Influenza Viral Pathogenesis

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

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 influenza epidemics are also very significant, resulting in up to 80,000 deaths in the US annually. Highly pathogenic avian H5N1 viruses continue to circulate panzootically in wild birds and poultry in many countries and continue to cause human and other mammalian spillover infections. A variety of experimental pathogenesis studies to model host adaptation, map viral virulence factors and host factors in disease progression, evaluate novel therapeutics and vaccines were performed. Influenza virus infections are a global public health problem, with a significant impact of morbidity and mortality from both annual epidemics and pandemics. The current strategy for preventing annual influenza is to develop a new vaccine each year against specific circulating virus strains. Because these vaccines are unlikely to protect against an antigenically divergent strain or a new pandemic virus with a novel hemagglutinin (HA) subtype, there is a critical need for vaccines that protect against all influenza A viruses, a so-called "universal" vaccine. Recent work has suggested that such broadly protective, or "universal", influenza virus vaccines might be achievable using vaccine strategies that target conserved B- and T-cell epitopes. A BPL-inactivated, whole virus cocktail reported on in the last annual report, has advanced into early clinical development. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development. Understanding how pandemic IAV adapt to humans and modeling the pathogenesis of pandemic and potentially pandemic IAV viruses is critical for mitigating future pandemics and to develop new therapeutic strategies. Recently, highly pathogenic avian influenza H5N1 viruses have become enzootic in multiple species of wild birds, and have caused often fatal epizootic infections in domestic poultry, multiple species of mammals, including dairy cattle, and important have been associated with human epizootic H5N1 infections in 2024. We are currently studying the pathogenicity of these viruses in experimental animal studies, and we will be evaluating the protective efficacy of the BPL-inactivated influenza vaccine, BPL-1357. Efforts to determine the viral genome sequence of additional cases from the 1918 influenza pandemic continue, providing further insights into this significant influenza pandemics, along with bacterial genomes associated with secondary bacterial pneumonias. This year, we work demonstrated that BPL-1357 universal influenza vaccine provides excellent protection against the recent highly pathogenic H5N1 strains, and studies of vaccine immune durability and environmental stability are ongoing. Other key projects include studies of the role of temperature optima for both human-adapted and avian-adapted influenza A virus PB1 polymerase proteins.