Rapid transient and longer-lasting innate cytokine changes associated with adaptive immunity after repeated SARS-CoV-2 BNT162b2 mRNA vaccinations

Margherita Rosati; Evangelos Terpos; Philip Homan; Cristina Bergamaschi; Sevasti Karaliota; Ioannis Ntanasis-Stathopoulos; Santhi Devasundaram; Jenifer Bear; Robert Burns; Tina Bagratuni; Ioannis P Trougakos; Meletios A Dimopoulos; George N Pavlakis; Barbara K Felber

doi:10.3389/fimmu.2023.1292568

Rapid transient and longer-lasting innate cytokine changes associated with adaptive immunity after repeated SARS-CoV-2 BNT162b2 mRNA vaccinations

Front Immunol. 2023 Nov 27:14:1292568. doi: 10.3389/fimmu.2023.1292568. eCollection 2023.

Authors

Affiliations

¹ Human Retrovirus Pathogenesis Section, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.
² Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
³ Center for Cancer Research Collaborative Bioinformatics Resource, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States.
⁴ Basic Science Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States.
⁵ Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.

Abstract

Introduction: Cytokines and chemokines play an important role in shaping innate and adaptive immunity in response to infection and vaccination. Systems serology identified immunological parameters predictive of beneficial response to the BNT162b2 mRNA vaccine in COVID-19 infection-naïve volunteers, COVID-19 convalescent patients and transplant patients with hematological malignancies. Here, we examined the dynamics of the serum cytokine/chemokine responses after the 3^rd BNT162b2 mRNA vaccination in a cohort of COVID-19 infection-naïve volunteers.

Methods: We measured serum cytokine and chemokine responses after the 3^rd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in COVID-19 infection-naïve individuals by a chemiluminescent assay and ELISA. Anti-Spike binding antibodies were measured by ELISA. Anti-Spike neutralizing antibodies were measured by a pseudotype assay.

Results: Comparison to responses found after the 1^st and 2^nd vaccinations showed persistence of the coordinated responses of several cytokine/chemokines including the previously identified rapid and transient IL-15, IFN-γ, CXCL10/IP-10, TNF-α, IL-6 signature. In contrast to the transient (24hrs) effect of the IL-15 signature, an inflammatory/anti-inflammatory cytokine signature (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, IL-1Ra) remained at higher levels up to one month after the 2^nd and 3^rd booster vaccinations, indicative of a state of longer-lasting innate immune change. We also identified a systemic transient increase of CXCL13 only after the 3^rd vaccination, supporting stronger germinal center activity and the higher anti-Spike antibody responses. Changes of the IL-15 signature, and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3^rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses.

Conclusion: These data revealed that repeated SARS-Cov-2 BNT162b2 mRNA vaccination induces both rapid transient as well as longer-lasting systemic serum cytokine changes associated with innate and adaptive immune responses.

Clinical trial registration: Clinicaltrials.gov, identifier NCT04743388.

Keywords: CXCL10/IP10; CXCL13; IFN-g; IL-15; Innate immunity; TNF-a; anti-spike neutralizing antibody; myeloid cell biomarkers.

Publication types

Comment

MeSH terms

Adaptive Immunity
Anti-Inflammatory Agents
BNT162 Vaccine
COVID-19* / prevention & control
Cytokines*
Humans
Interleukin-15
SARS-CoV-2
Vaccination

Substances

Cytokines
BNT162 Vaccine
Interleukin-15
Anti-Inflammatory Agents

Associated data

ClinicalTrials.gov/NCT04743388

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by funding from the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research to BF. The funders had no role in the experimental design, collection of data or writing the paper.