Autoantibodies against elements of autonomic regulation are present in individuals with post-COVID-19 vaccination syndrome

The researchers from Germany conducted this study to investigate the effects of anti-SARS-CoV-2 vaccination on the concentrations of autoantibodies against receptors and transmitters involved in autonomic regulation in individuals with post-COVID-19 vaccination syndrome (PCVS). Participants exhibited symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS) or related/overlapping syndromes. 

The symptoms of PCVS start shortly after the SARS-CoV-2 vaccination, and most commonly include malaise, chronic fatigue, cardiovascular disorders (orthostatic intolerance, tachycardia, palpitations), peripheral neuropathy (dysesthesia, hypesthesia), cognitive dysfunction, muscular dysfunction (myalgia, weakness, fibrillations), and gastrointestinal disorders (nausea, weight changes). The authors emphasized that the number of unreported cases of PCVS is high due to lack of diagnostic criteria, and it is not generally accepted that the PCVS exists.

The symptoms of the PCVS overlap with various multisystemic dysautonomia syndromes such as ME/CFS, POTS, fibromyalgia/chronic pain syndrome, small fiber neuropathy (SFN), and mast cell activation syndrome (MCAS). Previous data have shown that autoimmunity against receptors and transmitters involved in autonomic regulation was associated with incidence, duration, and severity of ME/CFS and POTS.

An increase in circulating antibodies against receptors involved in autonomic regulation was found in cases of severe COVID-19 with ME/CFS-like symptoms. In addition, previous studies have suggested that certain autoantibodies against elements of autonomic regulation could play a role in the PCVS. 




About the study

The study included 191 participants who developed the PCVS after anti-SARS-CoV-2 mRNA vaccination, and 89 healthy vaccinated controls. The majority of individuals with PCVS (159) were women, and the mean age was 40 years. They were diagnosed with ME/CFS, POTS or related/overlapping syndromes (fibromyalgia/chronic pain syndrome, SFN and MCAS), and/or exhibited at least three symptoms that confirm these syndromes. They were diagnosed at least five months after vaccination. The majority of healthy controls (71) were women, and mean age was 39 years.

Participants who developed the PCVS were vaccinated with one (47 cases), two (96 cases) or three doses (48 cases) of anti-SARS-CoV-2 mRNA Spikevax, Moderna or Comirnaty, and Pfizer/BioNTech vaccines. Moderna vaccines received 32 cases, and Pfizer/BioNTech vaccines received 159 cases. In 17 cases, the mRNA vaccination was preceded by one vaccination with a vector-based vaccine. Healthy controls received two doses of Spikevax, Moderna vaccines. The vaccination response in all participants was confirmed by sero-reactivity against SARS-CoV-2 spike S1 protein. Exclusion criteria were: the occurrence of symptoms after receiving other vaccines (including non-mRNA SARS-CoV-2 vaccines) or after acute SARS-CoV-2 infection, a history of ME/CFS, POTS or other potentially significant disease or syndrome, and adverse reactions to vaccination lasting more than two weeks after full vaccination.

Paired serum samples were taken 48 hours before the first vaccination and six months after the second vaccination. Commercially available immunoassays were used to evaluate antibodies against: angiotensin II type 1 receptor (AT1R), angiotensin-converting enzyme 2 (ACE-II), endothelin-1 type A receptor (ETAR), alpha-1 adrenergic receptor (α1-adr-R), alpha-2A adrenergic receptor (α2a-adr-R), alpha-2B adrenergic receptor (α2b-adr-R), alpha-2C adrenergic receptor (α2c-adr-R), beta-1 adrenergic receptor (β1-adr-R), beta-2 adrenergic receptor (β2-adr-R), muscarinic acetylcholine receptors M1–M5 (M1R–M5R), MAS 1 receptor (MASR) and interleukin-1 receptor IL-1-Rb.


The results

In 89 vaccinated healthy controls, almost all potentially relevant autoantibodies differed significantly before and after anti-SARS-CoV-2 mRNA vaccination. After vaccination, a decrease has been found for a cluster of receptor antibodies targeting the renin–angiotensin–aldosterone system and other components of cardiovascular regulation. Autoantibodies against AT1R, ETAR, M1R, M2R, M3R, M5R, α1-adr-R, α2a-adr-R, β1-adr-R, β2-adr-R and MASR have shown a decrease of 25-50%.

On the contrary, an increase (in median 15–25%) was observed for autoantibodies against IL-1-Rb, and α2b-adr-R. The α2b-adr-R receptors are involved in thrombogenesis, they are activated on the platelets by adenosine diphosphate, epinephrine or arachidonic acid. Only two of 16 tested receptor antibodies (α2c-adr-R and M4R) remained unaltered after vaccination in the group of healthy controls.

The researchers then examined the levels of receptor antibodies in participants who developed PCVS. Eight of the 16 receptor antibodies tested differed significantly between individuals with PCVS and healthy controls. Serum levels of six autoantibodies (AT1R, ETAR, M2R, M3R, β2-adr-R, and MASR) were significantly increased in individuals with PCVS compared to vaccinated healthy controls. It is noteworthy that serum levels of the same autoantibodies decreased in healthy controls after vaccination.

On the contrary, the levels of autoantibodies against IL-1-Rb and α2b-adr-R were significantly decreased in subjects with PCVS before and after vaccination compared to vaccinated controls. As mentioned before, the levels of these autoantibodies increased in healthy controls after vaccination. 

It is noteworthy that the significant effect of anti-SARS-CoV-2 vaccination on the concentrations of these autoantibodies was observed in healthy individuals who did not have the PCVS. According to the authors, it probably represents a physiological response to anti-SARS-CoV-2 mRNA vaccines. This adjustment appears to be attenuated, absent, or even reversed in individuals with PCVS. Antibodies that were altered in individuals with PCVS have been studied as disease markers, risk factors, or even therapeutic targets in POTS, ME/CFS, chronic heart failure, allograft rejection, rheumatic diseases and other diseases and conditions.

The researchers then used a basic panel of potentially relevant laboratory markers to examine whether their concentrations could distinguish individuals with PCVS from healthy vaccinated controls. These markers included total immunoglobulin (Ig)-G, SARS-CoV-2 serology (SAB, NAB), cardiac markers (pro B-type natriuretic peptide, Troponin T) and inflammation markers (interleukin (IL)-6 and C-reactive protein). Only IL-6 was identified as a potential discriminative biomarker of PCVS. The levels of IL-6 were significantly increased in most subjects with PCVS compared with healthy vaccinated controls. The increased IL-6 levels were correlated with an even greater increase in IL-8. These results showed that IL-6 and IL-8 were identified as additional biomarkers of PCVS. An increase in IL-6, which correlates with an even greater increase in IL-8, was also observed in patients with post-COVID and symptoms of ME/CFS.

In conclusion, autoantibodies against two receptors, angiotensin II type 1 receptor and alpha-2B adrenergic receptor, and serum levels of IL-6/IL-8 can distinguish individuals with PCVS from vaccinated individuals who did not develop PCVS. The authors believe that the PCVS is distinct from various acute autoimmune phenomena that have been reported in the context of SARS-CoV-2 vaccination, and that PCVS phenotype may encompass multiple clinical entities.

These findings may be important for understanding post-COVID-19 vaccination syndrome, and associated dysautonomia. The authors suggest that further research is needed to ascertain whether the proposed blood marker signature effectively differentiates the PCVS from syndromes and diseases such as long COVID and ME/CFS.

This article was published in Vaccines.


Journal Reference

Semmler A, Mundorf AK, Kuechler AS 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.