Stable Hemagglutinin is Key to Predicting Pandemic Influenza Risk

Category Health

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The findings by scientists at St. Jude Children's Research Hospital reveal that the stability of the viral protein hemagglutinin can help to predict the pandemic potential of flu strains, and should be tested for when assessing flu strains to include in the annual vaccine. Factors such as a mutation that destabilizes the virus in vaccines, or a protective mutation that prevents this, may help to increase vaccine efficacy and predict pandemic potential.

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Scientists at St. Jude Children’s Research Hospital found mutations that can improve or impair flu vaccines and may give clues to assess the pandemic potential of flu viruses in nature.

They found a mutation that destabilizes the virus in vaccines, but also a protective mutation that prevents this, suggesting a way to enhance vaccine efficacy. They also found that the stability of the viral protein hemagglutinin could help predict the pandemic potential of flu strains, implying that incorporating stability tests could improve pandemic risk assessments.

H3N2 is responsible for up to 30% of seasonal flu cases

Improving the seasonal influenza vaccine and public health specialists’ ability to predict pandemic potential in new flu strains may be possible due to new findings from scientists at St. Jude Children’s Research Hospital. The key is the stability of a viral protein that gains entry into human cells. The findings were published recently in the journal Science Advances.

"We found that the protein flu viruses use to enter cells, hemagglutinin, needs to be relatively stable and resistant to acid in an effective H3N2 flu vaccine," said senior and co-corresponding author Charles Russell, Ph.D., St. Jude Department of Infectious Diseases. "We found a mutation in hemagglutinin that makes the virus grow better in eggs also causes a mismatch in the vaccine. The mutation makes the virus unstable and makes it look less human-like." .

St. Jude's research focuses on the virus's hemagglutinin protein and its role in vaccine efficacy

The H3N2 virus is a subtype of Influenza A and is one of the culprits behind the seasonal flu. Many flu vaccines are made by growing the virus in chicken eggs, but the virus can gain mutations during that process. Some of those changes, like the one uncovered by the St. Jude group, make the vaccine less effective in generating the ideal immune response. At the same time, other mutations have more beneficial impacts.

The stability of the hemagglutinin protein plays a factor in how infectious the virus is when spread through the air

"We also found a different mutation in egg adaptation that doesn’t destabilize the hemagglutinin or make it less human-like," Russell said. "That mutation prevented the emergence of the destabilizing mutant. Going forward, incorporating this protective mutation or otherwise assuring hemagglutinin stability may help maintain vaccine efficacy." .

While egg-adaptive mutations are a well-known weakness in many current flu vaccine pipelines, scientists currently do not consider viral protein stability when assessing flu strains to include in the annual vaccine. This study suggests that testing flu strains’ hemagglutinin for an antigenic match to circulating viruses, then including only those with higher stability, may improve the vaccine by preventing the incorporation of strains with unstable proteins.

When stable, hemagglutinin can form a mousetrap-like pore that penetrates cell membranes

The scientists also found that hemagglutinin stability could be measured to better predict the pandemic potential of novel flu strains. Flu viruses with the unstable protein could not transmit in the air between ferrets, a model used to infer likely properties in humans. Moreover, viruses with the more stable protein version had a high airborne transmission rate.

"The top of the lungs and nose, called the upper respiratory tract, is mildly acidic," Russell said. "The viral protein needs to be able to resist mild acid when it’s outside of the cell in the respiratory tract. That’s why the stable hemagglutinin improves transmission." .

The research also discusses the effect of mutations during viral growth in eggs

Hemagglutinin is like a mousetrap, ready to strike and poke the cell membrane with its receptor-binding domain, Russell said. But it can only do that if it is stable enough to persist through the mild acidity of the upper respiratory tract to be available to attach to cells at the proper time and place.

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