Researchers from St. Jude Children’s Research Hospital and Washington University School of Medicine have identified the reasons behind the flu vaccine’s inconsistent effectiveness. They discovered that a particular type of immune cell known as T follicular helper cells plays an indirect role in the body’s response to the influenza virus. These cells often focus on less relevant parts of the virus, which could diminish the overall immunity. Their findings, published today in Nature Immunology, could lead to improvements in vaccine design.
“While the annual flu vaccine offers some degree of protection, its effectiveness could be enhanced,” stated Paul Thomas, PhD, a senior co-corresponding author from St. Jude Department of Host-Microbe Interactions. “Our research suggests that we could strengthen the vaccine by concentrating on the surface proteins of the influenza virus and minimizing the inclusion of its internal proteins that distract the immune response.”
The study revealed that although the flu vaccine increases immune responses in vaccinated individuals, these reactions don’t always target the best proteins. The most potent responses against the flu focus on two surface proteins: hemagglutinin and neuraminidase, which vary each year. Scientists adjust the vaccine annually to match the new surface proteins of the prevailing flu strains, keeping the rest of the vaccine stable. However, less effective immune responses occur when the vaccine targets the unchanging internal proteins instead of the more advantageous surface proteins.
“In the standard flu vaccine, we have a mix of proteins that we might not actually need,” Thomas explained. “To improve new vaccine formulations, we should direct the T-cell response solely towards the surface proteins. A straightforward method to achieve this would be to present only those surface proteins to immune cells, eliminating other irrelevant peptides.”
Identifying the gap in immunity through lymph node analysis
While prior studies have suggested reasons for the varying effectiveness of the influenza vaccine, this research offers a clearer understanding of the underlying mechanisms. An effective immune response against the flu relies on antibodies. Antibodies attach to specific proteins, both hindering their function and drawing immune cells. B cells produce antibodies but don’t determine which proteins to target. Instead, a different set of immune cells, known as T follicular helper cells, activate B cells inside the lymph nodes. This study is the first to provide an in-depth look at helper cells sourced from the lymph nodes of vaccinated individuals, offering fresh insights into how these T cells can either promote or hinder effective flu immunity.
“Most research focuses on blood samples, which are easy to collect, but not where the main T-cell response occurs,” said Stefan Schattgen, PhD, a co-first author from St. Jude Department of Host-Microbe Interactions. “By examining the lymph nodes directly over time, we gained a clearer perspective.”
To study the immune response following vaccination, the researchers analyzed lymph node samples from a small group of participants over two years. They identified the viral protein segments that the follicular helper T cells reacted to, revealing a tendency to respond to internal proteins. “We found that numerous T follicular helper cells were reacting to the same proteins year after year, without targeting the updated surface proteins that we want them to focus on,” Thomas noted.
Understanding the problematic response in lymph nodes
The researchers documented the immune cells’ responses within lymph nodes after vaccination, which contrasted with earlier studies and unveiled a new aspect of the inefficacy associated with the vaccine.
“In the bloodstream, we observe a brief, minor spike in anti-flu T-cell responses. In contrast, lymph nodes can maintain this response for several months,” Schattgen explained. “This establishes a ‘locked-in’ immunity to flu. So, if we start with a misguided immune response towards irrelevant targets, it can remain centered on that internal protein instead of adapting to the new, relevant surface proteins.”
Collectively, these findings illustrate that the annual flu vaccine’s effectiveness can be thwarted when the immune response is directed towards less useful proteins found in the vaccine that don’t change from year to year. This prolonged incorrect immune memory can hinder the development of new, more effective antibodies.
This phenomenon resembles the well-established immunological concept known as antigenic original sin or imprinting, where a person’s immune response to a new influenza infection is influenced by previous exposures to the virus. “We are uncovering the core mechanism behind what antigenic original sin actually entails,” Thomas remarked. “Robert Webster, PhD, an emeritus member of the St. Jude Department of Infectious Diseases, theorized about the role of B cells in this process many years ago. We have now demonstrated that T follicular helper cells likely play a crucial part in this imprinting process that influences B cells to recall memory responses preferentially.”
With these insights into why the influenza vaccine may be less effective for some individuals, the research team aims to use this understanding to enhance overall vaccine performance.
“It’s remarkable that we continue to uncover new aspects of how influenza vaccines interact with the human immune system,” Thomas stated. “It’s thrilling to reveal that there are still innovative approaches to improve these vaccines and deliver enhanced protection.”
Authors and funding
Other co-first authors of the study include Mohamed Ghonim from St. Jude and Jackson Turner from Washington University School of Medicine. Ali Ellebedy from Washington University School of Medicine is another co-corresponding author. Additional authors include Aaron Schmitz, Julian Zhou, Wooseob Kim, Katherine McIntire, Alem Haile, Michael Klebert, Teresa Suessen, William Middleton, Sharlene Teefey, and Rachel Presti from Washington University, along with Jeremy Chase Crawford, Hyunjin Kim, Walid Awad, and Robert Mettelman from St. Jude.
The study received funding from several sources, including the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) (75N93019C00052), the St. Jude Center of Excellence for Influenza Research and Surveillance (HHSN272201400006C), the St. Jude Center of Excellence for Influenza Research and Response (75N93021C00016), and various National Institutes of Health grants (U01-AI150747, U01-AI144616, and R01-AI136514), along with the National Institute of Allergy and Infectious Diseases (F32-AI157296, R21-AI139813, and 440 U01-AI141990), NIAID’s Centers of Excellence for Influenza Research and Surveillance (CEIRS) (HHSN272201400006C), and support from ALSAC, the fundraising and awareness organization for St. Jude.
