Posted October 3, 2022

Pamuk Bilsel, Ph.D., Chief Scientific Officer, FluGen, Inc.

Influenza (flu) is one of the world's greatest public health challenges. Approximately 8% of the American population will experience symptoms from flu-related respiratory illness annually, and children (0-17), older adults (65 or older), and people who are immunocompromised and/or have certain chronic medical conditions are more susceptible to flu infections.¹ Flu-related respiratory illness symptoms range from mild to severe and include fever, runny nose, cough, fatigue, and in the most severe cases, sometimes death. The flu is spread via droplets expelled from an infected person while coughing, sneezing, or talking. These droplets can then enter the nose or mouth of nearby people. The most effective prevention for flu-related respiratory illness is vaccination. Despite the Department of Defense's vaccination policy requiring all medically able uniformed military personnel to receive an annual flu vaccine, the flu virus remains one of the most common infectious diseases among active-duty Service Members and their dependents, demonstrably impacting military logistics and combat readiness.^2,3

Current flu vaccines approved by the U.S. Food and Drug Administration (FDA) must be created annually. Each year, the FDA's Vaccines and Related Biological Products Advisory Committee chooses specific flu strains to be included in the vaccine, based on data from the previous year.⁴ However, annual vaccine effectiveness studies, particularly those evaluating active-duty Service Members, indicate that current flu vaccines provide only low to moderate protection.^5,6 Two major causes limit annual flu vaccine effectiveness: strain subtypes not included in the annual vaccine and viral drift, small changes to a virus� genes that reduce protection from the vaccine. A truly universal flu vaccine would remain effective against subtypes and variants that emerge after viral drift.

Aspiring to meet the need for a universal flu vaccine, Dr. Pamuk Bilsel and her team at FluGen developed a novel vaccine, called M2SR, designed for intranasal delivery that contains a proprietary, live flu strain of their own design. Earlier preclinical studies of this vaccine strategy concluded that M2SR is capable of inducing a systemic immune response similar to the annual flu vaccine, but it does not produce infectious virus capable of causing or spreading illness. Further, the intranasal delivery method delivers the vaccine directly to the nasal mucosa, the primary source of infection. Intranasal vaccine delivery methods are easy to administer and noninvasive while providing protection both systemically and locally, whereas traditional intramuscular vaccines only provide systemic immunity.⁷ With this data in hand, the Peer Reviewed Medical Research Program (PRMRP) awarded FluGen a Clinical Trial Award (CTA) in Fiscal Year 2016 (FY16), addressing the FY16 Topic Area Influenza, to enable Dr. Bilsel and her team to conduct two unique clinical trials to test the M2SR vaccine's safety and efficacy in humans.

With the FY16 CTA, Dr. Bilsel and her team designed and executed two clinical trials: a human infection study, known as a challenge study, with a virus that has experienced viral drift and a dose-escalation study. In a 2021 Journal of Infectious Diseases article, Dr. Bilsel reported on the drifted virus challenge study. She led a randomized, double-blind clinical trial on 96 healthy adults (aged 18-55), and these subjects were either vaccinated with M2SR, tailored to a flu strain from 2007, or given a placebo. After four weeks, subjects were challenged with the drifted virus, a strain from 2015. The intranasal M2SR vaccine provided protection against infection and respiratory illness in the vaccinated population when compared to the placebo group. This result demonstrates the unique potential of the M2SR vaccine to offer protection against a variety of flu strains; therefore, it is more adaptable to the flu's annual viral drift and other flu viruses. The dose-escalation study determined that all concentrations of M2SR tested were safe and well tolerated by the 250 participants. The highest concentration of M2SR produced a more robust systemic immune response than the dose used in previous preclinical and clinical studies, including the challenge study described above. The results from the dose-escalation study will be available in an anticipated peer-reviewed article.

