Do Long COVID and COVID Vaccine Side Effects Share Pathophysiological Picture and Biochemical Pathways?

Abstract

COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin-angiotensin-aldosterone system (RAAS), the kininogen-kinin-kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects.

Keywords: COVID vaccine side effects; complement pathway; immuno-inflammatory pathways; kininogen-kinin-kallikrein system; long COVID pathophysiology; long COVID predictors; oxidative stress; renin angiotensin pathway.

Figure 1

Distribution of ACE2 receptor expression: The color gradient, ranging from orange (high expression) to green (low expression), illustrates the relative levels of ACE2 expression across various tissues and body fluids. Notably, the highest expression levels are observed in the oral cavity, gastrointestinal tract, and male reproductive organs. Adapted from Lesgards et al. (2023) [7].

Figure 2

Schematic overview of RAAS perturbation by spike protein. Adapted from Lesgards et al. (2023) [7]. Angiotensinogen, a precursor protein synthesized and secreted by the liv-er, is cleaved by renin (a proteolytic enzyme released by the kidneys) into angiotensin I (Ang I). Ang I is subsequently converted to angiotensin II (Ang II) through the catalyt-ic activity of angiotensin-converting enzyme (ACE). Ang II exerts its physiological effects primarily by binding to angiotensin II type 1 (AT1) and type 2 (AT2) receptors. Activation of the AT1 receptor (AT1R) by Ang II promotes vasoconstriction, cellular proliferation, fibrosis, and pro-inflammatory responses. ACE2 converts Ang-I and Ang-II to angiotensin (1–7). Ang (1–7) binds to the MAS receptor (MASR) to promote vasodilation, vascular protection, anti-fibrosis, anti-proliferation, anti-inflammation, and anti-angiogenesis actions.

Figure 3

Schematic overview of the kininogen–kinin–kallikrein (KKK) system (KKS) perturbation by spike protein. A. Angiotensin-converting enzyme (ACE) degrades bradykinin, a vasodilatory peptide that primarily signals through bradykinin B2 receptors (B2R). Bradykinin can also be processed by kininase I to form des-Arg⁹-bradykinin (DABK), which exerts vasoconstrictive and pro-inflammatory effects via bradykinin B1 receptors (B1R). B. SARS-CoV-2 infection disrupts the kallikrein–kinin system (KKS), favoring the accumulation of DABK and enhancing pro-inflammatory signaling. Adapted from Lesgards et al. (2023) [7].

Figure 4

Lectin pathway activation by SARS-CoV-2 and spike protein from mRNA vaccines. The lectin complement pathway is activated when mannose-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2) binds to pathogen surfaces. This complex cleaves complement components C4 and C2, generating the C3 convertase (C4b2a). The classical pathway is triggered by binding of the C1 complex to immunoglobulins or endogenous ligands, also resulting in C4 and C2 cleavage and formation of the C3 convertase (C4b2a). C3 convertase then cleaves C3 into C3a, an anaphylatoxin, and C3b, promoting the assembly of the C5 convertase (C4b2a3b or C3bBb3b). This leads to cleavage of C5 into C5a and C5b, with C5b initiating the terminal complement cascade, culminating in membrane attack complex (MAC, C5b-9) formation and pathogen lysis. Adapted from Lesgards et al. (2023) [7].