VaxNewMO — Department of Health and Human Services STTR Phase I: NIAID

Description

PROJECT SUMMARY Pneumococcal pneumonia remains the leading cause of bacterial pneumonia in both children under years of age and adults over years of age The standard preventative therapy is the conjugate vaccine Prevnar which consists of an immunogenic carrier protein covalently attached to one of thirteen pneumococcal capsular polysaccharides Although Prevnar has significantly reduced the burden of pneumococcal disease it only protects against of the plus pneumococcal serotypes furthermore current methods employed to expand the serotype coverage are notoriously slow requiring complex synthetic chemistries to link a new pneumococcal capsular polysaccharide to the immunogenic carrier protein Over the last decade we have been pioneering an innovative approach to conjugate vaccine development that drastically simplifies the production of glycoconjugates This glycoengineering strategy consisting of the exploitation of bacterial glycosylation machineries to generate bioconjugates eliminates the need of intricate chemical conjugation methods by employing conjugating enzymes to attach polysaccharides to acceptor proteins in Escherichia coli Two conjugating enzymes PglB and PglL have been commercially utilized to generate bioconjugates as they are able to transfer a wide variety of polysaccharides to proteins however neither are able to transfer polysaccharides containing glucose at the reducing end the first sugar of a growing polysaccharide chain This seemingly simple observation has enormous implications as approximately of pneumococcal capsules contain glucose at the reducing end Recently we have identified and patented the first conjugating enzyme that is able to efficiently transfer pneumococcal capsular polysaccharides containing glucose at the reducing end to an acceptor protein Based on this observation we will couple our novel conjugating enzyme technology with carrier proteins previously utilized in conjugate vaccine formulations streamlining the generation of a superior pneumococcal vaccine with broader serotype coverage Importantly our glycoengineering strategy does not require pathogenic organisms as a source of polysaccharide nor chemical reactions to link polysaccharides to proteins The proposed research in this phase I application will focus on Aim glycoengineering three commercial carrier proteins exotoxin A tetanus toxin fragment C and CRM to contain a modular glycotag with pneumococcal capsular polysaccharides generating a new bioconjugate vaccine for pneumococcal serotypes V and b Subsequently Aim we will demonstrate the immunogenicity and efficacy of our pneumococcal specific bioconjugate vaccine compared to the standard preventative therapy Prevnar Our next step for phase II funding is to expand the serotype coverage included in our bioconjugate vaccine develop a large scale purification scheme for obtaining our bioconjugate vaccine as well as pre clinical studies to further demonstrate the safety potency and efficacy of our next generation glycoengineered pneumococcal bioconjugate vaccine PROJECT NARRATIVE The proposal seeks to further develop an innovative technology that can be used to make conjugate vaccines against pneumococcus with broader coverage without the need of chemical procedures For the first time ever our group has identified a conjugating enzyme that is able to attach pneumococcal polysaccharides to an acceptor protein dramatically simplifying the synthesis of protein polysaccharide conjugates In this application we propose to apply our novel conjugating enzyme technology to carrier proteins previously utilized in conjugate vaccine formulations streamlining the generation of a superior pneumococcal vaccine with broader serotype coverage