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

Background: Influenza viruses cause a respiratory disease resulting in over 200,000 hospitalizations and ~36,000 deaths per year in the U.S. Older adults, over the age of 65, exhibit increased susceptibility to influenza viruses, accounting for 90% of annual influenza-related fatalities. Vaccination remains the primary method of influenza prevention, but alterations in immune function with age (immunosenescence) result in impaired vaccine responses, with estimates of efficacy as low as 9% in healthy older adults and even lower in older adults with underlying chronic diseases who are at risk for disability, hospitalization, and death. The influenza vaccination program is an essential component of the Department of Veterans Affairs (VA) health promotion and disease prevention programs. The Veterans Health Administration (VHA) has made influenza vaccination a priority. However, current vaccines have vaccine effectiveness (VE) rates as low as 9% in healthy older adults and even lower in older adults with underlying chronic diseases who are at risk for disability, hospitalization, and death. For H3N2 influenza strains, the VE in the >65 year-old age group is even lower. Multiple DOD studies have indicated that the current vaccines provide only low to moderate protection against influenza. FluGen has developed and started clinical testing of a new vaccine designed to meet the need for a universal influenza vaccine. The M2 deficient Single Replication (M2SR) vaccine carries a mutation that results in no M2 protein production by the virus. As a result, no viral progeny are produced by M2SR after an initial (single-round) infection with no subsequent cell-to-cell spread or virus shedding. Testing in animal models has shown M2SR can protect against drifted and shifted virus challenge, the properties sought in a universal influenza vaccine. The clinical studies proposed in this application will evaluate the protection offered by the M2SR vaccine versus a licensed vaccine in a human challenge model for influenza infection. Relevance to Topic Area: FY20 PRMRP Respiratory Health. Objectives: We propose to conduct an integrated phase 1b protocol (randomized double-blind, placebo-controlled) study to evaluate the ability of H3N2 M2SR to induce broad immunity in older adults over 65 years old. The ability will be tested by immunizing with seasonal H3N2 M2SR either alone or in conjunction with the standard of care vaccine in varying dosing regimens. Specific Aims: (1) Study start-up activities including development of database and subject recruitment plan. (2) Conduct of clinical study: vaccine dosing and clinical specimen collection. (3) Evaluate immune responses from subjects vaccinated with M2SR and inactivated standard of care vaccine. Study Design: Volunteers (>65 years old) will be screened for suitability and only subjects that pass inclusion/exclusion criteria will be enrolled. Subjects (50 per cohort, 6 cohorts including M2SR and High Dose Fluzone vaccine in various dosing regimens) will be dosed on day 1 followed by a day 29 second dose. Serum, nasal swabs and peripheral blood mononuclear cells will be collected and evaluated for immune responses. Clinical Impact: The ultimate goal of this program is to commercialize the M2SR flu vaccine. Successful completion of this project will demonstrate that M2SR elicits broad protective immune responses with a benchmark comparator vaccine allowing for the M2SR platform to advance in future clinical development towards licensure. A broadly reactive and effective vaccine such as M2SR in the general population as well as the highly vulnerable elderly population will have significant impact in the management of influenza virus-related diseases including reduced hospitalizations and death due to influenza complications. Military Relevance: Influenza is a contagious respiratory illness that has the potential to impact DOD readiness here and abroad. The military population may be deployed to geographic areas where information on circulating influenza strains may not be known. Vaccination with an effective vaccine such as M2SR would provide a protective advantage to military personnel by generating cross-reactive protective immune responses against circulating and previously unencountered pandemic strains. In addition, influenza complications are a leading cause of morbidity and mortality in older populations such as retired Veterans. Over 70% of those >65 years old receive influenza vaccines each year, yet efficacy rates in the elderly (20%-30%) are well below those for the overall population. A more effective vaccine with broader coverage could provide substantial benefits for the Veterans Administration as well. Recognizing the burden of influenza disease and associated complications, the VHA has made influenza vaccination a priority. Less