Development of a mammalian cell culture process for rapid Clinical-Scale production of novel Influenza Nanoparticle vaccines

Background Influenza virus infections cause seasonal epidemics, affecting millions of people worldwide. The World Health Organization (WHO) estimates ∼300,000-500,000 deaths per year worldwide due to seasonal influenza and more than $26.8-87.1 billion/year in healthcare costs in the United States alone [1]. Influenza, a segmented RNA virus achieves part of its ongoing virulence as a result of its strikingly high mutation rate, typically reported for Influenza A viruses of ~2 to 2.5 × 10−3mutations/site/ year. Thus, is the intense effort and energy devoted to achieving effective long-term human and veterinarian vaccines. Currently, licensed influenza vaccines are either trivalent (three influenza strains) or quadrivalent (four influenza strains), as either an injectable inactivated whole virus (IIV) or a nasal spray live attenuated vaccine (LAIV) [2]. Although efficacious, standard traditional Influenza vaccine production is laborious, only moderately high-throughput and requires physical plants housing and/or incubating millions of specific-pathogen-free eggs. Research targeting alternate strategies has been prodigious, both at the preclinical and even Phase I clinical level, and has investigated approaches such as split virion, subunit, DNA, and viral vectored vaccines. Among the recently-explored, more novel and potentially-promising strategies has been recombinant particulate vaccines generally comprising virus-like particles or nanoparticles. At the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), fusion proteins of N-terminal Influenza Hemagglutinin (HA) residues and C terminal H. pylori ferritin residues have been conceived, designed, expressed and determined to assemble into ferritin-like cage nanoparticles termed hemagglutinin ferritin nanoparticles (HAF-NP). HAF-NP used as immunogens in mouse immunization studies, elicited antibody titers more than seven-fold higher and neutralizing antibody titers with both extended breadth and greater potency than the seasonal trivalent inactivated vaccine. Neutralization of H1N1 viruses extended to viruses from 1934 to 2007, and ferrets were protected by HAF-NP vaccination against a heterologous virus [3].