Heterologous ABS from Llama and Chicken Egg Yolk to Prevent Rotavirus Diarrhea

We will explore oral administration of different passive heterologous antibodies (Abs), chicken egg yolk IgY and recombinant VHH fragments derived from llama heavy chain Abs as an alternative or complementary approach to vaccination for rotavirus (RV) diarrhea prevention and treatment. <P> The passive treatments will be evaluated in two neonatal animal models of RV disease, gnotobiotic (Gn) pigs and calves. The research will be done simultaneously, in the US at Dr. Saif's Lab, The Ohio State University (Gn pig) and in Argentina, at INTA in collaboration with Dr. Parreqo (neonatal calves), as an extension of NIAID, NIH Grant No. R01 AI033561-11 (6/25/03-12/31/08). The ongoing and long-term collaboration between Dr. Saif and Drs. Parreqo and Fernandez (INTA) has facilitated transfer of state-of-the-art technology for diagnosis (assays, reagents) and treatments (vaccines) for RV infections of cattle, the major agricultural commodity in Argentina. <P> Through this proposal we continue this collaboration related to improving both ruminant and human health by exploring new immunologic concepts (impact of passive heterologous Ab on active Ab responses to RV) and new treatments (passive IgY,VHH) in two neonatal animals susceptible to RV diarrhea: conventional calves with a normal gut microbial flora and Gn pigs lacking the microbial flora. The foreign collaborator will produce the Abs (llama VHH, chicken egg IgY, bovine IgG) and conduct the calf experiments. Students from INTA will be trained in Dr. Saif's lab to learn newer immunologic procedures (flow cytometry, etc) and work with specialized animal disease models (Gn pigs) as well as to enhance analytical skills related to mucosal immunity. Thus the INTA team will receive reagents and training related to the study of mucosal immune responses in Gn pigs that will be applied to the calf experiments. <P> Our collaboration will also further INTA's reputation as a Center of Excellence for basic and translational studies in the proposed areas. Development of recombinant Abs from llamas, will enable a sustainable application of this native animal for the development of VHH Ab applied to treat this and other diseases. This will benefit llama livestock production, as well as regional micro-economies for Argentina or other poorer developing countries of South America (Peru, Bolivia, etc) engaged in Camelid production. These heterologous passive Ab treatments would have profound impacts as supplements for premature infants or in severe RV outbreak settings (hospitals, day care centers, rural areas of developing countries). They represent complementary treatments to reduce RV diarrhea severity and deaths under conditions where RV vaccine use is not possible, too expensive, too late; or to treat cases of vaccine failure for both infants and ruminants.<P> PUBLIC HEALTH RELEVANCE: Rotavirus (RV) is the leading cause of diarrhea in young animals and human infants, worldwide. Currently, RV prevention in animals is based on inactivated RV maternal vaccines to enhance passive immunity, whereas live-attenuated RV vaccines have been recently approved for human infants. Vaccine efficacy and safety remain unclear especially in developing countries. <P> We will explore oral administration of different passive heterologous antibodies, llama heavy chain antibody fragments (VHH) and chicken egg yolk IgY as alternative/complementary approaches to control RV diarrhea for both animals and humans, in two animal models of rotavirus infection and disease gnotobiotic (Gn) pigs and neonatal calves. If our heterologous passive antibody (Ab) strategies are effective, these treatments would have the most profound impacts as supplements for premature infants or in severe RV outbreak settings (hospitals, day care centers, rural areas of developing countries), by providing an alternative rapid treatment to reduce RV diarrhea severity and deaths under conditions where RV vaccine use is not possible, too costly, too late; or to treat cases of vaccine failure.