A new study from St. Jude Children’s Research Hospital and Washington University School of Medicine has identified a key reason why flu vaccines sometimes offer limited protection. Researchers found that a specific type of immune cell, known as T follicular helper cells, often targets the wrong part of the virus, potentially leading to a less effective immune response. The findings, published today in Nature Immunology, could help guide improvements in vaccine design.
Flu Vaccine’s Immune Response May Be Misdirected
While annual flu vaccines provide some protection, their effectiveness varies. The best immune responses target the influenza virus’s surface proteins—hemagglutinin and neuraminidase—which change each season. Scientists update vaccines to account for these variations, but new research suggests the immune system may not always respond as expected.
“The annual flu vaccine provides some level of protection, but it could be better,” said Paul Thomas, Ph.D., senior co-corresponding author and a researcher in the St. Jude Department of Host-Microbe Interactions. “We found that the current flu vaccine formulation could likely be improved by focusing on the influenza surface proteins and excluding the virus’ internal proteins that distract the immune system.”
The study found that vaccinated individuals often generate an immune response against unchanging internal flu proteins rather than the more beneficial surface proteins. This could limit the vaccine’s effectiveness, as the immune system may be “stuck” responding to the same internal proteins each year instead of adapting to new flu strains.
A Closer Look at the Immune System’s Response
Scientists examined lymph node samples from study participants over two years to understand this phenomenon. Unlike blood samples, which provide only a brief snapshot of immune activity, lymph nodes offer a clearer view of how long-term immunity develops. The analysis revealed that T follicular helper cells were consistently responding to internal viral proteins rather than the updated surface proteins included in the vaccine.
“We found that a large group of T follicular helper cells are responding to the same proteins that they see yearly instead of targeting the surface proteins that we update and want them to target,” Thomas explained.
This misdirected immune response could explain why some individuals develop only partial immunity after vaccination. The findings also support a long-standing immunological theory known as “antigenic original sin” or imprinting, where the immune system preferentially recalls past flu exposures instead of adapting to new strains.
Improving Flu Vaccines Effectiveness
Modifying flu vaccines to remove unnecessary internal proteins and focus solely on surface proteins could enhance immune response.
“In the current standard flu vaccine, we have this mix of other proteins that may not need to be in there,” Thomas said. “New vaccine formulations should focus the T-cell response on surface proteins.”
With a clearer understanding of why flu vaccines sometimes underperform, scientists hope to develop more effective formulations that provide more potent and longer-lasting protection against influenza.
“It’s fascinating that we’re still learning how influenza vaccines work regarding the human immune response,” Thomas said. “And it’s exciting to show there are still new ways to improve these vaccines and provide better protection.”
Reference: Stefan A. Schattgen, Jackson S. Turner, Mohamed A. Ghonim, Jeremy Chase Crawford, Aaron J. Schmitz, Hyunjin Kim, Julian Q. Zhou, Walid Awad, Robert C. Mettelman, Wooseob Kim, Katherine M. McIntire, Alem Haile, Michael K. Klebert, Teresa Suessen, William D. Middleton, Sharlene A. Teefey, Rachel M. Presti, Ali H. Ellebedy, Paul G. Thomas. Influenza vaccination stimulates maturation of the human T follicular helper cell response. Nature Immunology, 2024.