FluGen's current protocols for creating the M2SR viral vaccine components are small-scale and labor-intensive, which poses a significant challenge to producing enough viral product for phase 2 and 3 clinical trials and eventual commercialization. FluGen was awarded a PRMRP FY18 Technology/Therapeutic Development Award, addressing the FY18 Topic Area Vaccine Development for Infectious Disease, to advance their novel vaccine development. With funding from this award, Dr. Bilsel and her team plan to develop and streamline Good Manufacturing Practice (GMP) platforms to increase the amount of viral product produced for four unique M2SR variants and to create a four-strain M2SR vaccine for FDA approval and commercialization. Four-strain vaccines are the current standard for annual flu vaccines on the market. With the single-strain M2SR vaccine's potency, a four-strain M2SR vaccine will provide more immunological triggers and create greater efficacy against a broader range of flu virus subtypes compared to currently available flu vaccines, which would be highly competitive in the flu vaccine market. These optimized GMP processes will result in more cost-effective development strategies for the M2SR vaccine for future clinical trials, which will help expedite FDA approval and commercialization.

Most recently, the PRMRP awarded FluGen a second CTA in FY20, addressing the FY20 Topic Area Respiratory Health, for the purpose of performing a clinical trial of their intranasal single-strain M2SR vaccine alone and in combination with an injectable inactivated vaccine in healthy, older adults (65 or older). This study, which combines intranasal and intramuscular delivery of flu vaccines, is the first of its kind. Participant dosing began in June 2022. This study also targets a gap in care for people aged 65 or older, who are more susceptible to severe respiratory illness stemming from flu infection. Further, evaluating both intranasal and intramuscular vaccinations could determine the validity of this approach for treating or preventing viral diseases beyond seasonal influenza.

The findings produced by Dr. Bilsel and her team provide strong evidence that their novel intranasal M2SR flu vaccine will provide greater protection from seasonal flu viruses and their viral drift. The Peer Reviewed Medical Research Program team believes this research may bring a closer solution for a more effective, universal flu vaccine. Such a vaccine has the potential to provide enhanced protection against the seasonal flu for Service Members, Veterans, their dependents, and individuals outside of the military community.

Publications:
Eiden J, Volckaert B, Rudenko O, et al. 2021. M2-deficient single-replication influenza vaccine-induced immune responses associated with protection against human challenge with highly drifted H3N2 influenza strain. Journal of Infectious Diseases jiab374. doi:10.1093/infdis/jiab374.

References:
¹Centers for Disease Control and Prevention. Key Facts About Influenza (Flu).

²Sanchez J, Cooper M, Myers C, et al. 2015. Respiratory infection in the US military: Recent experience and control. Clinical Microbiology Review. 3:743�800.

³Burns VM, Castillo FM, Coldren RL, et al. 2022. Perceptions of seasonal influenza vaccine among U.S. Army civilians and dependents in the Kaiserslautern military community: A mixed method survey. Military Medicine 187(3-4):e394�e403.

⁴U.S. Food & Drug Administration. Influenza Vaccine for the 2022-2023 Season.

⁵Centers for Disease Control and Prevention. CDC Seasonal Flu Vaccine Effectiveness Studies.

⁶Eick-Cost AA, Tastad KJ, Guerrero AC, et al. 2012. Effectiveness of seasonal influenza vaccines against influenza-associated illnesses among US military personnel in 2010-11: A case-control approach. PLoS One 7(7):e41435.

⁷Birkhoff M, Leitz M, and Marx D. 2009. Advantages of intranasal vaccination and considerations on device selection. Indian Journal of Pharmaceutical Sciences 71(6):729�731.

Links:
Public and Technical Abstracts: A Randomized, Placebo-Controlled Phase 2a Study in Healthy Volunteers to Evaluate the Cross-Protective Efficacy of M2SR in an Influenza Challenge Model

Public and Technical Abstracts: Development of a Novel Cell-Based, Live Influenza Vaccine with Universal Attributes

Public and Technical Abstracts: Safety and Immunogenicity of H3N2 M2SR Monovalent Influenza Vaccine Administered with Inactivated Flu Vaccine in Older Subjects

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