Abstract
Influenza viruses cause a significant number of infections and deaths annually. In addition to seasonal infections, the risk of an influenza virus pandemic emerging is extremely high owing to the large reservoir of diverse influenza viruses found in animals and the co-circulation of many influenza subtypes which can reassort into novel strains. Development of a universal influenza vaccine has proven extremely challenging. In the absence of such a vaccine, rapid response technologies provide the best potential to counter a novel influenza outbreak. Here, we demonstrate that a modular trimerization domain known as the molecular clamp allows the efficient production and purification of conformationally stabilised prefusion hemagglutinin (HA) from a diverse range of influenza A subtypes. These clamp-stabilised HA proteins provided robust protection from homologous virus challenge in mouse and ferret models and some cross protection against heterologous virus challenge. This work provides a proof-of-concept for clamp-stabilised HA vaccines as a tool for rapid response vaccine development against future influenza A virus pandemics.
Highlights
Influenza viruses are medically significant members of the Orthomyxoviridae family, causing an estimated 3–5 million severe infections resulting in 290,000–650,000 deaths annually[1]
In addition to regular seasonal outbreaks caused by strains circulating within the human population, there have been numerous influenza virus pandemics in the past century resulting from a new influenza strain entering the human population, with the most recent occurring in 20092–6
The virus titres detected in nasal wash samples from days 2–5 post infection were significantly reduced in H1 clamp and H1 inactivated zonal pool (IZP) vaccinated animals (p < 0.005) compared to animals vaccinated with phostphatebuffered saline (PBS) and the number of days at which virus shedding could be detected was reduced (Fig. 3C)
Summary
Influenza viruses are medically significant members of the Orthomyxoviridae family, causing an estimated 3–5 million severe infections resulting in 290,000–650,000 deaths annually[1]. Many stem-specific mAbs are invaluable in response to the SARS-CoV-2 pandemic in 2020, with reactive only with pre-fusion HA owing to the significant structural numerous vaccines progressing to clinical trials within a matter of months from virus discovery[46,47,48]. One such technology is the rearrangements and loss of epitopes that occurs in the HA stem domain upon transition to the post-fusion form.
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