Introduction: We propose to develop a prototype subunit mucosal vaccine for cryptosporidiosis, building on our discovery that mucosal IgA directed against Cp23 and Cp17 is associated with protection of children from re-infection Hypothesis: A mucosal vaccine will provide broadly neutralizing protection via mucosal IgA and IFNg. Premise: The presence of naturally acquired immunity against cryptosporidiosis indicates that a vaccine is feasible despite the presence of parasite genetic diversity. Significance: Currently no vaccine exists and therapy for infants is suboptimal. Cryptosporidiosis is a top ten cause of diarrhea in the 1st year of life in low and middle-income countries. In North America it is the leading etiology of water-borne diarrhea, a biodefense category B agent, and cause of chronic diarrhea in AIDS. Investigator: Dr. William Petri at the University of Virginia pioneered the identification of cryptosporidium as a major cause of infant diarrhea, discovered the importance in children of mucosal anti-cryptosporidium IgA for acquired immunity and has led the application of mucosal-targeted adjuvants for subunit vaccine design. The stage is thus set for rapid advancement of a cryptosporidiosis vaccine. Innovation: Innovation includes the discovery that fecal IgA against the cryptosporidium Cp23 and Cp17 antigens are associated with protection from re-infection, pioneering development of mucosal adjuvants for enteric infections, and demonstrating the genetic conservation of Cp23, CpGAPM2 and to a lesser extent Cp17 from genome resequencing. Approach:
Specific Aim 1. Develop a prototype mucosal vaccine. Antigens (Cp23, Cp17 and CpGAPM2) will be expressed in E. coli, purified and mixed with our lead pharmaceutically acceptable mucosal adjuvant.
Specific Aim 2. Optimize immunogenicity and test protection of the mucosal vaccine. Mucosal IgA and systemic IFNg will be optimized and protection tested in the mouse model of cryptosporidiosis. Environment: The Petri lab is part of a robust program on global health and microbial immunology/pathogenesis at the University of Virginia. Successful Completion of this high-risk and high-payoff exploratory project will provide a foundation for development of a mucosal vaccine for cryptosporidiosis.
Cryptosporidiosis is a top ten cause of diarrhea in the 1st year of life in low and middle-income countries and in North America is the leading etiology of water-borne diarrhea, a biodefense category B agent, and cause of chronic diarrhea in AIDS. We propose to develop a subunit vaccine to prevent this infection.
