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Working Paper

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Influenza is an annual health hazard with only about one-third of people in the United States receiving vaccinations for this pathogen. Epidemics are estimated to affect between 5% and 15% of the global population annually. Annually, the WHO estimates epidemics to result in between 3 and 5 million severe cases which lead to between 250,000 and 500,000 deaths. In industrialized countries, most of these deaths occur among victims who are chronically ill or are 65 years of age or older. In developing countries, particularly in tropic areas where transmission occurs year round, there is a higher rate of death to infection. For example in 2002, Madagascar experienced 800 deaths in 27,000 recorded cases of influenza over a 3 month period (WHO).

Recently, international awareness, spearheaded by the World Health Organization (WHO), has been paid to influenza since the pandemic outbreak and subsequent vaccine shortage during the H1N1 outbreak. Since then the WHO has published a set of guidelines to encourage production of safer and increasingly potent influenza vaccines for a greater number of recipients each year. WHO is attempting to increase public and private sector awareness of the importance of influenza vaccination to prevent any subsequent pandemics.

Current vaccines are produced in live, embryonated chicken eggs resulting in potential allergic reactions from animal products in the vaccines. Furthermore, this process is time-consuming and labor intensive, and the live, attenuated virus is considered to be a potential health risk for populations with suppressed immune function such as children, the elderly, and those who are sick or immunocompromised. Egg shortages can cause massive vaccine shortages, especially since only two companies currently produce most of the United States' influenza vaccines. We propose that virus- like particles offer a more robust and safer alternative to current vaccine manufacturing. Currently, FluBlok is a product that utilizes recombinant influenza antigens to produce a vaccine. We plan to take this strategy another step to creating replication-deficient, native conformation viruses to induce an immune response. These particles will retain all structural similarity to native virus and have been shown to produce more robust responses with smaller doses. Furthermore, these particles will carry no risk of influenza infection upon administration. Virus-like particles will become the next generation of vaccines, such as those for human papilloma virus currently manufactured, and should rectify the problems associated with egg-based production of influenza vaccines.

The proposed process is a fed-batch operation that will create about 100 million influenza vaccines during each influenza infection season from November to February, using insect cell lines and the baculovirus expression vector system (BEVS) to induce lytic formation of virus-like particles. This process will be performed in a single-use, disposable fermentation train with single-use components integrated in the purification process to take advantage of the timesaving techniques and disposable equipment. The production of influenza vaccines is time-sensitive with a limited duration of vaccine production from WHO's publishing strains to product shipment. Single-use equipment will be used to allow maximization of production time and minimization of down-time in this process.



Date Posted: 25 July 2014