goal of this Phase I SBIR is to evaluate the feasibility of a novel glycoconjugate staphylococcal toxin based vaccine Vaccine candidates have been designed that represent a critical structural domain at the N terminus of Hla AT fused to toxin and PSM We have shown previously that AT vaccine provides protection against bacteremia and pneumonia This proposal utilizes a unique and novel in vivo bioconjugation technology developed by Glycovaxyn Inc to conjugate this hybrid toxoid with capsular polysaccharide Type CP as proof of concept of the efficacy of the bioconjugate The bioconjugation technology involves E coli cells engineered to express the Campylobacter enzyme PglB as well as the genes required for S aureus CP biosynthesis PglB transfers N linked CP chains to the vaccine construct introduced into these cells This novel technology is a major development in glycoconjugate vaccine field with multiple advantages over the conventional chemical conjugation In the Specific Aim fusions of the three toxins will be generated and attenuating mutations identified and incorporated into the fusion construct The candidate vaccine will be tested for immunogenicity and then bioconjugates generated in Aim In Aim the protective efficacy of the vaccine candidate will be evaluated in two major disease models representing bacteremia sepsis and skin and soft tissue infections Upon successful completion of this proposed research we envision a Phase II SBIR in which similar bioconjugate will be produced for the other major S aureus capsular polysaccharide CP and the efficacy of the multivalent vaccine including combination other toxoid vaccines currently under development in our group extensively tested The ultimate goal is to build a strategic partnership with large pharma to transition the vaccine candidate into clinical development PUBLIC HEALTH RELEVANCE Staphylococcus aureus is a human pathogen causing serious infections that lead to over annual hospitalizations and approximately deaths per year in the US This problem is further complicated by the fact that the majority of circulatin S aureus strains are resistant to most available antibiotics known as methicillin resistant S aureus MRSA The best option for managing the emergence of MRSA is a preventive vaccine This proposal is a joint effort of two companies IBT inc and GlycoVaxyn inc each has a andquot state of the art technologyandquot to develop this andquot in vivo conjugated multivalent toxoid polysaccharide vaccineandquot