Pandemic Influenza Translational Research and novel universal countermeasure development

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Despite long-term investment, influenza continues to be a significant worldwide problem. Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Human volunteer influenza virus challenge studies are continuing at the NIH Clinical Center using both a 2009 influenza A/H1N1 virus and a 2012 influenza A/H3N2 virus under FDA-approved INDs. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies. In addition, a long-term study consisting of a 2 year follow up of patients who participated in previous challenge studies also continued to enroll with the first patients completing their 2 years follow up. These clinical studies over the past year have also included Phase II challenge studies to evaluate novel therapeutics and vaccines. We completed one study under a CRADA with Crucell/Johnson and Johnson by evaluating a novel monoclonal therapeutic antibody. We also completed another Phase II study under a CRADA with SEEK to evaluate a novel universal influenza vaccine. In addition, we were IRB approved to begin a challenge with a novel low pathogenesis avian influenza virus of subtype H10N7 under an IND with the FDA, the first time this has ever been achieved. This past year has led to significant breakthroughs in terms of understanding influenza immunity and issues to consider in development of universal vaccines. We have taken further steps to develop novel vaccines in collaboration with the VPES based off our work the previous year describing the importance of anti-neuraminidase antibodies over anti-HA and anti-HA stalk antibodies, the benefit of T-cell immunity, and the potential of mucosal immunity. We now have two vaccine candidates that have been manufactured, one a whole virus inactivated universal vaccine, and the other an NA based peptide vaccine. We are currently in the process of final preclinical studies and submission to FDA to begin Phase I trials. We also completed a study of mucosal immunity after vaccination and challenge that we expect will provide highly significant results later this year once the analysis is complete. In addition to these clinical studies we continued our collaborations with Rockefeller University, Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections.