Early immune response may determine who gets flu symptoms, study finds

Using human challenge studies, research reveals that a stronger early immune response can drive both the symptoms of infection and viral clearance.

Scientists have shown that the body’s earliest immune response, the innate immune response, is a key indicator of whether people will develop symptoms from flu and how their immune system will fight the virus.

The innate immune system provides the first line of defence against pathogens like viruses and bacteria and involves a combination of physical barriers (like skin) and cells that work to defend and protect the human body.

In this research, 27 healthy volunteers were deliberately exposed to the same dose of influenza A/H3N2 under carefully controlled conditions and with medical monitoring, allowing the researchers to track their immune responses from the very start of infection. The results show that those who develop symptoms have a faster and stronger innate immune response, which helps clear the virus but also results as symptoms of illness and inflammation.

Professor Christopher Chiu, Professor of Infectious Diseases and senior author said: “The innate immune system acts within the first few hours and days after virus exposure and is usually very difficult to catch as it is so rapid and dynamic. Here, using controlled human infection, we have shown how critical these early responses to infection are and explain why some people develop symptomatic disease while others remain asymptomatic, strongly supporting our approach to developing new treatments and preventative interventions.”

Tracking infections from the moment of exposure

Understanding why some people get more unwell with the flu than others has remained a challenge to investigate. The level of disease severity is due to a combination of viral, environmental, and host factors, but studying the moment of exposure and the initial immune response is extremely difficult in real-world conditions.

Using a controlled human challenge study where 27 healthy adults were infected with influenza, researchers have been able to build a detailed picture of how immune responses unfold in the initial hours and days after exposure. They did this by analysing both blood and nasal samples from the adults who were infected.

The response seen involved key immune cells from the innate system, such as monocytes and dendritic cells, and were triggered sooner and most strongly in symptomatic individuals.

The variation that was seen between the symptom-free and symptomatic individuals the scientists suggest could be explained by genetic factors, past exposure or “trained immunity” where long-term changes in immune function has been caused by prior infections or vaccinations.

Implications for future treatments

The results could have important implications for how vaccines are developed for influenza and other respiratory viruses as one key consideration in vaccine design is balancing the immune system activation with the side effects caused by inflammation so that those who get vaccinated do not experience severe illness symptoms.

The findings also could highlight biomarkers that could help predict who is likely to develop symptoms after infections. The scientist's caveat that the study was relatively small, particularly for asymptomatic cases but that the findings could provide a foundation for other studies and future clinical applications.

Papargyris, L., Xu, J., Broderick, C. et al. Innate immune responsiveness predicts enhanced cellular immunity and symptomatic disease after controlled human influenza infection. Nat Med (2026). https://doi.org/10.1038/s41591-026-04483-7