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The Flu Has a Formidable Foe in M2SR

The disease. Influenza (flu) is a contagious respiratory disease caused by influenza viruses. The influenza virus is transmitted easily from person to person via droplets and small particles produced when infected people cough or sneeze. Influenza tends to spread rapidly in seasonal epidemics. Infection usually lasts for about a week and is characterized by a sudden onset of high fever, aching muscles, headache and severe malaise, non-productive cough, sore throat and rhinitis. Some people are at high risk for serious flu complications, including the elderly, young children, pregnant women, and people with certain health conditions such as asthma, chronic lung disease, diabetes, heart disease, blood, kidney or lung disorders, or weakened immune systems. Worldwide, it is estimated that 3 to 5 million cases of severe influenza and 290,000 to 650,000 influenza-related deaths occur every year.

The vaccine. The most commonly used influenza vaccines are the trivalent or quadrivalent inactivated vaccines (TIV or QIV) which contain various preparations of antigens from three or four influenza viruses that are changed annually to try to match the predominant circulating strains. Despite the annual update, current vaccine effectiveness has varied from 10 to 60% in the U.S. over the last 10 years. The low effectiveness is due to two factors. First, the TIV and QIV vaccines induce immune responses limited to the surface hemagglutinin (HA) epitopes that vary significantly from virus to virus. The near constant evolution of the influenza virus can create years in which there is an outright mismatch between a strain picked for the vaccine and a predominant circulating virus. Second, efficacy is even lower for the elderly, the population most at risk of severe disease. A vaccine that would be more effective in all ages and could protect against drifted influenza stains would be a disruptive innovation in the current influenza vaccine market.

To address the need for influenza vaccines that induce broader and more protective immune responses, FluGen is developing a novel influenza vaccine technology first invented at the University of Wisconsin-Madison in the laboratories of Dr. Yoshihiro Kawaoka and Dr. Gabriele Neumann and exclusively licensed to FluGen. The M2SR vaccine contains vaccine viruses with a deletion in a portion of the M2 gene. M2SR viruses can infect cells, express the entire spectrum of influenza RNA and proteins, yet cannot produce any infectious virus particles. Thus, the M2SR vaccines do not shed infectious virus and do not cause any pathological signs of infection. The M2SR viruses can be engineered to express the HA and neuraminidase antigens (NA) of any influenza virus and can be manufactured in cell lines that stably express the M2 protein.

The Promise of Prevention

The novelty behind the M2SR vaccine is that the M2-deleted viruses activate the body’s immune defenses just like a wild type influenza infection without production of infectious viruses. M2SR induces potent innate immune responses (the body’s defense triggered when cells produce influenza RNA), humoral or antibody immune responses (inducing the production of antibodies that recognized influenza virus surface proteins) and cellular immune responses (triggering T cells that can destroy influenza infected cells). This is in contrast to inactivated influenza vaccines that only produce limited antibody responses to the surface of the virus or other live flu vaccines that are attenuated and require multi-cycle replication or cell-to-cell spreading for potency.

We believe the diverse immune response induced by M2SR will translate to improved efficacy, against routine seasonal influenza viruses, against “drifted” influenza viruses that cause international epidemics, and in older adults as well. In multiple preclinical models, the M2SR viruses have been found to be safe and induce robust immune responses that protect against “drifted” strains, mismatched influenza strains and protect against disease in older animals.

The continuous global spread of highly pathogenic avian influenza H5N1 and H7N9 viruses in avian species and their transmission to humans poses a significant threat to public health. Evolution of either these viruses to be able to spread from human to human could spawn a global pandemic. Development of a vaccine that can induce cross-protective immunity prior to emergence of a pandemic virus could reduce mortality and spread of the influenza virus during a pandemic. M2SR may be such a vaccine. In multiple preclinical studies of M2SR, a single dose of a H1N1 M2SR vaccine induced cross-protection against a highly pathogenic H5N1 avian influenza challenge virus in ferrets. Thus, M2SR has the potential to provide better efficacy against seasonal influenza and the potential to provide protection against future pandemic strains.

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