Pandemic Influenza Translational Research and novel universal countermeasure development

尽管进行了长期投资，但流感仍然是一个重大的世界性问题。甲型流感病毒（IAV）是一种重要的人类病原体，引起每年的流行病和偶尔的大流行。过去的大流行病造成了很高的发病率和死亡率。1918年的流感大流行被认为导致美国至少67.5万人死亡，全球4000万人死亡。1957年和1968年的流行病虽然不那么严重，但也对公共卫生产生了重大影响。一种新型猪源性甲型流感病毒在2009年大流行，造成41年来的第一次大流行。此外，每年的流行性流感病例也非常严重，导致美国每年多达49,000人死亡。

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. We continue our human challenge work both developing novel challenge models and continuing to utilize our previously developed models fo H1N1 and H3N2. The SARS-CoV-2 pandemic has limited our work with these models during the past 2 years but we hope to begin to move them forward again as we move into the post-pandemic period. We have completed analysis of a challenge study performed to evaluate mucosal immunity, which we hope to publish later this year. Although IRB approved to begin a challenge with a novel low pathogenesis avian influenza virus of subtype H10N7 under an IND with the FDA, we were unable to begin due to the pandemic and hope to begin in the near future. In addition we have GMP manufactured other useful challenge viruses including a pre-pandemic H1N1 and an influenza-B viruses. This past year has led to significant breakthroughs in terms of the 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 whole virus inactivated universal vaccine candidates that have been manufactured, and we are working on developing another candidate made up of NA peptides. We also initiated the first phase I trial of the first of the two whole virus candidates, BPL-1357 a truly universal vaccine candidate which has demonstrated broad protection in pre-clinical studies. This study includes both a mucosal and intramuscular arm, the first broadly protective vaccine study to do so for influenza. We continue with our serological studies including our long term study of individuals post participation in a challenge study. We also have completed a clinical study evaluating mucosal and systemic immunity in children after influenza vaccination that we expect to publish in the coming year as well as are continuing to enroll a longitudinal study of adults post COVID and Influenza vaccination to evaluate their mucosal and systemic responses, as well as the interactions between the two. In addition to these clinical studies we continued our collaborations with Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections.