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Live-attenuated ETEC Anti-Diarrhea Vaccine Construction via Synthetic Biology

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI109911-01A1
Agency Tracking Number: R41AI109911
Amount: $596,388.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA10-124
Solicitation Year: 2015
Award Year: 2014
Award Start Date (Proposal Award Date): 2014-06-15
Award End Date (Contract End Date): 2016-05-31
Small Business Information
25 Health Sciences Drive, Suite 107, Stony Brook, NY, 11790-3383
DUNS: 829942437
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (516) 448-5073
Business Contact
Phone: (516) 567-5888
Research Institution
FARMINGDALE, NY, 11735-1006
 Nonprofit college or university
DESCRIPTION provided by applicant The development of vaccine to combat Enterotoxigenic E coli ETEC is vital given the pathogenandapos s global impact on million individuals annually however an entirely new non conventional approach is needed Field studies have suggested that inert antigen based vaccines to combat ETEC have andquot essentially no efficacyandquot Therefore a vaccine that mimics a natural infection i e a live attenuated but not knockout strain will elicit the most robust protective response Building on a recently successfu advance developed by the principal investigator that uses synthetic biology to construct bacterial vaccines gene design software will be used to andapos re codeandapos the ETEC heat labile LT and heat stable ST toxins to have significantly decreased but not eliminated levels of expression This andapos re codedandapos strain could in the future serve as a live attenuated vaccine capable of immunizing against ETEC the most common cause of diarrhea in the developing world This approach developed by the PI is expected to yield positive results in ETEC because the approach specifically toxin customization has been successfully utilized for the development of a novel live attenuated Streptococcus Pneumoniae SP vaccine candidate Coleman JR et al JID Synthetic gene customization will achieve the construction of a live attenuated vaccine strain capable of immunizing against ETEC by swapping the genes encoding the target toxin with synthetic genes that have been andapos re codedandapos to use codon pairs that slow the rate of translation The synthetic re design will result in decreased but not entirely eliminated toxin expression Coleman JR Science Previous findings using SP strains expressing low levels of synthetic virulence factors were significantly less virulent than the wild type yet coul induce a protective immune response The PI found that synthetic bacterial strains expressing non damaging levels of toxin were even less virulent than a control knockout strain suggesting very low levels of virulence factor production may be needed to induce immunity and we believe this finding is pertinent for ETEC vaccine construction Coleman JR JID We believe a similar finding will occur in synthetically modified ETEC strains The heat labile LT toxin of ETEC is required for attachment and colonization on the intestinal mucosa thus all killed and LT knockout strains in the past have been ineffective as vaccines Johnson AM J Bac Qadri F Vaccine Furthermore it is known that protection against a second natural infection was attributed mostly to the LT and ST toxin profile of the naturally infecting strain an much less to the specific serotype of the strain Johnson AM et al Therefore by utilizing SAVE andapos re codingandapos of the LT and ST toxin genes one could construct vaccine strains that secrete low levels of the wild type toxins which are a known necessity for subsequent immunity We hypothesize that synthetically modified ETEC producing low sub pathogenic levels of these toxins will provide the necessary host attachment and induction of the immune response as seen in SP The SAVE approach could provide the solution to what has been sought by the ETEC vaccine field for decades inclusion of the LT and ST toxins at levels capable of immune stimulation however low enough to avoid toxicity diarrhea Steinsland H J Clin Microbiol We have performed an initial pilot experiment and have transformed the ETEC H strain with one derivation of a andapos de optimizedandapos LT toxin and seek funds here to support the construction of additional strains and characterize them in vitro and in vivo This project is ideally suited for the STTR program a defined experiment in Phase I which if successful represents a significant advance and will allow for expansion in Phase II At the conclusion of this Phase I we believe we will have a well characterized live attenuated vaccine strain to combat ETEC In Phase II this strain will be further characterized in vivo in an animal system that actually mimics human infections piglets and possibly in the clinic Results from this study could have a very large global impact given that currently there is no vaccine against ETEC We seek to simultaneously yield high impact results while expanding the applicability of rational gene design to bacterial pathogens PUBLIC HEALTH RELEVANCE The most robust defense against infectious disease is vaccination Using synthetic biology and rational gene design we propose an entirely novel method for the construction of a vaccine against Enterotoxigenic E Coli the globally leading cause of diarrhea

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