After receiving a vaccine, you might have noticed symptoms like muscle soreness or headache. You may also have experienced other effects such as fatigue, changes in mood, or feeling less interested in meeting with people. Maybe you have thought of all of these “side effects” as a bit irritating, trying to time your vaccine injection so it interferes as little as possible with your daily plans. Yet, these symptoms show that your immune system is reacting to the vaccine and thus preparing you for future encounters with pathogens.
When the immune system is activated, immune cells release inflammatory proteins called cytokines. These cytokines communicate with the brain, which leads to changes in how we feel and behave. Such changes in behaviour are known as “sickness behaviour” and include, for instance fatigue and changes in social behaviour. Fighting an infection demands a lot of energy to fuel the immune system, so sickness behaviour can be seen as adaptive since it helps us preserve energy, for example by making us want to rest (Dantzer R. 2001).
Researchers use different experimental models to study how humans respond to inflammation. For example, a fragment of bacteria (lipopolysaccharide, LPS) can be injected to activate the immune system, producing a strong inflammatory response for a few hours (Lasselin J. 2025). On the other hand, vaccine models provide an interesting approach to study more subtle inflammatory changes and their effect on mood and behavior.
Providing participants with a flu shot is one vaccine model used to study inflammation-induced changes in behaviour (Khulman K. R. et al., 2018). However, we still do not have a clear picture on how a flu shot affects different aspects of sickness behaviour. A recent study addressed this, by conducting a randomised controlled trial investigating how a vaccine injection affects cytokine levels in blood plasma, as well as experienced sickness behaviour (Jolink T and Feldman M. et al., 2025).
Immune activation from vaccines trigger a necessary immune response in the body, helping us build up protection for future encounters with pathogens.
Methods
In this study, Tatum Jolink, Mallory Feldman and colleagues (2025) conducted a randomised, double-blind placebo-controlled trial. A total of 52 participants received an influenza vaccine injection, and 50 participants received a saline injection (placebo). Just prior to the injection, participants provided a baseline blood sample. Twenty-four hours after the injection, they returned for a second visit, during which they provided an additional blood sample and completed several questionnaires assessing mood and behaviour symptoms.
To assess the inflammatory response, four cytokines were measured: interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Sickness behavior was measured using the Sickness Questionnaire (SicknessQ) as well as with two additional items (fatigue and muscle pain), and mood was assessed with the Positive and Negative Affect Schedule (PANAS-X). Participants also answered questions about their sleep the previous night (i.e., first night post-injection), and their feelings of social disconnect.
Results
Participants who received the influenza vaccine showed higher levels of all four cytokines post-injection compared to those who received the placebo, indicating an inflammatory response to the flu shot. These results align with previous findings suggesting that the influenza vaccine can temporally trigger the body’s immune response (e.g., Kuhlman K.R. et al., 2024).
There was no significant difference between the two groups after the injection in mood, in how they slept the night before, or in how they felt socially connected with others. The influenza vaccine also did not induce any sickness behaviour, as measured with the SicknessQ, though participants who received the influenza vaccine did report greater muscle aches compared to those in the placebo condition. Despite this, in the influenza vaccine group, participant who exhibited a larger increase in TNF-α post-injection, reported feeling more tired, feeling warmer, and less motivated for activities.
The influenza vaccine triggered an inflammatory response, but compared to the placebo group, there were no substantial observed effects on mood or behaviour.
Conclusions
This well-controlled study adds to the growing evidence that the influenza vaccine can be used to study small increases in inflammation. The findings suggest that although the influenza vaccine triggered an immune response, participants who received it did not report feeling sicker compared to the placebo group. Yet, a larger increase in TNF-α after the vaccine injection was associated with certain aspects of sickness behaviour (e.g., tiredness).
In sum, the stronger inflammation-induced sickness behavior typically seen with more intense immune challenges (e.g., Lasselin J. et al., 2021) was absent.
Although the influenza vaccine triggered an immune response, the stronger inflammation-induced sickness behavior typically observed with more intense immune challenges was absent.
Strengths and limitations
A major strength of this study is that it is the first randomised, placebo-controlled trial to investigate the effects of an influenza vaccine on inflammatory markers in blood plasma and how these changes relate to sickness behaviour. The findings therefore strengthen the evidence for using the model to investigate how subtle fluctuations in inflammation can influence mood and behavior. Also, the absence of sickness behaviour in vaccinated individuals indicates that stronger immune challenges may be required to study various aspects of sickness behaviour in humans. This is further supported by the association between higher TNF-α levels after the vaccine and some aspects of sickness behaviour, indicating that stronger immune responses may be needed to trigger such changes. This knowledge may be important for future studies.
As noted by the authors, the study sample was limited in both size and generalisability, as it consisted of young, healthy participants. The limited sample size is particularly concerning given that participants received either the vaccine injection or the placebo injection. Previous research indicates that people react quite differently to inflammatory challenges (e.g., Lasselin J. 2021). A within-subject design, where participants receive the vaccine at one time and the placebo at another time, could have been more advantageous, as it would allow for investigation of vaccine-related changes in various self-reported factors within each individual.
Moreover, although the authors found that the influenza vaccine increased levels of all measured cytokines, the data also show a lot of variations between participants. Some individuals did not show an observable increase in every measured cytokine. Such individual differences are interesting and could be looked at more closely in future studies.
