Redness, pain at the injection site, fever, fatigue and headache are some of the common temporary reactions that can occur after vaccination. However, not everyone experiences these effects in the same way. While some people may develop noticeable symptoms after vaccination, others may experience little or no reaction at all.
New research from the Center for Vaccinology at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) has identified a possible biological explanation for these differences.
The researchers found that a person's innate immune system may already be more reactive before vaccination, particularly through a stronger interferon-related antiviral response. According to the study, individuals with a more active baseline interferon response were more likely to experience stronger temporary symptoms following vaccination.
The findings have been published in Science Translational Medicine.
Why Do Vaccines Cause Side Effects?
Vaccines are designed to activate the immune system so that the body can learn to recognise a particular antigen and prepare an immune response against future infection.
This immune activation can also produce temporary inflammatory effects. These may include:
- Pain or redness at the injection site
- Swelling
- Fatigue
- Headache
- Fever
- Muscle aches
- Flu-like symptoms
These reactions are generally mild and temporary. However, the intensity of these symptoms can differ substantially between individuals. Some people may experience several symptoms for a day or two, while others may notice almost nothing after receiving the same vaccine.
Researchers Looked at Immune Responses Before and After Vaccination
To investigate why these differences occur, researchers monitored the immune systems of 51 healthy individuals who received two doses of an mRNA COVID-19 vaccine.
Participants were monitored for seven days following each vaccination, allowing the researchers to compare their immune responses with the symptoms they experienced. The study identified an association between pre-existing interferon-related immune activity and subsequent vaccine reactions.
What Is Interferon?
Interferons are signalling proteins involved in the body's natural antiviral defence system. When cells detect a viral infection, they can produce interferons. These molecules send signals to neighbouring cells and help prepare them to defend against viruses. Importantly, people do not necessarily begin with the same level of interferon-related immune activity.
According to the researchers, some individuals had a stronger interferon-related immune signature even before receiving the vaccine.
The study suggests that this baseline immune state may influence how strongly the body responds to vaccination and, consequently, how many temporary symptoms a person experiences.
Your "Immune Baseline" May Matter
The researchers describe this pre-existing immune state as part of an individual's immunological "capital." Why some people naturally have a stronger interferon-related immune signature is not yet fully understood.
The researchers suggest that several factors could potentially contribute, including:
- Genetic differences
- Differences in the microbiome
- Previous inflammatory events
- Other factors affecting the immune system
However, the study does not establish that any one of these factors is responsible for differences in vaccine reactions. Further research will be required to understand what determines an individual's baseline interferon response.
Why Can the Second Dose Produce More Reactions?
The researchers also identified another possible mechanism in an animal model. After the first vaccination, the immune system develops antibodies and T cells capable of recognising the vaccine antigen. When a subsequent dose is administered, this existing immune memory can rapidly amplify the activation of certain innate immune cells. One group of cells highlighted by the researchers is monocytes, a type of white blood cell involved in inflammatory responses.
The researchers found that these cells can become more strongly activated after subsequent vaccination, potentially contributing to increased inflammation and symptoms. This may help explain why some people experience more noticeable reactions following a second dose than after their first vaccination.
Does Having Side Effects Mean the Vaccine Is Working Better?
No.
One of the important messages from the research is that the severity of vaccine side effects should not be used as a measure of vaccine effectiveness.
A person who experiences fever, fatigue or arm pain is not necessarily developing better protection than someone who experiences no symptoms. Similarly, experiencing little or no reaction does not mean that the vaccine has failed to work. The immune response responsible for generating protection and the inflammatory mechanisms responsible for temporary symptoms are related but are not necessarily the same thing.
Could This Research Lead to Better-Tolerated Vaccines?
The findings could have implications for future vaccine development. Researchers are interested in understanding how to separate the biological mechanisms that are important for generating a strong protective immune response from those that primarily contribute to unwanted inflammatory symptoms.
If these mechanisms can be better distinguished, it may eventually become possible to develop vaccines that maintain strong immune protection while producing fewer unwanted reactions. The UNIGE/HUG team is now investigating whether similar mechanisms occur with other types of vaccines, rather than only the mRNA COVID-19 vaccine examined in this research.
What Does This Mean for the Public?
The study provides another explanation for something many people have already observed: two people can receive the same vaccine and have very different experiences afterward. Differences in vaccine reactions may partly reflect the state of the person's innate immune system before vaccination.
Importantly, however, the presence or absence of side effects should not be interpreted as a reliable indication of how well an individual is protected. As Prof. Arnaud Didierlaurent of UNIGE/HUG concludes, a mild reaction—or even no symptoms at all—does not mean that a vaccine is ineffective.
Key Takeaways
1. Vaccine reactions vary considerably between individuals.
Some people experience pain, fever or fatigue, while others have few or no noticeable symptoms.
2. Baseline immune activity may play a role.
People with a stronger interferon-related antiviral signature before vaccination were more likely to experience stronger temporary reactions.
3. Interferons are important antiviral signalling molecules.
They help activate the body's innate immune defence.
4. The second dose may trigger stronger innate immune activation.
Existing immune memory can contribute to increased activation of cells such as monocytes.
5. Side effects are not a measure of vaccine effectiveness.
Having strong symptoms does not necessarily mean stronger protection, and having no symptoms does not mean the vaccine has not worked.
6. More research is needed.
The researchers are investigating whether the mechanisms identified in this study also apply to other vaccines.
The study was conducted by researchers from the Center for Vaccinology at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG). The research was supported by the HUG Private Foundation, Giorgio Cavaglieri Foundation and Moderna and was published in Science Translational Medicine.
Source: University of Geneva (UNIGE)
