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Principal Investigator: Zaid Abdo
Organization: COLORADO STATE UNIVERSITY
Fiscal Year: 2024
Award: $720,054
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
Novel recombinant Rotavirus vaccine utilizing the probiotic microorganism Lactobacillus acidophilus
Despite the worldwide licensure and availability of two rotavirus vaccines in 2006, it is estimated that rotavirus
kills approximately 215,000 children each year. Children under the age of 5 in developing countries are
significantly more likely to be affected by severe rotavirus disease as the currently available vaccines have lower
efficacy (50-60%) as compared to developed nations (>85%). The ongoing morbidity and mortality as well as the
risk posed by current live-attenuated vaccines, necessitate the development of a next generation human
rotavirus vaccine. We have developed an orally-delivered, mucosal vaccine platform that employs Lactobacillus
acidophilus. We have brought together innovative adjuvant and antigen-expression strategies in unique
constructs with demonstrated potential to induce robust mucosal and systemic immune responses. This platform
offers several important feasibility advantages as it employs a commensal designated as GRAS (generally
regarded as safe) by the FDA, is inexpensive to produce, does not require cold-chain, and is needleless. We will
utilize a novel CRISPR-Cas9 system adapted to L. acidophilus to engineer sophisticated vaccine constructs that
will be tested using a homotypic mouse rotavirus challenge. Induction of homotypic and heterotypic neutralizing
antibodies will be assessed using a novel, highly sensitive assay. We will assess vaccine strain colonization
and potential off-target effects on the microbiome. Finally, we will perform a direct comparison of our rLA
rotavirus vaccine against a human live attenuated vaccine in the gnotobiotic pig model using animals
transplanted with human infant fecal microbiome. Efficacy against human rotavirus challenge will be determined.
At the completion of these proposed studies, we aim to have a rLA construct ready to proceed toward human
clinical trials.
Terms: <0-11 years old><5 year old><5 years of age><Address><Adjuvant><Affect><Age><Agonist><Animals><Antibiotic Resistance><Antibody Response><Antigenic Determinants><Antigens><Assay><Attenuated><Attenuated Vaccines><BALB C Mouse><BALB/c><Binding Determinants><Bioassay><Biological Assay><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Capsid><Capsid Proteins><Cas nuclease technology><Cause of Death><Cell Body><Cells><Cessation of life><Child><Child Youth><Children (0-21)><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Coat Proteins><Cold Chains><Country><Data><Death><Developed Countries><Developing Countries><Developing Nations><Development><Disease><Disorder><Engineering><Epitopes><Family suidae><Flagellin><Gene Transcription><Genetic Transcription><Genome><Gnotobiotic><Gnotobiotics><Groups at risk><Hospital Admission><Hospitalization><Human><IgA><Immune Cell Activation><Immune response><Immunization><Immunize><Immunoglobulin A><Immunological response><Inbred BALB C Mice><Individual><Industrialized Countries><Industrialized Nations><Infant><Injections><Intestinal Invagination><Intussusception><Knowledge><L acidophilus><L. acidophilus><Lactobacillus acidophilus><Length><Less-Developed Countries><Less-Developed Nations><Licensing><Licensure><Live-attenuated Vaccine><M cell><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Immune Responses><Mucosal Tissue><Mucous Membrane><Murine><Mus><Oral><Organism><Pathogenicity><People at risk><Peptides><Persons at risk><Pigs><Populations at Risk><Probiotics><Proteins><RNA Expression><Recombinants><Recommendation><Resistance to antibiotics><Resistant to antibiotics><Risk><Rotavirus><Rotavirus Infections><Rotavirus Vaccines><Rotavirus disease><Safety><Subunit Vaccines><Suidae><Swine><System><Technology><Testing><Third-World Countries><Third-World Nations><Transcription><Transplantation><Under-Developed Countries><Under-Developed Nations><Vaccines><Viral><Viral Coat Proteins><Viral Outer Coat Protein><Virulence><Virus><Virus Replication><World Health Organization><access to vaccination><access to vaccines><age 5 years><ages><antibiotic drug resistance><antibiotic resistant><attenuate><attenuates><comparable efficacy><comparative efficacy><compare efficacy><deliver vaccines><developed country><developed nation><developed nations><developing country><developing nation><developmental><diarrheal disease><diarrheal illness><enteral pathogen><enteric pathogen><enteropathogen><fecal microbiome><five year old><five years of age><gastrointestinal><host response><immune activation><immune response to vaccination><immune response to vaccines><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><innovate><innovation><innovative><interest><intestinal pathogen><intestine pathogen><kids><live vaccine><live vaccines><living system><microbiome><microorganism><mortality><mouse model><mucosal vaccine><murine model><neutralizing antibody><new vaccines><next generation><next generation vaccines><novel><novel vaccines><oral vaccine><pig model><piglet model><porcine><porcine model><programs><resistance gene><resistance locus><resistant gene><stool microbiome><stool-associated microbiome><suid><swine model><transplant><vaccination access><vaccination availability><vaccination protocol><vaccine access><vaccine associated immune response><vaccine availability><vaccine candidate><vaccine delivery><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine platform><vaccine protocol><vaccine strategy><viral multiplication><viral replication><virus multiplication><youngster>