Scientists at Scripps Research have developed a new design strategy to stabilize the critical hemagglutinin (HA) protein found in influenza viruses, according to a study published on August 13, 2026, in Nature Communications. The breakthrough offers a blueprint for building advanced nanoparticle vaccine candidates that could improve immune responses against diverse influenza strains.
Scientists Unveil Blueprint to Stabilize Flu Proteins for Nanoparticle Vaccines
Influenza viruses constantly shapeshift to evade the human immune system. This occurs in key proteins such as HA, which controls how the virus attaches to and enters human cells. Viruses can evade immunity through the gradual accumulation of mutations or through reassortment events that introduce substantially different viral proteins, potentially leading to flu pandemics. According to the research reports, influenza viruses cause up to 5 million cases of severe illness and claim between 290,000 and 650,000 lives worldwide each year. Additionally, four major pandemics since 1918 have caused tens of millions of deaths.
While seasonal flu vaccines remain the primary approach for targeting circulating strains, most commercial vaccines are produced using an older method that involves growing them in chicken eggs. Vaccine development is shifting toward more modern methods using proteins and nucleic acids, which offer greater flexibility, efficiency, and scalability.
Targeting the 95th Amino Acid to Stop Structural Instability
On the surface of the influenza virus, groups of three identical HA proteins form bundles called trimers. These trimers coordinate binding and entry into human cells, but they frequently misfold or fall apart when exposed to temperature changes or acidic conditions, presenting a challenge for scientists attempting to generate stable lab-grown proteins for vaccines.
Researchers observed that across various flu viruses infecting humans, birds, and pigs, a specific location at the 95th amino acid of the HA protein was consistently water-loving.
At the core of the trimer, there are many oily residues that tend to group together. But then in the middle of this oily group, there’s one pretty big and disruptive water-like amino acid. So, I wondered, will the structure be more stable if we change this to an oily amino acid as well?
said Zhu, according to Scripps.
By replacing this water-loving amino acid at position 95 with an oily one, the structure of the HA trimer from the 2009 California pandemic flu strain closed suddenly and became more stable. Members of Zhu’s lab tested this substitution across a variety of flu viruses. They found that this substitution, combined with a related mutation called “NS” designed for influenza B viruses, made the overall HA structure more stable.
Self-Assembling Nanoparticles Display Viral Proteins
Once a framework for developing stable trimers across multiple influenza viruses was established, the team displayed up to 20 copies of these trimers on Zhu’s proprietary self-assembling protein nanoparticles (SApNPs). This technology organizes many copies of viral proteins into clusters that the immune system can recognize more easily.
When tested in mice, the HA trimer-containing nanoparticles remained in lymph nodes far longer than free-floating trimers and prompted more robust immune responses. This framework could eventually inform the design of next-generation vaccines across diverse influenza viruses.
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