An experimental influenza vaccine carrying over 80,000 variations of hemagglutinin antigens resulted in a stronger immune response in mice and ferrets towards the less variable parts of the virus. This is a significant advancement in the Duke Human Vaccine Institute’s efforts to develop a universal and long-lasting flu shot.
Duke researchers have made progress in the fight against influenza viruses by creating a vaccine that prompts the immune system to focus on a less variable part of the virus surface.
Their approach showed promising results in experiments with mice and ferrets, indicating a potential breakthrough in flu vaccine development.
This new vaccine approach, which was published on May 1 in the journal Science Translational Medicine, is part of a 5-year-old effort to create a longer-lasting universal flu vaccine that could protect against all versions of the virus. Influenza kills approximately half a million people worldwide each year, despite the availability of vaccines. If successful, this new approach could lead to more broadly-protective flu vaccines and reduce the need for an annual shot tailored to the specific strains of the virus. Influenza strains are identified using a shorthand code, such as H5N1, which indicates the specific surface proteins they carry.Hemagglutinin (HA) is a protein shaped like a lollipop that attaches to a receptor on a human cell, allowing the virus to enter the cell. Neuraminidase (N) is a second protein that helps the newly made virus to leave the host cell and infect other cells.
Nicholas Heaton, PhD, an associate professor of molecular genetics and microbiology at Duke, who led the research, explained, “There’s five to 10 times more hemagglutinin than neuraminidase on the virus particle. When testing for protection against a strain of flu, we measure what antibodies do to hemagglutinin in your blood.”The most reliable way to predict what could happen to you is by looking at the level of hemagglutinin-directed immunity in your body. This type of immunity is strongly linked to protection against the flu. Vaccines work by training the immune system to respond to specific parts of the virus that are expected to be the most dangerous in the upcoming flu season. The need for a new flu shot each year is not because the vaccine loses its effectiveness, but because the flu virus constantly changes the surface proteins that the vaccines target. Flu shots and immune systems usually focus on the head of hemagglutinin, rather than the stalk.constantly changing details in the head region, leading to a continuous battle between vaccine development and viruses. On the other hand, the stalk undergoes fewer changes. Several researchers have conducted experiments to determine which areas of the hemagglutinin can change while still allowing it to function. According to Heaton, it has been found that changing the stalk significantly affects its functionality. In response, the Duke team aimed to create proteins that trigger an immune response targeting the stalk rather than the head, as the virus has adapted to have rapidly changing details in the head region.The immune system identifies these (features on the head region). However, these are the shapes the virus can alter. That’s a cunning strategy,” Heaton said.
By employing gene-editing, they generated over 80,000 versions of the hemagglutinin protein with modifications in one segment right on the top of the head domain. They then administered a vaccine containing a mixture of these variations to mice and ferrets for testing.
Due to the wide range of head conformations presented to the immune system and the relatively consistent stalks, these vaccines elicited a greater production of antibodies to the stalk portion of hemagglutinin in response. “The opportunity isThe immune system’s ability to recognize the head portion repeatedly is compromised due to its diversity, as stated by Heaton. In experiments and animal testing, the experimental vaccine elicited a stronger immune response to stalk regions because of their consistency. This enhanced the overall immune response to the vaccine and, in some cases, even improved antibody responses to the head region of the protein. According to Heaton, antibodies against the stalk function differently and their protective mechanism may not necessarily block the initial infection. This led to the idea of exploring how the immune system responds to different regions of the protein.”If we could develop a vaccine that provides protection against both types of antibodies, that would be a game changer. What if we could generate antibodies for both the head and stalk regions to prepare for potential vaccine mismatches or pandemics?”
“According to the study, the answer is yes, we can achieve that,” Heaton explained.
In some experiments, all of the mice who received the highly variant vaccine were able to avoid illness or death from what should have been a lethal dose of flu viruses.
The next phase of the research will focus on determining if the same level of immunity can be achieved with a smaller number of antibodies.
The study involved screening a library of over 80,000 hemagglutinin variants.
Funding for this research came from the NIH/National Institute of Allergy and Infectious Diseases (75N93019C00050). The Duke Regional Biocontainment Laboratory, which was used in the study, received partial support for its construction from the NIH/NIAID (UC6 AI058607).
Zhaochen Luo and Nicholas Heaton hold a patent for the methods used in creating large antigen libraries for this study.
