Broad-spectrum, multivalent platform for pan-influenza vaccine

Abstract VIVA Viral Vaccines is developing a vaccine platform that leverages multiple innovations to meet key requirements for the rapid development and deployment of highly protective, broad-spectrum, distribution- enabled vaccines against seasonal and pandemic viral threats. Influenza is a serious public health concern, causing an estimated 1 billion infections and 650,000 deaths globally each year and accounting for 65% of the economic burden from all vaccine-preventable diseases. Current influenza vaccines suffer from several drawbacks, including the inability to protect against heterologous strains. Thus, vaccines must be reformulated and administered annually, and are only 10-60% effective. Additionally, there is growing concern for a potential antigenic shift resulting in the emergence of a new pandemic strain, and there is no way to predict these shifts or the resulting strains, as current vaccines offer no protection against pandemic influenza. VIVA Viral offers a solution through a novel vaccine and platform that targets the influenza neuraminidase (NA) protein, an enzymatic tetramer that cleaves sialic acid to release viral particles from host cells. The hemagglutinin protein (HA) is the target of current influenza vaccines and has a high potential for mutations that lead to immune escape. NA is highly conserved within serotypes however, and NA vaccines are known to provide broad heterologous immunity against diverse influenza strains. NA production is low in mammalian cells though, leading these vaccines to be produced in insect cell lines, which exhibit major glycosylation differences. VIVA has enabled efficient production of multivalent virus-like particles (VLPs) in mammalian cells that contain NA serotypes found in seasonal human influenza A strains. Ultimately, this allows for the production of VLPs in mammalian cells via presentation of viral glycoproteins in native conformation on particles that act as viral mimics, which enhances the resulting immune response. In this Phase I STTR, we will evaluate our multivalent NA-based vesicular stomatitis virus (VSV) vaccine platform in mice to evaluate the breadth of immune responses and then in ferrets against human challenge strains. The Specific Aims of this project are: 1. VIVA will produce multivalent VSVs in mammalian cells using NAs for N1, N2, influenza B, and avian influenza N1. The quality of the resulting VSVs will be evaluated using western blots, enzymatic activity assays, flow cytometry/virometry, and electron microscopy; 2. Mice will be vaccinated with the multivalent VSV vaccines and infected with homologous and heterologous influenza strains to evaluate neutralizing antibody response and protective effects; and 3. Ferrets will be vaccinated with the VSV vaccine and then challenged with homologous and heterologous human influenza strains. Study endpoints will include weight loss, survival, neutralizing antibody titers, lung viral loads, and signs of lung pathology.