Using influenza vaccines to provide heterologous protection through trained innate immunity

Vaccines are one of the most powerful tools we have to protect people from infectious diseases. Traditionally, vaccines are designed to train the adaptive immune system to recognize and fight a specific virus or bacterium. However, recent discoveries show that the first line of defense in our immune system, the innate immune system, can also develop a type of "memory." This process called trained innate immunity, allows the body to respond more strongly to a wide range of infections, not just the one the vaccine was originally designed for. Some vaccines, such as the tuberculosis vaccine (BCG), have already been shown to reduce illness and death from unrelated respiratory infections, demonstrating this broad protective effect. Seasonal influenza vaccines are used worldwide every year, but it is not yet well understood whether they can also trigger trained innate immunity and provide this kind of extra, non-specific protection. Because flu vaccines are given to millions of people annually and come in different forms, understanding their broader effects could help us improve protection against new or unexpected infectious diseases. This research will test how different types of influenza vaccines influence trained innate immunity. Using mouse models, we will; 1) Study how flu vaccines change the activity and behavior of key immune cells, 2) Test whether these changes improve protection against unrelated infections, such as COVID-19 or pneumonia, and 3) Identify which immune cells and molecular signals are responsible for this extra protection. By uncovering how flu vaccines can strengthen broad immune defenses, this project could guide the design of next-generation vaccines that not only protect against their target disease but also provide rapid, wide-ranging protection during future outbreaks and pandemics. Additionally, the flu platform with the best heterologous protection can be utilized during pandemics when pathogen-specific vaccines are not readily available.