Live Attenuated Oral Typhoid-Shigellosis Vaccine

DESCRIPTION provided by applicant Vaccines are a rational and cost effective means for protecting against infectious diseases in travelers military personnel and in endemic developing country populations Our goal in this proposal is to address several significant vaccine needs the need for an easy to administer needle free and safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration the lack of a licensed vaccine for prevention of morbidity and mortality due o shigellosis and development of a multivalent oral vaccine that will simultaneously protect against multiple disease agents i e enteric fever plus the major causes of shigellosis To address these challenges we exploit the extensive safety record of the existing live oral attenuated Salmonella Typhi Ty a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever with cross protection against some paratyphoid fevers and shigellosis Further we hypothesize that this vaccine can be formulated to be safe stable and highly immunogenic and can be easily administered orally The current proposal is aimed at creating multivalent vaccine strains Ty a expressing S sonnei form O polysaccharide Ty a Ss and Ty a expressing S flexneri a form O polysaccharide Ty a Sf a We will also create acid resistant Ty a Ss and Ty a Sf a by adding Shigella glutamate decarboxylase GAD genes into vaccine candidates and fully characterize each strain genetically and biochemically Immunogenicity and protective efficacy against S Typhi Ty S sonnei G and S flexneri a T in mice of Ty a Ss Ty a Sf a Ty a Ss GAD and Ty a Sf a GAD will be assessed by immunization via intranasal installation of doses followed by mucosal challenge In Phase II we will conduct similar work for S flexneri a and finalize a temperature stable dried product as rapidly dissolvable wafers or tablets conduct all pre clinical IND enabling studies finalize a clinical protocol and submit an IND This Phase I project will provide the foundation for the Phase II to complete construction of a quadrivalent anti shigellosis vaccine that will protect against more than of shigellosis worldwide PUBLIC HEALTH RELEVANCE Our goal is to develop a multivalent oral vaccine that will simultaneously protect against multiple disease agents is easy to administer needle free is a safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration To address these challenges we exploit the extensive safety record of the existing live oral attenuated Salmonella Typhi Ty a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever with cross protection against some paratyphoid fevers and shigellosis We hypothesize that this vaccine can be formulated to be safe stable highly immunogenic and can be easily administered orally