Article

BNT162b2 vaccine decreases cytokine responses to heterologous pathogens in children up to six months after vaccination

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). BNT162b2 (Pfizer- BioNTech) and mRNA 1273 (Moderna) vaccines were the first messenger RNA (mRNA)-based vaccines ever approved. In both vaccines, a mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 spike (S) glycoprotein. In this study, the Australian authors investigated the heterologous and specific immunological effects in children aged 5 to 11 years who received two doses of BNT162b2 COVID-19 vaccine.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. The S protein is a glycosylated homotrimer with each monomer composed of subunits S1 and S2, separated by host cell proteases. The S1 domain comprises the N-terminal domain (NTD), the receptor binding domain (RBD) with a receptor binding motif (RBM), and two C-terminal domains.

About the study

The COSI BAIR is a single-arm clinical trial in which all participants received two doses of the BNT162b2 vaccine (Pfizer, USA), 8 weeks apart. COSI BAIR participants were a subgroup of the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) randomized controlled trial, aimed to investigate whether neonatal BCG vaccination can protect children from infections, allergies, and asthma in childhood. Neonates were randomly assigned to receive or not receive the BCG vaccine in the first ten days of life. Participants from both groups were recruited for the COSI BAIR study.

The study included 29 children. The age limit was five to eleven years. The exclusion criteria were hypersensitivity to the BNT162b2, previous COVID-19 vaccination, previous COVID-19 confirmed by polymerase chain reaction, clinically significant illness, and receipt of BCG vaccine outside the MIS BAIR trial.

The paired blood samples were taken from participants, the first was taken immediately before the first BNT162b2 vaccination, and the second 28 days after the second BNT162b2 vaccination. The samples from eight children were taken 6 months after the second BNT162b2 vaccination. The researchers used whole blood stimulation assay to examine in vitro cytokine responses to heterologous stimulants, such as SARS-CoV-2 antigens, Toll-like receptor agonists and killed pathogens like heat-killed (HK) Haemophilus influenzae type B, HK Listeria monocytogenes, BCG, HK Staphylococcus aureus, HK Escherichia coli, hepatitis B virus surface antigen, and HK Candida albicans.

The supernatants were analyzed using a cytokine assay that enabled the detection of 27 pro-inflammatory and anti-inflammatory cytokines and chemokines, such as eotaxin, basic fibroblast growth factor basic (FGF), granulocyte-colony stimulation factor (G‐CSF), granulocyte-macrophage colony-stimulating factor (GM‐CSF), interferon-γ (IFN‐γ), interleukin (IL)‐1β, IL‐1rα, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐9, IL‐10, IL‐12(p70), IL‐13, IL‐15, IL‐17, IFN-γ-induced protein (IP‐10), monocyte chemoattractant protein (MCP‐1), macrophage inflammatory protein (MIP)‐1α, MIP‐1β, platelet-derived growth factor-BB (PDGF‐BB), regulated upon activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-α (TNF‐α) and vascular endothelial growth factor (VEGF).

The SARS-CoV-2 S protein and its RBD were quantified by ELISA.

Results

Results one month after the second dose of the BNT162b2 vaccine

At 28 days after the second dose of the BNT162b2 vaccine, cytokine and chemokine responses to bacterial, fungal, viral, and Toll-like receptor agonist stimulation showed a general decrease compared to responses before the vaccination. The largest decreases were observed for IFN-γ and MCP-1.

A stimulation with BCG, H. influenzae, S. aureus, hepatitis B antigen, poly (I: C), and R848 decreased the responses of IL-6, IL-15, and IL-17. Stimulation with L. monocytogenes decreased the responses of IL-15, TNF-α, and IP-10, whereas H. Influenzae and S. aureus stimulation decreased the response of IL-8. RANTES was the only analyte that increased in response to heterologous stimulants (L. monocytogenes and C. albicans) 28 days after the second dose of the BNT162b2 vaccine.

These results demonstrated that the BNT162b2 vaccine in children decreased the responses of inflammatory cytokines (IFN-γ, MCP-1, IL-6, IL-8, and IL-15) to heterologous bacterial, fungal, and viral stimulation.

