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Randomized Controlled Trial
. 2023 Sep;4(9):e692-e703.
doi: 10.1016/S2666-5247(23)00171-4. Epub 2023 Aug 7.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study

Xianming Zhu  1 , Kelly A Gebo  2 , Alison G Abraham  3 , Feben Habtehyimer  2 , Eshan U Patel  4 , Oliver Laeyendecker  5 , Thomas J Gniadek  6 , Reinaldo E Fernandez  2 , Owen R Baker  2 , Malathi Ram  4 , Edward R Cachay  7 , Judith S Currier  8 , Yuriko Fukuta  9 , Jonathan M Gerber  10 , Sonya L Heath  11 , Barry Meisenberg  12 , Moises A Huaman  13 , Adam C Levine  14 , Aarthi Shenoy  15 , Shweta Anjan  16 , Janis E Blair  17 , Daniel Cruser  18 , Donald N Forthal  19 , Laura L Hammitt  20 , Seble Kassaye  21 , Giselle S Mosnaim  22 , Bela Patel  23 , James H Paxton  24 , Jay S Raval  25 , Catherine G Sutcliffe  20 , Matthew Abinante  26 , Patrick Broderick  27 , Valerie Cluzet  28 , Marie Elena Cordisco  27 , Benjamin Greenblatt  29 , Joann Petrini  27 , William Rausch  27 , David Shade  4 , Karen Lane  30 , Amy L Gawad  31 , Sabra L Klein  31 , Andrew Pekosz  31 , Shmuel Shoham  2 , Arturo Casadevall  31 , Evan M Bloch  1 , Daniel Hanley  30 , David J Sullivan  31 , Aaron A R Tobian  32
Affiliations
Randomized Controlled Trial

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study

Xianming Zhu et al. Lancet Microbe. 2023 Sep.

Abstract

Background: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection.

Methods: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta).

Findings: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations.

Interpretation: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals.

Funding: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

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Conflict of interest statement

Declaration of interests KAG reports consultancy work for the Aspen Institute, Teach for America, serving as a non-paid member of a scientific advisory board for Pfizer, and writing COVID-19 management guidelines for UpToDate. AGA reports consultancy work for Implementation Group, Hirslanden Klinik, and Elsevier. ERC reports receiving unrestricted research grants from Gilead and Merck paid to the Regents of the University of California and participating in an advisory board to Theratechnologies for an unrelated topic. JSC reports consultancy work for Merck and Company in 2021. TJG reports employment by Fenwal, a Fresenius Kabi Company. LLH reports research funding to Johns Hopkins Center of American Indian Health from AstraZeneca, US Centers for Disease Control and Prevention, Merck, NIH, and Pfizer. MAH reports contracts from Gilead Sciences, Insmed, and AN2 Therapeutics to the University of Cincinnati. GSM reports research grant support from Teva, Alk-Abello, Genentech, Novartis, GlaxoSmithKline, and Sanofi-Regeneron, serving as an immediate past president of the American Academy of Allergy Asthma and Immunology, and is co-chair of the Continuous Assessment Program Examination for the American Board of Allergy and Immunology. BP reports participating in part of the COVID-19 trials and pulmonary arterial hypertension trials. JHP reports research funding from MindRhythm. JSR is a consultant and advisor with Sanofi Genzyme, and a board of directors member with the American Society for Apheresis. SK reports helping to produce educational materials related to HIV with Integritas Communications and Vindico Medical Education. AC reports serving on the scientific advisory board of SAB Biotherapeutics. EMB reports personal fees and non-financial support from Terumo BCT, Abbott Laboratories, Tegus, and UptoDate, is a member of the US Food and Drug Administration Blood Products Advisory Committee, and served on a convalescent plasma guideline panel. DH reports personal fees from Neurelis, Neurotrope, and medicolegal consulting. DJS is a founder and board member with stock options (macrolide for malaria) for AliquantumRx and reports consulting for Hemex Health and royalties for malaria diagnostic test control standards to Alere. SLH reports serving on the data monitoring committee for Pfizer. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Baseline cytokine and chemokine concentrations, stratified by vaccination status at screening
IFN=interferon. IL=interleukin. IP-10=inducible protein-10. MCP-1=monocyte chemoattractant protein-1. MIP-1α=macrophage-inflammatory protein-1α. TNF-α=tumour necrosis factor-α. VCAM-1=vascular cell adhesion molecule-1. VEGF-A=vascular endothelial growth factor-A. *p values were calculated from student t tests, using log10 transformed cytokine and chemokine concentrations. Concentration differences between groups were considered significant after adjusting for multiple comparison using Bonferroni correction when p<0·0024. Significant p values are marked in red.
Figure 2:
Figure 2:. Day 90 cytokine and chemokine concentrations, stratified by day 90 vaccination status
*p values were calculated from student t tests, using log10 transformed cytokine and chemokine concentrations. Concentration differences between groups were considered significant after adjusting for multiple comparison using Bonferroni correction when p<0·0024. Significant p values are marked in red. IFN=interferon. IL=interleukin. IP-10=inducible protein-10. MCP-1=monocyte chemoattractant protein-1. MIP-1α=macrophage-inflammatory protein-1α TNF-α=tumour necrosis factor-α. VCAM-1=vascular cell adhesion molecule-1. VEGF-A=vascular endothelial growth factor-A.
Figure 3:
Figure 3:. Differences in cytokine and chemokine concentrations between unvaccinated and fully vaccinated participants at screening, day 14, and day 90
Each analyte had a separate mixed effect model, and all the models were adjusted for age, sex, BMI, hypertension, diabetes, trial groups, and COVID-19 waves. Trial groups were not adjusted at screening, since participants were transfused after screening. Among the covariates, only BMI has missing data, and the prevalence of missingness was 5%. Available case method was used to handle missing data. Significance after adjusting for multiple comparison using Bonferroni correction was defined by a p value cutoff of 0·0024. IFN=interferon. IL=interleukin. IP-10=inducible protein-10. MCP-1=monocyte chemoattractant protein-1. MIP-1α=macrophage-inflammatory protein-1α TNF-α=tumour necrosis factor-α. VCAM-1=vascular cell adhesion molecule-1. VEGF-A=vascular endothelial growth factor-A.
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