The newly emerged SARS-CoV-2 virus is known for its numerous virulence factors, which together with the immunological processes following infection contribute to the organism’s deterioration during coronavirus disease 19 (COVID-19). The pathogenesis of the illness involves both humoral and cellular immunological responses , with cell-mediated immunity being discussed as the primary and most effective immune response to viral infection . Immune memory and reinfection remain non-elucidated. However, great hopes were devoted to developing an efficient vaccination against the virus. Additionally, several therapeutic alternatives have been explored to identify an effective and specific therapy for COVID-19. At this point of knowledge, we may presume that the interaction between the SARS-CoV-2 and the individual’s immune system substantially impacts the disease's progression and prognosis, especially in patients with chronic diseases, including inflammatory and autoimmune [3, 4].
However, many concerns existed regarding the efficacy and safety of the novel COVID-19 vaccines, stepped in phase III clinical trials, especially in patients with autoimmune and inflammatory rheumatic diseases . As a result, the first COVID-19 vaccine approved for emergency use by the US FDA on December 11, 2020, and by the EMA on December 21, 2020, is the mRNA-based vaccine Comirnaty developed in collaboration between Pfizer and BioNTech. Accordingly, the FDA and the EMA immediately authorized the Moderna COVID-19 vaccine for use on December 18, 2020, and January 06, 2020. Both vaccines use a single-stranded mRNA coding for the spike protein of the SARS-CoV-2.
There is a widespread misconception that the mechanism of action of the mRNA vaccines is new and unexplored; however, this is far from the case. As early as 1990, the first article was published describing immunization with mRNA in mice, which leads to intracellular translation of a protein. In 1992, the same process was demonstrated in rats . Experiments in mice with mRNA vaccines encoding proteins of various viruses were published in 1993, 2012 (influenza virus), 2016 (rabies virus), 2013, 2016 (HIV), and 2017 (Zika virus). In pigs, such experiments were published in 2016 (rabies virus) and macaques in 2017 (Zika virus). The first clinical trials on the efficacy and safety of mRNA vaccines against the Zika virus were conducted in 101 healthy volunteers in 2017 .The same year, the results of a clinical trial examining the use of mRNA vaccines encoding influenza virus proteins in 23 participants were published. In 2018, the FDA and EMA approved the first Onpattro (Patisiran) mRNA vaccine for the treatment of Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP) in adults .
In 2020, Comirnaty was tested in a clinical trial involving 40,000 people, with a breakthrough (infection 2 weeks after the second dose) found in 8 people. Thus determines more than 95% efficiency .
The principle of action of the Comirnaty vaccine implicates the administration of non-infectious non-replicating mRNA. Understanding the mechanisms of action of COVID-19 vaccines would help clinitians, especially immunologists and rheumatologists, in their practice. Moreover, investigating the elicited immune response, mainly cellular immune response, could be of practical benefit to measure the effectiveness of mRNA vaccines.
The mRNA molecule contains a 5′ cap, untranslated regions (UTR) before and after the genuine coding sequence, and a poly(A) tail at the 3′ end of the single strand. The mRNA carries a transcript encoding the Spike (S) protein of the SARS-CoV-2 virus . As with all mRNA vaccines, this transcript encodes the corresponding protein using the myocyte translation apparatus [6, 7]. mRNA got packaged in lipid nanoparticles (LPN), which degrade in endosomes, and thus mRNA is released and enters the cytoplasm . However, it is essential to note that mRNA is not retained in the cytoplasm and does not enter the nucleus due to the exposition of RNase, which degrades it within a few days .
Meanwhile, in ribosomal complexes, mRNA translates, resulting in the formation of the S protein. The myocyte presents it on its surface along with the HLA-I molecule. Cytotoxic T (Tc) cells attack the corresponding complex. Tc cells secrete IFNγ and act cytotoxic on the myocyte, allowing the S-protein to enter the extracellular space (Fig. 1).Intramuscular administration of mRNA/LNP results in a local inflammatory response in the muscle and the regional lymph nodes. Antigen-presenting cells (APCs) are involved, among which dendritic cells (DCs) play a significant role. They absorb the S protein and present it together with HLA-II, leading to recognition by T helper cells . Thus, it targets both Th2 cells secreting IL-4 and mediating the activation of the humoral immune response, as well as Th1 cells secreting IFNγ and determining the cellular immune response. Along with attracting APC, mRNA/LNP has a strong effect on the innate immune system. Genes encoding the synthesis of IL-1β, MyD88, as well as gene complexes responsible for lipid uptake (LDLR), their processing (CTSL), and loading (TAP-2) are activated . The mRNA itself is a typical pathogen-associated molecular pattern (PAMP) and activates endosomal (TLR-7) and cytoplasmic sensors (RIG-1)  (Fig. 1). However, we have to mention also that methylpseudouridine supports the linear structure of vaccine mRNA and thus, reduces immunogeneicity of vaccine because of TLR7 and RIG-1 .
The main effect of their activation is enhanced synthesis of type I interferons (IFNs-I). IFN-I activates the genes responsible for synthesizing Mx proteins and the chemokines CXCL-10 and CXCL-11 . IFN-I also acts on DCs. They mature and express high levels of HLA-II and the costimulatory molecules CD80, CD86, all of which are associated with their ability to present both HLA-I and HLA-II molecules . Moreover, under the influence of IFNs-I, the unique ability of DCs to cross-present is enhanced, allowing the antigenic presentation of the exogenous S peptide by HLA-I on Tc lymphocytes .
Intramuscular administration of mRNA/LNP leads to long-term production of the target protein, which determines the effective interaction in the germinal centers of the lymph nodes between T and B lymphocytes . Tc cells and Th1 cells play a crucial role in the immune response after immunization with mRNA vaccines. While Th1 lymphocytes got primed upon presentation of the S protein by DCs, Tc cells got activated by cross-presentation by DCs and by recognizing the S protein expressed by myocytes (Fig. 1). All this allows us to try to answer the question “do I have cellular immune protection” by examining the levels of specifically secreted IFNγ by these types of Th1 and Tc cells. Therefore, using an interferon-gamma release assay (IGRA) test, the present study aimed to monitor cellular postvaccination immunity in healthy subjects vaccinated with Comirnaty in January/February 2021.