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medRxiv

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination

View ORCID ProfileBornaliBhattacharjee,PeiwenLu,Valter SilvaMonteiro,AlexandraTabachnikova,KexinWang,William B.Hooper,VictoriaBastos,KerrieGreene,View ORCID ProfileMitsuakiSawano,ChristianGuirgis,Tiffany J.Tzeng,FrederickWarner,PavlinaBaevova,KathyKamath,JackReifert,DaniceHertz,BrianneDressen,LauraTabacof,JamieWood,LilyCooke,MackenzieDoerstling,ShadanNolasco,AmerAhmed,AmyProal,DavidPutrino,LeyingGuan,View ORCID ProfileHarlan M.Krumholz,View ORCID ProfileAkikoIwasaki
doi: https://doi.org/10.1101/2025.02.18.25322379
Bornali Bhattacharjee
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
Peiwen Lu
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
Valter Silva Monteiro
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
Alexandra Tabachnikova
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
Kexin Wang
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
11Department of Biostatistics, Yale School of Public Health, New Haven, CT,USA
William B. Hooper
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
Victoria Bastos
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
Kerrie Greene
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
Mitsuaki Sawano
3Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale New Haven Hospital Center for Outcomes Research and Evaluation, Yale New Haven Hospital, CT,USA
Christian Guirgis
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
4Department of Molecular, Cellular, and Developmental Biology, Yale College, New Haven, CT,USA
Tiffany J. Tzeng
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
Frederick Warner
3Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale New Haven Hospital Center for Outcomes Research and Evaluation, Yale New Haven Hospital, CT,USA
5Department of Internal Medicine, Yale School of Medicine, New Haven, CT,USA
Pavlina Baevova
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
Laura Tabacof
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Jamie Wood
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Lily Cooke
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Mackenzie Doerstling
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Shadan Nolasco
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Amer Ahmed
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Amy Proal
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
10Polybio Research Foundation, Boston, MA,USA
David Putrino
9Cohen Center for Recovery from Complex Chronic Illness, Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York City, NY,USA
Leying Guan
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
11Department of Biostatistics, Yale School of Public Health, New Haven, CT,USA
Harlan M. Krumholz
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
3Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale New Haven Hospital Center for Outcomes Research and Evaluation, Yale New Haven Hospital, CT,USA
12Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT,USA
Akiko Iwasaki
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT,USA
2Center for Infection and Immunity, Yale School of Medicine, New Haven, CT,USA
13Howard Hughes Medical Institute, Chevy Chase, MD,USA
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SUMMARY

COVID-19 vaccines have prevented millions of COVID-19 deaths. Yet, a small fraction of the population reports a chronic debilitating condition after COVID-19 vaccination, often referred to as post- vaccination syndrome (PVS). To explore potential pathobiological features associated with PVS, we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study. Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls. These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches.

Competing Interest Statement

In the past three years, H.M.K. received expenses and/or personal fees from United Health, Element Science, Eyedentifeye and F-Prime; he is a co-founder of Refactor Health, HugoHealth and MedRxiv; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare & Medicaid Services and through Yale University from the Food and Drug Administration, Johnson & Johnson, Google and Pfizer. A.I. co-founded and consults for RIGImmune, Xanadu Bio and PanV and is a member of the Board of Directors of Roche Holding and Genentech. B.D. reports being a plaintiff in a lawsuit against AstraZeneca alleging breach of contract following her volunteer participation in 2020 in their COVID-19 vaccine clinical trial. She is also a co-chair of REACT19, a non-profit organization offering financial, physical, and emotional support for those suffering from long term COVID-19 vaccine adverse events. D.H serves on the Advisory Board of REACT19.

Funding Statement

This study was funded in part by the Howard Hughes Medical Institute Collaborative COVID-19 Initiative.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Yale University Institutional Review Board on April 1, 2022 (HIC# 2000032207). Informed consent was provided by participants electronically. Each participant was assigned a unique identifier as part of the de-identification protocol managed by the study coordinator. These identifiers were kept confidential and were not accessible to anyone outside the research team. A subset of the MY-LC cohort approved by the Mount Sinai Program for the Protection of Human Subjects (#20-01758) were included for validation of one of the assays.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

  • This version of the manuscript has been revised for:1. We have added additional COI information.2. Deleted the word "health" which was repeated twice on page 26 (Inclusion and Exclusion Criteria).3. Lines 112-113: "...whereas the control cohort consisted of 22 participants with 11 from each biological sex" has been corrected and reads "whereas the control cohort consisted of 22 112 participants, including 13 females and 9 males".

Data Availability

The flow data repository ID is FR-FCM-Z8FZ for all the raw .fcs files generated for flow cytometry analyses at the Flow Repository platform. Custom codes used for computational analyses will be made available by authors upon reasonable request.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted February 25, 2025.
Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination
BornaliBhattacharjee,PeiwenLu,Valter SilvaMonteiro,AlexandraTabachnikova,KexinWang,William B.Hooper,VictoriaBastos,KerrieGreene,MitsuakiSawano,ChristianGuirgis,Tiffany J.Tzeng,FrederickWarner,PavlinaBaevova,KathyKamath,JackReifert,DaniceHertz,BrianneDressen,LauraTabacof,JamieWood,LilyCooke,MackenzieDoerstling,ShadanNolasco,AmerAhmed,AmyProal,DavidPutrino,LeyingGuan,Harlan M.Krumholz,AkikoIwasaki
medRxiv2025.02.18.25322379;doi: https://doi.org/10.1101/2025.02.18.25322379
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