Scalable Manufacturing and Toxicity Testing of Intranasal M2SR Influenza Vaccine

Seasonal influenza virus infections are one of the most serious respiratory infections in man, causing significant annual hospitalizations, loss of life, and productivity in the U.S. and the rest of the world. Licensed influenza vaccines are only moderately effective (50%-60%) and need to be matched annually to the strains currently circulating (drifted viruses). They are much less effective during years in which the vaccines are not matched to the circulating viruses. In addition, in the last century there have been four antigenic shifts among circulating viruses (changing one hemagglutinin [HA] subtype to another), each resulting in a global influenza pandemic. Current vaccines offer no protection against an emerging pandemic virus, and it can take up to 6 months before a matched pandemic vaccine can be produced. This creates an incumbent need for universal influenza vaccines with a high level of protection (>90%) against circulating strains that also can protect against emerging pandemic virus. To overcome the limitations of currently available influenza vaccines, FluGen is developing a Quadrivalent M2SR flu vaccine that provides broad-spectrum immunity including neutralizing antibody, mucosal, and cellular immune responses. The quadrivalent formulation contains two flu A strains (H1N1 and H3N2) and two flu B strains (Yamagata and Victoria lineages). The influenza A viruses are produced in M2VeroA helper cells, and the influenza B viruses are produced in BM2Vero helper cells. M2SR is administered intranasally and confers protection against influenza by multiple immune mechanisms. In humans and in animal models, serum antibodies, mucosal antibodies, and influenza-specific T cells have been elicited following M2SR immunization. We have successfully demonstrated proof-of-concept drift protection and immunogenicity with monovalent M2SR in humans and drift protection with the Quadrivalent M2SR in animal models. Next steps are to advance the Quadrivalent M2SR product, manufactured in a scalable upstream platform to support an Investigational New Drug (IND) submission to the U.S. Food and Drug Administration (FDA). These proposed studies address Fiscal Year 2022 Peer Reviewed Medical Research Program Portfolio: Infectious Diseases, Respiratory Health; Topic Area: Viral Diseases and Respiratory Health; and Strategic Goal: Prevention. The overall objective of this project is to further develop the M2SR universal influenza vaccine and its production platform. Achievement of these Good Manufacturing Practice (GMP) manufacturing objectives will enable advancing into clinical trials with a first-in-human study for the Quadrivalent M2SR. Building upon the success of the transfer of the M2SR platform to microcarriers and the successful development of an upstream and downstream purification process at the 10L scale, in this proposal we plan for the GMP manufacturing of each of the monovalent influenza A M2SR vaccine virus Bulk Drug Substance (BDS) for H1N1 and H3N2 to support clinical testing of the Quadrivalent M2SR. There are two aims associated with these objectives: 1) Manufacture of engineering batches at 50L scale of Quadrivalent M2SR vaccine 2) IND-enabling Good Laboratory Practice (GLP) toxicology study in ferrets of Quadrivalent M2SR vaccine This project will demonstrate the capability to manufacture M2SR vaccine at the 50L scale for all four monovalent subtypes of the vaccine: H3N2, H1N1, B/Yamagata, and B/Victoria. The material will then be used in a GLP toxicology study in ferrets enabling submission of an IND for the Quadrivalent M2SR. The project will manufacture clinical material for clinical testing of the Quadrivalent M2SR in the short term and support future commercial development towards M2SR licensure. The development of a broadly reactive influenza vaccine like M2SR will reduce influenza morbidity and mortality. This will have a significant public health and military impact. Influenza infections among military personnel are known to impact Department of Defense readiness here and abroad. Vaccination with a universal M2SR vaccine would help maintain military readiness by protecting military personnel from both seasonal and pandemic strains. Finally, influenza complications are a leading cause of morbidity and mortality in older adults, like retired military Veterans. A more effective vaccine with broader coverage could provide substantial benefits for the retired military population served by the Veteran's Administration as well. Less