Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Controls
2.3. Validation of SARS-CoV-2 Vaccination and Infection
2.4. Ethics
2.5. Laboratory Measurements
2.6. Statistical Methods
3. Results
3.1. Impact of SARS-CoV-2 Vaccination on Receptor Antibodies in Healthy Controls
3.2. GPCR Antibodies in Post-Vaccination Controls and PACVS-Affected Subjects
3.3. Discrimination of PACVS from Post-Vaccination Controls Based on Interleukins
3.4. Exclusion of SARS-CoV-2 Infection/COVID-19 Reconvalescence as Confounder of PACVS
4. Discussion
4.1. Salient Findings
- In healthy persons not affected by PACVS, the repertoire of receptor antibodies involved in cardiovascular regulation and immune homeostasis undergoes long-term adjustment following SARS-CoV-2 mRNA vaccination.
- The above adjustment seems blunted, absent or even inversed in persons who present clinical phenotypes of PACVS after SARS-CoV-2 mRNA vaccination.
- PACVS-afflicted persons can be distinguished from individuals subjected to SARS-CoV-2 mRNA vaccination without developing PACVS based on serum levels of IL-6/IL-8 and antibodies against AT1R and α2b-adr-R.
4.2. Limitations
- Our study is restricted to SARS-CoV-2 mRNA vaccines, for which we had an appropriate control cohort. Whether our findings apply to chronic sequelae following other types of SARS-CoV-2- vaccinations, or even vaccinations in general, remains to be investigated.
- The clinical PACVS phenotype studied here is based on a long list of symptoms. It is heterogeneous and possibly encompasses more than one clinical entity. Moreover, the selection of studied PACVS cases is biased by the exclusion of 71 applicants with potentially confounding co-morbidities or medications who could nevertheless suffer from PACVS.
- The PACVS cohort was recruited five or more months after vaccination. Matching pre-vaccination sera from these same persons could not be obtained. Consequently, vaccination-associated serological alterations in the PACVS cohort could not be determined intra-individually but had to be judged by comparing with a matched post-vaccination control cohort.
- Receptor antibodies were determined by IgG binding to the native receptors. We and others have previously demonstrated that such antibodies can modulate receptor function in several ways [38]; however, the functional properties of receptor antibodies were not directly assessed in this study.
- Our observation has been limited to a period of 5–6 months after vaccination. We do not know how long the observed effects last beyond this period.
4.3. The Physiological Response of Receptor Antibodies to SARS-CoV-2 mRNA Vaccination
- Downregulation of a cluster of receptor antibodies targeting the renin–angiotensin–aldosterone system and other components of cardiovascular regulation. Incidentally, some of these receptor antibodies are frequently increased in POTS [20,23,24], ME/CFS [18,22,25], severe COVID-19 [28,29,30,31,32], chronic heart failure [39,40] and allograft rejection [41]. The most distinctive candidate of this cluster is the AT1R antibody.
- Two receptor antibodies were upregulated. One of these, the IL-1-Rb antibody, is thought to play a role in immune homeostasis [35] and to have a protective effect against certain rheumatic diseases [42]. The α2b-adr-R receptor, on the other hand, plays a role in thrombogenesis and its inhibition by small molecule antagonists counteracts platelet aggregation induced by adenosine diphosphate, epinephrine or arachidonic acid in blood samples of healthy individuals [43].
4.4. Putative Pathogenic Role of Blunted Receptor Antibody Adaptation in PACVS
4.5. The Blood Marker Signature of PACVS
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
α1-adr-R-AB | Alpha-1 adrenergic receptor antibody |
α2a-adr-R-AB | Alpha-2A adrenergic receptor antibody |
α2b-adr-R-AB | Alpha-2B adrenergic receptor antibody |
α2c-adr-R-AB | Alpha-2C adrenergic receptor antibody |
ACE-II-AB | Angiotensin-converting enzyme 2 antibody |
AT1R-AB | Angiotensin II type 1 receptor antibody |
β1-adr-R-AB | Beta-1 adrenergic receptor antibody |
β2-adr-R-AB | Beta-2 adrenergic receptor antibody |
CRP | C-reactive protein |
