Fighting the Flu: Pathway towards a universal vaccine

Every year, between three and five million people around the world contract life-threatening cases of the flu. Ultimately, as many as 500,000 die. These striking numbers are due in part to a lack of understanding of the science behind the body’s immune response to the flu, which makes it difficult to develop effective vaccines. A team led by Professor Susan Kaech, Yale Associate Professor of Immunobiology, set out to better understand on the molecular level how the body attacks the flu virus.

What Kaech’s team found was a previously unknown step in the body’s immune response to a flu virus – a signaling protein called transforming growth factor-β (TGF-β). This protein aids antiviral antibody production, and without it, mice were impaired in their protective attack against influenza infection. With new knowledge, the Yale team hopes that better vaccines will be developed to counter all strains of the flu.

Current vaccine strategies are limited in many ways. While everyone is advised to get the annual flu shot, not all people who receive the vaccine develop immune protection. Since knowing which flu strain will be most virulent in a given year is a bit of a guessing game, vaccines do not always target the right variant. “Given that the antibodies our body generates after the flu vaccine are highly protective, we wanted to learn more about the signals that regulate antibody production during influenza infection with the hope that we may be able to enhance or manipulate these signals to make more broadly protective and longer-lasting vaccines,” Kaech said.

Professor Susan Kaech led the research on molecular-level immune response to influenza virus in mice, conducted here at Yale. Image courtesy of the Howard Hughes Medical Institute.


To address these issues, the Yale scientists studied the immune response to influenza, in which T cells and B cells work together to target the virus. When a virus enters the body, a small number of T cells recognize the virus and are activated. Some of these cells then differentiate into a type of T cell, commonly referred to as a T follicular helper cell, that helps B cells manufacture antibodies against the virus. Without the assistance of follicular helper T cells, very few antibodies against influenza are produced and the infection is not well controlled. But little is known about how follicular helper T cells are generated, especially in the lung during influenza infection.

TGF-β elucidates this process somewhat. The signaling protein is necessary for B cell responses and antibody production, as Kaech’s team observed in mice. Importantly, when the T cells were unable to “see” TGF-β signals, they failed to differentiate into follicular helper T cells and antiviral antibody production was effectively reduced.

This discovery represents a key step towards a universal flu vaccine. While there are a variety of potential avenues for creating a vaccine against all flu strains, this study identifies that TGF-β may be a new ingredient to add to the vaccine, as it could elicit a stronger protective antibody response. TGF-β is widely known for being an immunosuppressive factor in the immune system. This new work opens up an alternate approach to how it may function — paradoxically, as an activating signal to stimulate antiviral immunity.

“It is often these types of discoveries that break convention that lead to the greatest advances,” Kaech said. “We hope that further work on TGF-β will aid in our pursuit of a ‘universal’ flu vaccine that can protect against all types of flu strains.”

Cover Image: A scanning electron microscope picture shows the H5N1 flu strain, known as the avian flu, transmitted by birds. Image courtesy of the Guardian.