Influenza virus remains a heavy economic burden and poses pandemic threats to public health worldwide, causing 250,000-300,000 deaths annually and 3-5 million cases of severe illness. While seasonal egg-based influenza vaccines are effective, they require annual update to keep pace with viral mutations (antigenic drift). This effort is still insufficient to address significant changes in the influenza genes (antigenic shift), resulting in pandemic outbreak. These facts strongly suggest a pressing need to develop broadly protective influenza vaccines that can be produced in large quantities rapidly. This challenge can be broken down into two perspectives: (1) a low-cost, high-capacity influenza vaccine manufacturing process in Baker’s yeast, Saccharomyces cerevisiae (S.c); and (2) immunology-informed molecular design of influenza vaccines that provide protection against multiple influenza strains (i.e., heterosubtypic protection). This project focuses on developing a novel Baker’s yeast-based system for influenza virus-like particle (VLP) manufacturing and engineering. Compared to other vaccine types such as live attenuated, inactivated or subunit vaccine, VLPs strike a perfect balance of safety (protein-based without viral genetic material), strong immunogenicity (viral mimicry for antigen presentation), and molecular tunability. In addition, a major drawback of the current influenza vaccine is its molecular design, which consists of influenza surface proteins that are the main targets of antigenic drift and shift. This means that these proteins can easily mutate to avoid pre-existing immune response, making them inadequate in the production of a universal influenza vaccine. This project proposes a different vaccine strategy that targets a more conserved surface protein that is less susceptible to mutation. M2 protein has not significantly changed since 1918 and has been shown to elicit protective T cell responses in mice, thus is a promising candidate for universal influenza vaccine. This work outlines the optimization of this process and the study of immunization elicited by M2 VLPs. For the first time, full-length M2 virus-like particles have been produced using baker’s yeast and are expected to dramatically change the future of influenza vaccination.

Affordable universal influenza vaccine: M2-based virus-like particles (VLPs)

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