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Principal Investigator: SAUL r TZIPORI
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2021
Award: $206,250
Funding agency: National Institute of Allergy and Infectious Diseases
We seek NIH funding to develop a vaccine against cryptosporidiosis for children in LMIC. As no effective
therapies exist, there is a critical need for vaccination to reduce morbidity and mortality attributed to
cryptosporidiosis, which is estimated to cause diarrhea in >10 million children and kills more than half a million
children each year. The Global Enteric Multicenter Study (GEMS) ranked Cryptosporidium as the 2nd most
prevalent pathogen (1st rotavirus; 3rd Enterotoxigenic E. coli; 4th Shigella spp.) causing moderate-to-severe
diarrhea (MSD) in children in 4 sites in sub-Saharan Africa and 3 in South Asia. The GEMS further made the
case that controlling these 4 pathogens will eliminate > 90% of MSD in children. Much progress had been
made towards this goal in that vaccines already exist for rotavirus or are in clinical trials for ETEC and Shigella.
However, vaccine development and testing against Cryptosporidium, a eukaryote with many serious technical
obstacles, lags, and there has been minimal scientific progress to overcome these challenges since the first
few surface proteins were discovered more than 20 years ago. To address these gaps, we identified novel
parasite antigens, developed novel immunocompetent rodent models of infection, and deployed innovative
intradermal mRNA immunization technology developed by our CureVac partners. In this proposal, we
demonstrate the experience, skills, innovative mRNA vaccine technology and use of rodent models and
reagents to identify an effective panel of mRNAs against cryptosporidiosis as the first step. Using reverse
vaccinology, immunoproteomics, gene expression, and comparative genomics to other related protozoa, we
identified a panel of 32 novel candidates derived from C. hominis and used by CureVac to generate mRNAs.
Specific Aim 1 focuses on screening 32 (or more as needed) mRNAs encoding C. hominis in the enteric mouse
model intradermally and orally challenged with C. tyzzeri to identify a panel (~4-6) immunogens, which will then
be confirmed in the IT rat model which is susceptible to infections with C. hominis or C. parvum. Specific Aim 2
will identify immune mechanisms that drive vaccine-induced protection in the two rodent models.
This proposal, if awarded, will lead to identifying a panel of immunogens that together protect mice against
challenge with C. tyzzeri; and rat trachea against infections with C. hominis and C. parvum. We anticipate that the
proposed research will form the first step leading ultimately to the development of an effective vaccine to protect
infants and children at risk, mostly in LMIC.
Terms: <0-11 years old><2 year old><2 years of age><Address><Africa South of the Sahara><Animals><Antigen Targeting><Antigens><Apicomplexa><Asia><Award><Bacillary Dysentery><C parvum><C. parvum><Case Fatality Rates><Causality><Child><Child Youth><Children (0-21)><Clinical Evaluation><Clinical Testing><Clinical Trials><Common Rat Strains><Country><Cryptosporidiosis><Cryptosporidium><Cryptosporidium infection><Cryptosporidium parvum><Death Rate><Development><Diarrhea><ETEC><Economic Income><Economical Income><Effectiveness><Enteral><Enteric><Etiology><Eukaryota><Eukaryote><Funding><Future><Gene Expression><Genes><Genotype><Gnotobiotic><Gnotobiotics><Goals><Human><Immune><Immunes><Immunization><Immunocompetent><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunology procedure><Immunostimulation><Income><Infant><Infection><Investigation><Mammalia><Mammals><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Multi-center studies><Multicenter Studies><Murine><Mus><NIH><National Institutes of Health><Oocysts><Oral><Parasites><Parasitic infection><Pathogenicity><Phenotype><Prokaryotae><Prokaryotic Cells><Protozoa><Protozoal><RNA vaccine><RNA-based vaccine><Rat><Rats Mammals><Rattus><Reagent><Reporting><Research><Risk><Rodent><Rodent Model><Rodentia><Rodents Mammals><Rotavirus><S hominis><S. hominis><Shigella><Shigella Dysentery><Shigella Infections><Site><Sporozoites><Staphylococcus hominis><Sub-Saharan Africa><Subsaharan Africa><Surface Proteins><T gondii><T. gondii><Technology><Testing><Toxoplasma gondii><Trachea><Trachea Proper><Uganda><United States National Institutes of Health><Vaccination><Vaccine Research><Vaccines><Work><age 2 years><aged 2 years><aged two years><causation><clinical test><comparative genomics><develop a vaccine><development of a vaccine><developmental><disease causation><effective therapy><effective treatment><enterotoxigenic E coli><enterotoxigenic E. coli><enterotoxigenic E.coli><enterotoxigenic Escherichia coli><evaluate vaccines><experience><experiment><experimental research><experimental study><immune competent><immunogen><immunologic assay><immunologic assay/test><infected with Cryptosporidium><innovate><innovation><innovative><low income country><mRNA><mRNA vaccine><mRNA-based vaccine><mortality><mouse model><murine model><novel><parasite infection><pathogen><prokaryote><research clinical testing><screening><shigellosis><skills><tech development><technology development><two year old><two years of age><vaccine development><vaccine evaluation><vaccine formulation><vaccine screening><vaccine testing><vaccine-induced immunity><vaccine-induced protection><vaccinology><windpipe><youngster>