Universal Flu Vaccine a Nanoparticle That Is All Stalk, No Head

Designs for universal flu vaccines try to emulate the relatively changeless parts of viral proteins, not the highly variable parts that are targeted by seasonal vaccines. The changeless parts, however, tend to be unstable. To develop a vaccine candidate that can present stabilized versions of these relatively changeless structures, scientists based at Georgia State University built double-layered protein nanoparticles. According to these scientists, their vaccine candidate can protect mice against divergent strains of influenza.

Seasonal flu vaccines provide protective immunity against influenza viruses by targeting the exterior head of the virus’s surface protein, which is hemagglutinin (HA). The influenza virus trains the body to produce antibodies against inactivated virus particles containing the head of this protein, ideally preventing the head from attaching to receptors and stopping infection. However, the head is highly variable and is different for each virus, creating a need for better vaccines. This study uses a new approach and instead targets the inside portion of the HA protein known as the stalk, which is more conservative and offers the opportunity for universal protection.

“Vaccination is the most effective way to prevent deaths from influenza virus, but the virus changes very fast and you have to receive a new vaccination each year,” said Bao-Zhong Wang, Ph.D., associate professor in the Institute for Biomedical Sciences at Georgia State. “We’re trying to develop a new vaccine approach that eliminates the need for vaccination every year. We’re developing a universal influenza vaccine. You wouldn’t need to change the vaccine type every year because it’s universal and can protect against any influenza virus.

“What we wanted to do is to induce responses to this stalk part of the influenza surface glycoprotein, not the head part. This way you’re protected against different viruses because all influenza viruses share this stalk domain. However, this stalk domain itself isn’t stable, so we used a very special way to make this vaccine construct with the stalk domain and had success.”

Details about the stalk-targeting vaccine candidate appeared in the journal Nature Communications, in an article entitled “Double-Layered Protein Nanoparticles Induce Broad Protection against Divergent Influenza A Viruses.” The article describes how the Georgia State scientists fabricated layered nanoparticles by desolvating tetrameric M2e into protein nanoparticle cores and coating these cores by crosslinking headless Has.

“We fabricated PNps [protein nanoparticles] approximately the size of the influenza A virions with a core of M2e displaying a shell of conserved hrHA domains,” the authors explained. “The binding of soluble hrHA to the desolvated PNps is speculated to be mediated through interaction of hydrophobic residues and fixed by DTSSP [3,3′-dithiobis(sulfosuccinimidyl propionate)] crosslinking primary amines.”

“To our knowledge,” they continued, “this design avoids the risk of instability shown by virus-like particles under osmotic stresses or during changes in salt concentration and prevents off-target immune responses against self-assembly motifs, such as the ferritin or hepatitis B core protein used in some PNp designs.”

The nanoparticle, Dr. Wang explained, protects antigenic protein so it won’t be degraded. “Our immune cells have a good ability to take in this nanoparticle,” he added, “so this nanoparticle is much, much better than a soluble protein to induce immune responses.”

To determine the effectiveness of the nanoparticle vaccine, the researchers immunized mice twice with an intramuscular shot. Then, the mice were exposed to several influenza viruses: H1N1, H3N2, H5N1, and H7N9. Immunization provided universal, complete protection against lethal virus exposure and dramatically reduced the amount of virus in the lungs.

Next, the researchers would like to test the nanoparticle vaccine in ferrets, which are similar to humans in the orchestration of their respiratory system.

“This vaccine is composed of very conserved domains. That’s the reason why the induced immunity can offer universal protection,” said Lei Deng, Ph.D., first author of the current study and a postdoctoral researcher in the Institute for Biomedical Sciences at Georgia State. “The seasonal influenza vaccines induce the dominant immune response against the head domain of the HA molecules, which is hypervariant. That is why we have to adopt new influenza strains for the new vaccine every year. Our vaccine overcomes this problem. For long-term protection, longevity of induced immunity in human still needs to be tested in further clinical tests.”