An immunotherapeutic IgY formulation against norovirus diarrhea

Project Summary/Abstract for STTR Phase I Application: An immunotherapeutic IgY formulation against norovirus diarrhea Human norovirus (HuNoV) infects millions of people globally each year, causing diarrheal illness resulting in more than 200,000 deaths annually, particularly in the very young, the very old, and the immunocompromised. There is currently neither an effective vaccine nor effective treatment for HuNoV infections. Compounding the problem is the fact that HuNoV strains mutate rapidly and unpredictably, which can reduce the impact of any targeted therapeutic when faced with novel emerging strains. This proposal’s long-term objective is to evaluate a novel approach to the prevention or treatment of HuNoV diarrhea: using anti-HuNoV antibodies, purified from eggs of hens immunized with nanoparticles representing multiple strains of HuNoV, to provide “passive immunity” to the intestinal tract. These antibodies are called “IgY” to indicate that they are immunoglobulins from egg yolks. The applicant has already demonstrated that anti-HuNoV IgY can stop HuNoV viruses from replicating in a human intestinal cell model, and this project is the natural extension of that work. The project’s Specific Aim 1 is to produce and thoroughly characterize IgY produced against three different strains of the predominant HuNoV viral genotype, GII.4. By using so-called “P24” nanoparticles representing all three strains as the immunizing antigens, the IgY produced will target all three variants, offering a proof that broad-spectrum protection can be achieved using inexpensive and readily-produced antigens. Once the antibodies have been characterized and their ability to bind to and inhibit all three viral strains has been established, the project’s Specific Aim 2 will be to evaluate the protective effect of the anti-HuNoV antibodies in a gnotobiotic pig model that has been shown to recapitulate human HuNoV diarrhea. Pigs will be pre-treated for one day with the active antibodies or control (unimmunized) antibodies, and then will be infected with a large dose of one HuNoV GII.4 variant. The animals’ signs and symptoms of diarrhea will be monitored for an additional seven days, to help us understand both how well the treatment prevented diarrhea, and in those animals that develop diarrhea, how well it minimizes the disease severity or duration. If the project successfully demonstrates significant protection against HuNoV in this model, human safety, tolerability, and effectiveness studies will be performed, ultimately resulting in regulatory approval to use anti-HuNoV IgY to prevent and/or treat HuNoV diarrhea. Such a readily available treatment is expected to significantly reduce human suffering and provide substantial societal benefit, especially among the most vulnerable populations in the US and around the world.