Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID

Connor B Grady; Bornali Bhattacharjee; Julio Silva; Jillian Jaycox; Lik Wee Lee; Valter Silva Monteiro; Mitsuaki Sawano; Daisy Massey; César Caraballo; Jeff R Gehlhausen; Alexandra Tabachnikova; Tianyang Mao; Carolina Lucas; Mario A Peña-Hernandez; Lan Xu; Tiffany J Tzeng; Takehiro Takahashi; Jeph Herrin; Diana Berrent Güthe; Athena Akrami; Gina Assaf; Hannah Davis; Karen Harris; Lisa McCorkell; Wade L Schulz; Daniel Griffin; Hannah Wei; Aaron M Ring; Leying Guan; Charles Dela Cruz; Harlan M Krumholz; Akiko Iwasaki

doi:10.1038/s43856-025-00829-3

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID

Commun Med (Lond). 2025 May 9;5(1):163. doi: 10.1038/s43856-025-00829-3.

Authors

Connor B Grady^#^{1

2}, Bornali Bhattacharjee^#^{3

4}, Julio Silva^#³, Jillian Jaycox³, Lik Wee Lee⁵, Valter Silva Monteiro³, Mitsuaki Sawano⁶, Daisy Massey⁶, César Caraballo^{6

7}, Jeff R Gehlhausen³, Alexandra Tabachnikova³, Tianyang Mao³, Carolina Lucas³, Mario A Peña-Hernandez^{3

8}, Lan Xu³, Tiffany J Tzeng³, Takehiro Takahashi³, Jeph Herrin⁷, Diana Berrent Güthe⁹, Athena Akrami^{10

11}, Gina Assaf¹¹, Hannah Davis¹¹, Karen Harris⁹, Lisa McCorkell¹¹, Wade L Schulz^{4

6

12}, Daniel Griffin¹³, Hannah Wei¹¹, Aaron M Ring³, Leying Guan^{4

14}, Charles Dela Cruz^{4

8

15}, Harlan M Krumholz^{4

6

16

17}, Akiko Iwasaki^{18

19

20}

Affiliations

¹ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
⁴ Center for Infection and Immunity, Yale School of Medicine, New Haven, CT, USA.
⁵ Adaptive Biotechnologies, Seattle, WA, USA.
⁶ Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA.
⁷ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁸ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
⁹ Survivor Corps, Washington, DC, USA.
¹⁰ Sainsbury Wellcome Centre, University College London, London, UK.
¹¹ Patient-Led Research Collaborative, Washington, DC, USA.
¹² Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
¹³ Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York City, NY, USA.
¹⁴ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
¹⁵ Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
¹⁷ Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. akiko.iwasaki@yale.edu.
¹⁹ Center for Infection and Immunity, Yale School of Medicine, New Haven, CT, USA. akiko.iwasaki@yale.edu.
²⁰ Howard Hughes Medical Institute, Chevy Chase, MD, USA. akiko.iwasaki@yale.edu.

^# Contributed equally.

Abstract

Background: The symptomatic and immune responses to COVID-19 vaccination of people with Long COVID are poorly characterized.

Methods: In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.

Results: At 12 weeks post-vaccination, self-reported improved health is seen in 10 out of 16 participants, 3 have no change, and 3 have worse health although 2 report transient improvement after vaccination. One participant reporting worse health was hospitalized twice with chest pain (after each dose). Symptom outcomes are most associated with plasma biosignatures. Higher baseline sIL-6R is associated with symptom improvement, and stably elevated levels of IFN-β and CNTF are associated with no improvement. Significant elevation in SARS-CoV-2-specific TCRs and spike protein-specific IgG are observed at 6 and 12 weeks after vaccination. No changes in reactivities are observed against herpes viruses and self-antigens.

Conclusions: In this study of 16 people with Long COVID, vaccination is associated with increased SARS-CoV-2 spike protein-specific IgG and T cell expansion in most participants. Specific immune features are associated with symptom change after vaccination and most participants experience improved health or no change following vaccination.

Plain language summary

The impact of the COVID-19 vaccine on unvaccinated individuals suffering from Long COVID is uncertain. This study assessed the experience and biological markers of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health after vaccination, three reported worsening health, with one hospitalized twice with chest pain. Vaccination boosted the body’s immune responses against the virus that causes COVID-19. We identified biological markers that correlate with the changes in overall health after vaccination. Given that the study was small, more research is needed to confirm these results.

Abstract

Plain language summary

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