Engineering Influenza Virus-Like Particles as Universal Flu Vaccines
Influenza virus infection poses a significant global disease burden, causing an estimated three to five million cases of severe illness and 290,000-650,000 deaths each year worldwide. Vaccination is currently the most efficient strategy against infection, however, over the last 15 years in the United States, the reported efficacy of seasonal influenza vaccines has been largely underwhelming, less than 50% in all but four years and even as low as 19% during 2014-2015 season. One of the primary causes of this inefficacy is the traditional egg-based platform with a 6-9 month production timeline. During that time virus mutations (antigen drift) lead to vaccine inefficiency. Moreover, the need for hundreds of millions of chicken eggs make the manufacturing method unequipped to handle pandemics (antigenic shift), as was the case with the 2009-2010 H1N1 “swine flu” outbreak in North America. Virus-like particle (VLP) is a three dimensional structure of virus but lack viral genetic material and ability to replicate. VLP is a safe, highly immunogenic alternative to traditional influenza vaccines and can be produced in a much shorter timeframe (< 3 months) and larger scale. Efficiently incorporating the highly conserved influenza viral proteins into virus-like particles (VLPs) has the potential to enable future “universal” vaccine development.
In this study, we will develop a recombinant expression system capable of synthesizing influenza VLPs with tunable densities of influenza antigens including HA and matrix protein M2, both of which contain highly conserved sequences across different influenza strains. We will evaluate the vaccine efficacy of these engineered VLPs against influenza heterosubtypic strains in mouse, and compare it to the existing flu vaccines. Further, we will employ the CyTOF technology that allows us to simultaneously detect 40 biomarkers on single immune cells at a rate of ~500 cells per second. This high-dimensional analysis of the immune system will enable a comprehensive interrogation of the immune responses induced by the engineered VLPs and flu vaccines with the goal to identify cellular and/or molecular components that are important for eliciting a protective immunity against influenza. Towards this goal, we will pool expertise from various disciplines including protein/cellular engineering, immunology, and bioinformatics.
Enhancing the Yield and Quality of Influenza Virus-like Particles (VLPs) Produced in Insect Cells by Inhibiting Cytopathic Effects of Matrix Protein M2
Published in ACS Synthetic Biology