In contrast, at 28 days after the second dose of the BNT162b2 vaccine, cytokine and chemokine responses to SARS-CoV-2-specific stimuli were increased compared to the responses before the vaccination. The largest increases were observed in the responses of IL-6, IL-15, GM-CSF, IL-10, IL-12p70, IL-2, and IL-13, as well as of chemokines MIP-1β and RANTES to irradiated SARS-CoV-2, S1 and S2 subunit stimulation. The responses of TNF-α, G-CSF, PDGF-BB, VEGF, FGF-basic, IL-4, IL-17, and IP-10 increased following stimulation with S1 and S2 subunits.

MCP-1 was the only analyte that decreased following the SARS-CoV-2-specific stimulation with N protein or irradiated SARS-CoV-2. 

Of note, the analysis of participants who did not receive the BCG vaccination in the MIS BAIR trial revealed that the BCG status had a negligible or no effect on cytokine responses after the BNT162b2 vaccination.

 

Results six months after the second dose of the BNT162b2 vaccine

This analysis included eight children who had samples before the first BNT162b2 vaccination and 6 months after the second BNT162b2 vaccination and remained negative for the SARS-CoV-2 N protein.

The results showed a sustained decrease in cytokine response to viral stimulants, but not to bacterial stimulants six months after the second BNT162b2 vaccination compared to the response before the vaccination.

The responses of IL-6, IL-15, TNF-α, GM-CSF, PDGF-BB, VEGF, FGF-basic, IL-10, IFN-γ, IL-2, IL-4, IL-5, IL-9, IL-13, and eotaxin decreased after hepatitis B antigen and poly (I: C) stimulation. Hepatitis B antigen stimulation decreased the responses of IL-1β, IL-12p70, IL-17, and MIP-1β, whereas Poly (I: C) stimulation decreased the responses of IL-1ra, IL-7, and MIP-1α.

C. albicans stimulation decreased the responses of MCP-1 and eotaxin but increased the responses of IL-1β, IL-1ra, IL-8, FGF-basic, IL-12p70, IL-8, and MIP-1. Bacterial stimulations, like BCG, E. coli, H. influenza, and L. monocytogenes increased the response of IL-8. Stimulation with E. coli and H. influenzae increased the responses of TNF-α and G-CSF. BCG stimulation increased the response of RANTES but decreased the response of IP-10.

The response of IL-1β was markedly increased with R848 stimulation.

Importantly, the responses of most cytokines and chemokines, like IL-1β, IL-1ra, IL-6, G-CSF, GM-CSF, VEGF, FGF-basic, IFN-γ, IL-2, IL4, IL-5, IL-17, MIP-1α, and MIP-1β to SARS-CoV-2-specific stimuli remained higher six months after the second BNT162b2 vaccination. Also, stimulation with the SARS-CoV-2 N protein increased the responses of 22/27 cytokines and chemokines.

The correlation between SARS-CoV-2-specific immunity and heterologous cytokine responses

Titers of anti-S protein and anti-RBD total IgG antibodies were measured before the first BNT162b2 vaccination and 28 days and 6 months after the second BNT162b2 vaccination. All participants had robust anti-S protein and anti-RBD IgG antibody titers 28 days after the second BNT162b2 vaccination, and these titers positively correlated.

However, the titer of anti-RBD IgG antibody did not correlate with a cytokine response to heterologous stimulation. This suggests that changes in cytokine responses to heterologous stimulants were unrelated to the specific antibody response to the vaccine.

Conclusion

This study demonstrated that the BNT162b2 mRNA vaccine alters cytokine responses to heterologous stimulants, like killed pathogens, Toll-like receptor agonists, and SARS-CoV-2 antigens in children, and that these effects can persist for up to six months after vaccination. Notably, decreased immune response to other pathogens makes children more susceptible to other infections. Accordingly, these findings highlight the need for further investigation and consideration of vaccination policy.

This article was published in the Frontiers in Immunology.

Journal Reference

Noé A, Dang TD, Axelrad C, Burrell E, Germano S, Elia S, Burgner D, Perrett KP, Curtis N and Messina NL (2023) BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists. Front. Immunol. 14:1242380. (Open Access)  https://doi.org/10.3389/fimmu.2023.1242380

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