ETAR-AB | Endothelin-1 type A receptor antibody |
IL-1-Rb-AB | Interleukin-1 receptor type 2 antibody |
IL-6/-8 | Interleukin 6/8 |
M1R-AB | muscarinic acetylcholine receptor M1 |
M2R-AB | muscarinic acetylcholine receptor M2 |
M3R-AB | muscarinic acetylcholine receptor M3 |
M4R-AB | muscarinic acetylcholine receptor M4 |
M5R-AB | muscarinic acetylcholine receptor M5 |
MASR-AB | MAS 1 receptor antibody |
MCAS | Mast cell activation syndrome |
ME/CFS | Myalgic encephalomyelitis/chronic fatigue syndrome |
NAB | PanIg reactivity against SARS-CoV-1 nucleocapsid protein |
pBNP | pro-brain natriuretic peptide |
PEM | Post exertional malaise |
POTS | Postural tachycardia syndrome |
PACVS | Post-acute COVID-19 vaccination syndrome |
ROC | Receiver-operator characteristics |
SAB | PanIg reactivity against SARS-CoV-1 spike S1 protein |
SFN | Small fiber neuropathy |
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Median 1 | 25% Perc. | 75% Perc. | ∆ vs. PACVS (p, U-Test) | |
---|---|---|---|---|
AT1R | ||||
PACVS 2 (n = 191) | 15.2 | 12.1 | 21.3 | - |
Contr. pre 3 (n = 89) | 15.6 | 12.4 | 21.1 | N.S. 5 |
Contr. post 4 (n = 89) | 10.4 | 8.1 | 12.4 | <0.0001 |
ETAR | ||||
PACVS (n = 191) | 13.5 | 10.8 | 18.5 | - |
Contr. pre (n = 99) | 15.4 | 11.6 | 19.5 | N.S. |
Contr. post (n = 89) | 11.0 | 8.8 | 13.8 | 0.0001 |
IL-1-Rb | ||||
PACVS (n = 191) | 4.9 | 3.8 | 6.9 | - |
Contr. pre (n = 89) | 5.1 | 4.2 | 7.2 | N.S. |
Contr. post (n = 89) | 6.2 | 5.3 | 8.2 | <0.0001 |
M3R | ||||
PACVS (n = 191) | 10.6 | 7.9 | 16.4 | - |
Contr. pre (n = 89) | 11.9 | 8.0 | 18.2 | N.S. |
Contr. post (n = 89) | 6.6 | 4.8 | 9.2 | <0.0001 |
β2-adr-R | ||||
PACVS (n = 191) | 12.8 | 8.9 | 16.6 | - |
Contr. pre (n = 89) | 20.9 | 11.2 | 39.6 | N.S. |
Contr. post (n = 89) | 9.3 | 5.8 | 14.4 | <0.0001 |
MASR | ||||
PACVS (n = 191) | 50.2 | 41.7 | 62.1 | - |
Contr. pre (n = 89) | 53.1 | 42.8 | 67.6 | N.S. |
Contr. post (n = 89) | 39.2 | 31.7 | 45.7 | <0.0001 |
M2R | ||||
PACVS (n = 191) | 11.8 | 8.9 | 16.9 | - |
Contr. pre (n = 89) | 16.9 | 11.3 | 27.2 | <0.0001 |
Contr. post (n = 89) | 7.7 | 6.2 | 11.7 | <0.0001 |
α2b-adr-R | ||||
PACVS (n = 191) | 13.8 | 9.9 | 18.6 | - |
Contr. pre (n = 89) | 21.6 | 13.8 | 30.6 | <0.0001 |
Contr. post (n = 89) | 27.9 | 20.9 | 43.2 | <0.0001 |
ROC (AUC ± SE) | ROC (p) | Cut-off (U/mL) 1 | Sensitivity (%) 2 | |
---|---|---|---|---|
AT1R | 0.824 ± 0.027 | <0.0001 | ≤10.7 | 89.7 |
ETAR | 0.681 ± 0.035 | <0.0001 | ≤11.5 | 64.9 |
M3R | 0.741 ± 0.034 | <0.0001 | ≤12.4 | 40.3 |
β2-adr-R | 0.681 ± 0.036 | <0.0001 | ≤11.6 | 66.5 |
α2b-adr-R | 0.828 ± 0.025 | <0.0001 | ≥25.2 | 90.3 |
M2R | 0.703 ± 0.034 | <0.0001 | ≥14.2 | 64.4 |
MASR | 0.675 ± 0.037 | <0.0001 | ≤44.0 | 72.3 |
IL-1-Rb | 0.913 ± 0.019 | <0.0001 | ≥5.8 | 66.5 |
IL-6 | 0.850 ± 0.022 | <0.0001 | ≥2.3 | 82.0 |
PACVS ± COVID 1 | PACVS w/o COVID vs. post-vacc. CTR 2 | |||
---|---|---|---|---|
Median Effect Size 3 (%) | Significance (p) 4 | Median Effect Size 3 (%) | Significance (p) 4 | |
AT1R | +12.8 | 0.01 | +43 | <0.0001 |
ETAR | +7.9 | 0.11 | ||
β2-adr-R | +7.2 | 0.07 | ||
M3R | +20.3 | 0.05 | +44.4 | <0.0001 |
IL-1-Rb | +6.3 | 0.08 | ||
α2b-adr-R | +4.8 | 0.50 | ||
M2R | +9.5 | 0.06 | ||
MASR | +4.1 | 0.40 | ||
IL-6 | −1.3 | 0.33 |
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Semmler, A.; Mundorf, A.K.; Kuechler, A.S.; Schulze-Bosse, K.; Heidecke, H.; Schulze-Forster, K.; Schott, M.; Uhrberg, M.; Weinhold, S.; Lackner, K.J.; et al. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines 2023, 11, 1642. https://doi.org/10.3390/vaccines11111642
Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K, Heidecke H, Schulze-Forster K, Schott M, Uhrberg M, Weinhold S, Lackner KJ, et al. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines. 2023; 11(11):1642. https://doi.org/10.3390/vaccines11111642
Chicago/Turabian StyleSemmler, Amelie, Anna Katharina Mundorf, Anna Sabrina Kuechler, Karin Schulze-Bosse, Harald Heidecke, Kai Schulze-Forster, Matthias Schott, Markus Uhrberg, Sandra Weinhold, Karl J. Lackner, and et al. 2023. "Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers" Vaccines 11, no. 11: 1642. https://doi.org/10.3390/vaccines11111642