The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines are examples of monovalent mRNA vaccines that stimulate mRNA to produce viral spike (S) protein, which then triggers an immune response. COVID-19 vaccines elicit both the innate and adaptive immune responses. The immune system stimulation results in the secretion of cytokines, which facilitate cell signaling and immune regulation. In this longitudinal study, the authors from Saudi Arabia investigated the cytokine profile changes in young individuals who had been vaccinated with mRNA-type COVID-19 vaccines at least one year before.
Previous studies provided clear histological evidence of off-target biodistribution of genetic vaccines, leading to the synthesis of S proteins and potentially triggering autoimmune and inflammatory responses. These effects are detectable in the cerebral and myocardial tissues, which can lead to clinically evident pathological damage. Therefore, some authors emphasized the need for biodistribution studies and specific benefit-harm assessment for COVID-19 genetic vaccines.
About the study
Participants were recruited in November 2020, before the start of the COVID-19 vaccination campaign. Individuals with chronic diseases were excluded from the study. Anthropometric measurements included height, weight, body mass index (BMI), waist and hip circumferences, and blood pressure.
All subjects in this study were vaccinated with the Pfizer mRNA vaccine. After receiving their second booster dose, adolescents were followed up for an average of 14.1 ± 3.6 months and adults for an average of 13.3 ± 3.0 months. During the follow-up, participants underwent routine blood sample collection procedures and anthropometric assessments.
A total of 18 serum cytokines, including epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), interferon-gamma (IFN-γ), interleukin-1 alpha (IL-1α), IL-1β, IL-4, IL-6, IL-7, IL-13, IL-17E, IL-17F, monocyte chemoattractant protein-1 (MCP1), MCP3, macrophage colony-stimulating factor (MCSF), platelet-derived growth factor (PDGF-AA), transforming growth factor-alpha (TGF-α), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF)-A were assessed using multiplex assay kits.
Results
84 subjects ( 36 males and 48 females) participated in this study with a mean age of 27.2 ± 12.3 years. Female participants were significantly older than male participants.
Serum cytokine levels
All participants who had been vaccinated with the last dose of the Pfizer vaccine before 4 months or less, showed a significant increase in serum levels of cytokines, chemokines, and growth factors, including EGF, FGF2, IFN-γ, IL-1β, IL-4, IL-6, IL-7, IL-17E, MCP1, MCP3, TNF-α, and VEGF-A. A reduction after vaccination was only observed for MCSF. When adjusted for age, EGF, IL-4, IL-6, MCP3, TNF-α, and VEGFA remained statistically significant. In participants vaccinated with the last dose of the Pfizer vaccine before 5 months or more, only TNF-α, IL-4, MCP3, and VEGFA concentrations were significantly elevated.
The cytokines that have been shown to persist for months after COVID-19 vaccination play different roles in the immune response and inflammation. EGF and FGF2 are involved in cellular proliferation and wound healing, contributing to tissue repair. IFN-γ and TNF-α are key players in promoting Th1 immune responses, enhancing the activation of macrophages and cytotoxic T-cells. IL-6 and IL-1β, are associated with inflammation, and, IL-4 and IL-13 are crucial for Th2 responses. It has been reported that post-acute sequelae of COVID-19 are associated with a triad of IL-1β, IL-6, and TNF-α. MCPs facilitate the recruitment of immune cells to sites of inflammation, while MCSF supports the survival and proliferation of macrophages.
Age and gender differences
A gender-specific analysis showed a more significant increase in pro-inflammatory cytokines, including IL-4, IL-6, and TNF-α in men than women.
Age-specific analysis showed that older adults experienced a more pronounced increase in EGF, IL-6, MCP1, and TNF-α. Adolescents had a greater increase in only VEGF-A, which induces the proliferation and migration of vascular endothelial cells and is essential for physiological and pathological angiogenesis. Interestingly, a study that investigated cytokine responses to heterologous pathogens, Toll-like receptor agonists, and SARS-CoV-2 antigens in children aged 5 to 11 years vaccinated with two doses of the BNT162b2 mRNA COVID-19 vaccine, found an increased in vitro response of VEGF after stimulation with the S1 and S2 subunits of the S protein one and six months after the second BNT162b2 vaccination. https://discovermednews.com/mrna-covid19-vaccine-decreases-responses-to-heterologous-pathogens-in-children/ Also, previous data emphasized that S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the VEGF-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors and be responsible for diffuse microvascular and neurological damage. (Talotta, R. Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects? Microorganisms 2022, 10, 2452. https://www.mdpi.com/2076-2607/10/12/2452)
In addition, a study that correlated biomarkers of endothelial dysfunction with pulmonary function test in 137 patients with long COVID and 20 healthy volunteers found that long COVID patients had increased levels of biomarkers related to angiogenesis and von Willebrand factor (VWF) without increased inflammatory or platelet activation markers. VEGF-A and VWF were associated with persistent CT findings of pulmonary lesions and impaired diffusing capacity for carbon monoxide (DLCO) measurement. Moreover, following adjustment for age, sex, and body mass index, VEGF-A emerged as the most significant predictive factor associated with pulmonary CT lesions and impaired DLCO measurement. (Philippe A et al. VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients. Angiogenesis 2024; 27, 51–66. https://doi.org/10.1007/s10456-023-09890-9)Â
Conclusion
This longitudinal study investigated the effects of mRNA COVID-19 vaccination on the cytokine profiles in young adults. The results showed increased cytokine levels even one year after vaccination. Furthermore, the results indicated differences in cytokine levels based on gender and age. There was an increase in pro-inflammatory cytokines in men and adults compared to women and adolescents.
According to the authors, these results could be related to the persistent production of the spike protein, the highly inflammatory nature of mRNA-LNP, and the persistent stimulation of the immune system.
This article was published in Immunity, Inflammation and Disease.
Journal Reference
Alghamdi A, Hussain SD, Wani K et al. Altered Circulating Cytokine Profile Among mRNA-Vaccinated Young Adults: A Year-Long Follow-Up Study.Immunity, Inflammation and Disease, 2025; 13: e70194. https://doi.org/10.1002/iid3.70194
