Single amino acid swap expands nanoparticle vaccine approach to influenza viruses
Influenza viruses constantly shapeshift to evade recognition by the immune system. This shapeshifting occurs in critical proteins like hemagglutinin (HA), which controls how the virus attaches to human cells before entering them. Influenza viruses can evade immunity in two major ways: through the gradual accumulation of mutations that make HA harder for the immune system to recognize or through…
Influenza viruses constantly alter their shape to avoid detection by the immune system, often through changes in the hemagglutinin (HA) protein. Seasonal flu vaccines currently target the most prevalent viral strains circulating in a given season, but these vaccines may not be effective against rapidly evolving viruses. To address this issue, researchers at Scripps Research have developed a method to stabilize the HA protein and use it in nanoparticle vaccine candidates.
These self-assembling protein nanoparticles (SApNPs) organize viral proteins into clusters that the immune system can more easily recognize.
The HA protein is naturally prone to changing shape, which is essential for viral entry into human cells. The senior author, Jiang Zhu, aims to find a trigger that can stabilize the HA protein, making it effective for use in a nanoparticle vaccine. The researchers identified a specific location in the HA protein—the 95th amino acid—which consistently interacts with water molecules.
By substituting this water-loving amino acid with an oily one, they found that the HA protein became more stable and less likely to misfold or break apart. This swap also improved the protein's stability under acidic conditions.
The team further improved the stability of the HA protein by incorporating other known stabilizing mutations, such as HKE from Johnson & Johnson for influenza A viruses and a related mutation called NS for influenza B viruses. They then displayed up to 20 copies of the stabilized HA trimers on their proprietary SApNP technology and tested them in mice. The HA trimer-containing nanoparticles remained in the mice's lymph nodes for longer periods and induced more robust immune responses compared to free-floating trimers.
The researchers' findings could potentially lead to the development of universal influenza vaccines that provide cross-protection against diverse viral strains. The study represents a significant step towards a platform technology for structure-guided protein vaccines, which can be applied to various virus families, including hepatitis C virus, Ebola, respiratory syncytial virus (RSV), and HIV.
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