Why RSV Makes Babies Sicker Than COVID—New Research Reveals the Immune System Difference

Researchers have discovered that respiratory syncytial virus (RSV) and COVID-19 trigger fundamentally different immune responses in infants, which helps explain why RSV typically causes more severe disease. A new study published in Science Translational Medicine found that while both are respiratory viruses, they dysregulate the immune system in opposite ways—RSV suppresses the immune response, while COVID-19 triggers an overactive inflammatory response.

Why Do Infants Get Sicker From RSV Than COVID-19?

During the COVID-19 pandemic, doctors noticed something puzzling: infants hospitalized with RSV infection often developed much more severe symptoms than those admitted with SARS-CoV-2 (the virus causing COVID-19), despite both being respiratory RNA viruses. Researchers from St. Jude Children's Research Hospital and The Jackson Laboratory decided to investigate why.

The team compared immune responses at the single-cell level in infants hospitalized with either virus against healthy infants. They measured proteins, genes, and epigenetic signatures—essentially the molecular switches that control how genes turn on or off—in blood samples.

The results were striking. Severe RSV in infants was linked to unexpectedly low levels of systemic inflammation and a poorly coordinated early immune response, primarily involving natural killer cells, which are specialized immune cells that fight viral infections. This pattern is the opposite of what happens with COVID-19, where infants develop a hyperinflammatory immune response.

How Does RSV Reprogram the Infant Immune System?

What surprised researchers most was that the antiviral responses looked similar on the surface, but when they examined how immune genes were regulated, striking differences emerged. "RSV appears to reprogram parts of the infant immune system at the epigenetic level; which are molecular switches that control how genes are turned on or off," explains Duygu Ucar, PhD, Professor at The Jackson Laboratory.

This epigenetic reprogramming is significant because it suggests RSV doesn't just cause immediate illness—it may alter how the immune system responds in the future. "These changes may help explain why RSV can lead to more severe disease and possibly influence how the immune system responds in the future," Ucar concluded.

According to Dr. Octavio Ramilo, chair of the Department of Infectious Diseases at St. Jude Children's Research Hospital, "We showed, for the first time, that two similar respiratory viruses, RSV and SARS-CoV-2, cause very different types of immune dysregulation in young infants. The host response differs depending on the infecting virus at the chemical, cellular and even epigenetic level".

How These Findings Could Change Treatment Strategies

• Personalized Immune Support: Understanding that RSV suppresses immune function while COVID-19 triggers excessive inflammation means doctors may need to use opposite treatment approaches—boosting immunity for RSV patients while reducing inflammation for COVID-19 patients.
• Better Vaccine Development: The discovery that RSV reprograms immune genes at the epigenetic level could inform the design of more effective RSV vaccines that prevent this harmful reprogramming rather than just triggering antibody production.
• Improved Clinical Monitoring: Knowing that RSV causes low inflammation rather than high inflammation means doctors should monitor different biomarkers and warning signs in RSV-infected infants compared to those with COVID-19.
• Drug Development Targets: The identification of natural killer cells as central to RSV's immune dysregulation opens new avenues for antiviral drugs that specifically support these cells rather than using broad anti-inflammatory treatments.

The implications extend beyond understanding why infants get sicker. Since RSV suppresses the immune response rather than overwhelming it, treatments that work for COVID-19—such as anti-inflammatory medications—might actually make RSV worse by further dampening immune function. Conversely, strategies to boost natural killer cell activity could be beneficial for RSV but harmful for COVID-19 patients experiencing cytokine storms.

This research underscores why one-size-fits-all approaches to treating respiratory viruses in infants may be ineffective or even counterproductive. As our understanding of how different viruses manipulate the immune system deepens, treatment protocols will likely become increasingly tailored to the specific virus causing infection.