Differences in autoantibodies against receptors involved in autonomic regulation between individuals with post-COVID-19 vaccination syndrome and vaccinated healthy subjects

The post-COVID-19 vaccination syndrome (PCVS) starts shortly after the COVID-19 vaccination. The most commonly reported symptoms are malaise, chronic fatigue, cardiovascular disorders (orthostatic intolerance, tachycardia, palpitations), peripheral neuropathy (dysesthesia, hypesthesia), muscular disorders (myalgia, weakness), gastrointestinal disorders (nausea, weight changes) and cognitive disorders. The presentations of PCVS overlap with various multisystemic dysautonomia syndromes such as myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), fibromyalgia/chronic pain syndrome, small fiber neuropathy (SFN), and mast cell activation syndrome (MCAS). As previous studies have shown the correlation between autoimmune response against receptors and transmitters involved in autonomic regulation and the incidence, duration, and severity of ME/CFS or POTS, the researchers from Germany in this study investigated the concentrations of autoantibodies against receptors involved in autonomic regulation in individuals who developed PCVS. The researchers pointed to a high number of unreported PCVS cases due to a lack of diagnostic criteria and the fact that PCVS existence is not generally accepted.

Of note, a recent study on patients who developed new-onset small fiber neuropathy after COVID-19 demonstrated that some of them experienced post-exercise malaise, neurovascular dysregulation, and dysautonomia consistent with ME/CFS.  https://discovermednews.com/dysautonomia-and-neuropathy-in-small-fiber-neuropathy-after-covid-19/

 

 

 

 

About the study

 

The study enrolled 280 participants, 191 vaccinated participants who developed PCVS after mRNA COVID-19 vaccination, and 89 healthy vaccinated controls. The majority of participants in both groups were women, in participants with PCVS 159 of 191, and in healthy controls 71 of 89. The mean age in PCVS participants was 40 years and in healthy controls 39 years.

Individuals who developed PCVS were vaccinated with one (47 cases), two (96 cases), or three doses (48 cases) of Spikevax, Moderna/Comirnaty, or Pfizer/BioNTech mRNA COVOD-19 vaccines. Pfizer/BioNTech vaccines received 159 cases and Moderna vaccines 32. In 17 cases, the mRNA vaccination was preceded by one vaccination with a vector-based vaccine. Healthy controls were vaccinated with two doses of Spikevax and Moderna vaccines. The vaccination response in all participants was confirmed by sero-reactivity against the S1 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. Exclusion criteria were as follows: the occurrence of symptoms after receiving other vaccines (including non-mRNA COVID-19 vaccines) or after acute COVID-19, a history of ME/CFS, POTS, or other potentially significant disease or syndrome, and adverse reactions 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. Immunoassay was used to evaluate antibodies against angiotensin II type 1 receptor, angiotensin-converting enzyme 2, endothelin-1 type A receptor, the group of adrenergic receptors, such as 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), and beta-2 adrenergic receptor (β2-adr-R), the group of muscarinic acetylcholine receptors M1–M5 (M1R–M5R), MAS1 receptor and interleukin (IL)-1 receptor.

 

Results

 

The concentrations of autoantibodies against receptors involved in autonomic regulation before and after vaccination

 

The concentrations of almost all potentially relevant autoantibodies differed significantly in both groups before and after vaccination. Interestingly, the results were more extensive in the group of vaccinated healthy controls than in participants diagnosed with PCVS.

In vaccinated healthy controls, a cluster of autoantibodies targeting the renin-angiotensin-aldosterone system and other components of cardiovascular regulation decreased after vaccination compared to pre-vaccination levels. A decrease of 25-50% was found for autoantibodies against angiotensin II type 1 receptor, endothelin-1 type A receptor, the group of muscarinic acetylcholine receptors (M1R, M2R, M3R, M5R) the group of adrenergic receptors (α1-adr-R, α2a-adr-R, β1-adr-R, β2-adr-R) and MAS1 receptor.

After vaccination, concentrations of autoantibodies against IL-1 receptor, and adrenergic receptor α2b-adr-R, involved in thrombogenesis, increased (in median 15–25%) in vaccinated healthy controls and decreased in participants suffering from PCVST.

As the effect of COVID-19 vaccination on the levels of autoantibodies against receptors involved in autonomic regulation was much more extensive in healthy individuals than in participants who developed PCVS, the authors speculated that these findings probably represent a physiological response to mRNA vaccination. 

 

Comparison between individuals with post-COVID-19 vaccination syndrome and vaccinated healthy subjects 

 

The concentrations of autoantibodies against 8 of 16 receptors differed significantly between individuals with PCVS and healthy controls. Individuals with PCVS had higher levels of autoantibodies against six receptors, angiotensin II type 1 receptor, endothelin-1 type A receptor, M2 and M3 muscarinic acetylcholine receptors, β2 adrenergic receptor, and MAS1 receptor than healthy controls, and vice versa, the same autoantibodies were decreased in healthy controls compared to participants who developed PCVS.

The authors also examined whether levels of total immunoglobulin-G, cardiac markers (pro-B-type natriuretic peptide, troponin), and inflammation markers interleukin (IL)-6, IL-8, and C-reactive protein could distinguish individuals with PCVS from healthy vaccinated controls. Only IL-6 and IL-8 were identified as potential discriminative biomarkers of PCVS. The levels of IL-6 and IL-8 were higher in most subjects with PCVS than in healthy vaccinated controls. Of note, an increase in IL-6 correlating with an even greater increase in IL-8 was observed in patients diagnosed with ME/CFS.

 

Conclusion

 

This study has shown differences in autoantibodies against receptors involved in autonomic regulation between individuals diagnosed with post-COVID-19 vaccination syndrome and vaccinated healthy subjects. The authors suggested that these findings may be important for understanding PCVS and associated dysautonomia. 

 

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.  https://doi.org/10.3390/vaccines11111642