A strength of the study is that it examined how the influenza vaccine affects several aspects such as symptoms, social experiences, sleep, and mood. However, a limitation is that all outcomes were self-reported. Previous research using the influenza vaccine has suggested that this model may be particularly well-suited for studying automatic behaviours (Jolink T. et al., 2022). These behaviours are implicit, as illustrated by measurements such as the reaction time required for a participant to move away from an object or another person. The present randomised controlled trial could therefore have benefited from combining subjective and objective outcomes, which could help to further clarify how this vaccine model differs from stronger immune challenges, and for which research purposes it may be best suited. For example, future studies could include both self-reported and objectively measurable sleep quality or compare self-reported sickness symptoms with observable expressions of sickness.
This study supports the use of vaccine models to explore inflammation’s subtle effects, but highlights key design and measurement limitations that must be address in future studies.
Implications for practice
After reading this post, it is possible that your next vaccine shot will be followed by thoughts of which symptoms that may follow. If it is a flu shot, the presented evidence indicates that although your immune system will be activated, you may not feel differently. Yet, as also noted by the authors, more studies with larger and more diverse samples are needed to fully understand how influenza vaccines affect us.
Understanding how the “dose” of inflammation relates to different aspects of sickness behaviour is important to clarify the function and possible adaptiveness of these behavioral changes (Lindsay, 2022). For example, a mild inflammatory challenge may alter your behaviour in an implicit way, such as increased social approach towards close others (Jolink T. et al., 2022). In contrast, a strong activation of the immune system may be required for you to explicitly express a need for care (Hansson L. et al., 2024). Understanding these differences can help us better grasp inflammation-related health conditions and improve care. For instance, if care-seeking behaviors are only triggered once inflammation reaches a certain threshold, this could be important in health care settings.
Although the inflammation caused by a vaccine injection is adaptive and short-term, helping us build protection for future encounters with pathogens, long-term chronic inflammation can be maladaptive. Chronic inflammation is a well-recognised risk factor for several mental health conditions, including depression and schizophrenia (you can read more about this in these Mental Elf blogs on inflammation). Although the influenza vaccine did not substantially affect the behavior or mood measures assessed here, previous research has demonstrated acute effects on social behaviour (Jolink T. et al., 2022) and depressive symptoms (Khulman K. R. et al., 2018). Thus, this model can be used to help us understand the mechanisms by which inflammation contributes to different mental health conditions.
This study supports the use of vaccine models to explore inflammation’s subtle effects but highlights key design and measurement limitations that must be address in future studies.
Statement of interests
Dr. Muscatell was the opponent at my doctoral defence, and we have discussed and submitted a funding application for future collaborations. I used ChatGPT-5 to help check the grammar and to improve the clarity and the style of my initial draft.
Editor
Edited by Éimear Foley. AI tools assisted with language refinement and formatting during the editorial phase.
Links
Primary paper
Jolink, T.A., Feldman, M.J., Antenucci, N.M., Cardenas, M.N., West, T.N., Nakamura, Z.M., Muscatell, K.A., 2025. Effects of a mild inflammatory challenge on cytokines and sickness behavior: A randomized controlled trial using the influenza vaccine. Brain. Behav. Immun. 128, 429–439. https://doi.org/10.1016/j.bbi.2025.04.018
Other references
Dantzer, R., 2001. Cytokine-Induced Sickness Behavior: Where Do We Stand? Brain. Behav. Immun. 15, 7–24. https://doi.org/10.1006/brbi.2000.0613
Hansson, L.S., Tognetti, A., Sigurjónsson, P., Brück, E., Wåhlén, K., Jensen, K., Olsson, M.J., Toll John, R., Wilhelms, D.B., Lekander, M., Lasselin, J., 2024. Perception of unfamiliar caregivers during sickness – Using the new Caregiver Perception Task (CgPT) during experimental endotoxemia. Brain. Behav. Immun. 119, 741–749. https://doi.org/10.1016/j.bbi.2024.04.031
Jolink, T.A., Fendinger, N.J., Alvarez, G.M., Feldman, M.J., Gaudier-Diaz, M.M., Muscatell, K.A., 2022. Inflammatory reactivity to the influenza vaccine is associated with changes in automatic social behavior. Brain. Behav. Immun. 99, 339–349. https://doi.org/10.1016/j.bbi.2021.10.019
Kuhlman, K.R., Radin, A., Cole, S.W., Bower, J.E., 2024. Psychosocial predictors of the innate immune response to influenza vaccination. Psychoneuroendocrinology 163, 106989. https://doi.org/10.1016/j.psyneuen.2024.106989
Kuhlman, K.R., Robles, T.F., Dooley, L.N., Boyle, C.C., Haydon, M.D., Bower, J.E., 2018. Within-subject associations between inflammation and features of depression: Using the flu vaccine as a mild inflammatory stimulus. Brain. Behav. Immun. 69, 540–547. https://doi.org/10.1016/j.bbi.2018.02.001
Lasselin, J., 2025. Putting oil on the fire: Do people with high inflammation react differently to immune stress? The Mental Elf.
Lasselin, J., 2021. Back to the future of psychoneuroimmunology: Studying inflammation-induced sickness behavior. Brain Behav. Immun. – Health 18, 100379. https://doi.org/10.1016/j.bbih.2021.100379
Lasselin, J., Lekander, M., Benson, S., Schedlowski, M., Engler, H., 2021. Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression. Mol. Psychiatry 26, 3672–3683. https://doi.org/10.1038/s41380-020-00869-2
Lindsay, E.K., 2022. Small “doses” of inflammation initiate social sickness behavior. Brain. Behav. Immun. 102, 40–41. https://doi.org/10.1016/j.bbi.2022.02.012
