COVID-19 vaccines adverse events: potential molecular mechanisms

Abstract

COVID-19 is an infectious disease caused by a single-stranded RNA (ssRNA) virus, known as SARS-CoV-2. The disease, since its first outbreak in Wuhan, China, in December 2019, has led to a global pandemic. The pharmaceutical industry has developed several vaccines, of different vector technologies, against the virus. Of note, among these vaccines, seven have been fully approved by WHO. However, despite the benefits of COVID-19 vaccination, some rare adverse effects have been reported and have been associated with the use of the vaccines developed against SARS-CoV-2, especially those based on mRNA and non-replicating viral vector technology. Rare adverse events reported include allergic and anaphylactic reactions, thrombosis and thrombocytopenia, myocarditis, Bell's palsy, transient myelitis, Guillen-Barre syndrome, recurrences of herpes-zoster, autoimmunity flares, epilepsy, and tachycardia. In this review, we discuss the potential molecular mechanisms leading to these rare adverse events of interest and we also attempt an association with the various vaccine components and platforms. A better understanding of the underlying mechanisms, according to which the vaccines cause side effects, in conjunction with the identification of the vaccine components and/or platforms that are responsible for these reactions, in terms of pharmacovigilance, could probably enable the improvement of future vaccines against COVID-19 and/or even other pathological conditions.

Keywords: Adverse drug reactions; Adverse events; COVID-19 vaccines; Mechanisms; Pharmacovigilance; Side effects.

Fig. 1

Proposed mechanism of allergic and anaphylactic reactions, following mRNA vaccination. a PEG nanoparticle packaging S protein mRNA enters an APC cell, such as dendritic cells, via endocytosis. The mRNA is then translated to S protein, in the ribosomes. b The APC presents free floating PEG or S protein epitopes, as antigens, to T helper cells. The latter secrete cytokines and thus lead to B cell activation. c B cells produce IgE antibodies against PEG or S protein epitopes. d Antigen specific IgE antibodies bind to FcεRI receptor. The engagement of the aforementioned receptor leads to histamine release from basophils and/or mast cells, thus leading to allergic/anaphylactic reactions

Fig. 2

Proposed mechanism for VITT syndrome, following vaccination with viral vector DNA vaccines. a and b Platelets secrete PF4 (anionic), which potentially forms complexes with viral vector DNA (cationic). c IgG antibodies against PF4-viral DNA complexes are produced. d The IgG antibodies bind to FcγRIIa receptor, whose engagement leads to platelet activation and aggregation

Fig. 3

Proposed mechanism for Guillain–Barre syndrome, following COVID-19 vaccination. The immune cells produce antibodies against S protein. In terms of molecular mimicry, as S protein cross-reacts with gangliosides, the antibodies also damage the neurons, thus leading to their demyelination

Fig. 4

Potential mechanisms leading to autoimmunity flares and/or new-onsets of disease. a Following COVID-19 vaccination, the mRNA or the viral vector DNA enters a cell via endocytosis. b In endosomes, the ssRNA or the double-stranded DNAs (dsDNA) are sensed by TLR7/8 or TLR9 respectively. TLRs engagement triggers a series of signal transduction pathways, resulting in the formation of interferon regulatory factor 7 (IRF7) and NF-kB. c After being formed, both IRF7 and NF-kB translocate to the nucleus. In the nucleus, genes transcription leads to interferon type I activation and proinflammatory cytokines generation