The development of multiple vaccines against the SARS-CoV-2 virus within a year of the emergence of the COVID-19 outbreak is unprecedented and a huge achievement for medicine. The effectiveness of many vaccines has grown beyond expectations, and many hope that the epidemic will soon be reversed. However, some challenges remain. Vaccination is still incomplete in developed countries and has barely begun to be implemented in many developing countries, suggesting that achieving worldwide immunity against the virus could take several years. . There is also a growing problem of hesitancy to get vaccinated, especially among young people, who often have strong immune systems to COVID-19, with little or no symptoms. proof. In addition, it is well documented that the COVID-19 vaccine can have significant side effects; indeed, fear of these side effects could lead to widespread SARS-CoV-2 infection in some populations. So, what are the side effects of the COVID-19 vaccine – and can they be paradoxically beneficial?

In keeping with rapid development and production, Pfizer and Moderna’s mRNA-based vaccines have received the most attention for adverse effects of vaccination (1, 2). As with other vaccines, these effects can sometimes be the result of local, delayed-onset allergic reactions. However, in the majority of cases, the main patient complaint is usually a combination of fever, headache, myalgia, and general malaise, affecting ~60% of injectors after the second dose of the drug. Vaccine. These symptoms can be troubling and have been the subject of commentary in newspapers and leading scientific journals. However, aside from the vague mention of the ongoing immune response, the actual cause of the side effects went largely unnoticed. So what are the causes of these effects? As discussed here, most symptoms can be simply attributed to the overproduction of cytokines that play an important role in promoting the early stages of the immune response, specifically type I interferons. (IFN-I).

The features and functions of IFN-I have been reviewed in many studies (3, 4). In summary, IFN-I consists of a mixture of IFN-β, multiple subtypes of IFN-α, and several other IFNs. IFN-I together with the closely related IFN-III (IFN-λ) are induced immediately after pathogen exposure and have potent antiviral effects, acting throughout the body (for IFN-I) and in the respiratory system (for IFN-III). These effects prevent local viral replication and thus prevent the virus from spreading to other locations. IFN-I is produced mainly by macrophages and dendritic cells.Dendritic cell: DC), including both conventional and plasmacytic DCs, and are generated through interactions with pathogen-associated molecular patterns (Pathogen Associated Molecular Pattern: PAMP) is expressed by the associated pathogenic virus or bacteria (Figure 1). PAMPS then interacts with pattern recognition receptors (Pattern recognition receptor: PRR) expressed by DCs, including toll-like receptors (Toll-like receptor: TLR) and members of the RIG-I-like receptor family; for mRNA-based vaccines, PAMP (mRNA) is recognized by multiple PRRs, namely TLR7,8 and 9, RIG-I and MDA5.

The receptor for IFN-I, IFNAR, is expressed by all nucleated cells, and exposure to its binding induces a complex chain of intracellular signaling events leading to the production of a variety of cytokines. and other mediators against related pathogens. In particular, the early production of IFN-I is critical to induce an optimal immune response. IFN-I induces DC activation and thereby allows these cells to present antigens to immature CD4+ and CD8+ T cells (Figure 1); Activated CD4+ cells then stimulate B-cell-specific antibody production, while CD8+ cells differentiate into cytotoxic effector cells. For these two types of T cells, IFN-I acts in part by improving the immunogenicity of DCs, specifically by enhancing the surface expression of molecules that stimulate T-cell activation. In addition, IFN-I exerts a direct stimulatory effect on T cells, promoting optimal expansion of these cells and formation of long-lived memory cells, including T cells. CD4+ and CD8+ .

For highly pathogenic viruses, IFN-I generation can sometimes be excessive and lead to pathogenic “cytokine storms” (3, 4). However, this may not be true for COVID-19, as SARS-CoV-2 antagonizes IFN-I production and results in below-normal blood levels of IFN-I, especially IFN-β. often even in critically ill patients (5). Therefore, it appears that the overproduction of proinflammatory cytokines such as IL-6 detected in severe COVID-19 disease is IFN-I-mediated. Furthermore, it is worth noting that critically ill patients often have high levels of autoantibodies to IFN-I (6). This finding implies that disease severity in these patients is related to the reduction of IFN-I in the early stages of infection. In support of this view, there is increasing evidence that exogenous infusion of IFN-I is effective when given early in the disease and also when used prophylactically, especially intranasally. The important issue is whether IFN-I therapy given late at this stage of the disease exacerbates the pathogenesis or is simply ineffective at this stage remains unclear. Currently, however, in contrast to other viruses, there is little or no evidence that IFN-I has a pathogenic effect during SARS-CoV-2 infection.

To date, we have not been able to identify direct evidence of IFN-I production following SARS-CoV-2 vaccination. However, this is more likely to occur when other mRNA vaccines are known to be potent inducers of IFN-I (7). Therefore, the important question is whether the production of potent IFN-I explains the adverse effects of the COVID-19 vaccine. In considering this question, it should be noted that IFN-I has been used therapeutically for many years, now to treat hepatitis B and C and multiple sclerosis. In these settings, IFN-I injection induces fever, headache, and fatigue similar to current COVID-19 vaccines. Furthermore, when used repeatedly, the therapeutic use of IFN-I can also lead to depression and cognitive delays and thus closely mimic the poorly understood clinical condition of the syndrome. chronic fatigue (8). Given that IFN-I stimulates the synthesis of various cytokines and chemokines, which of these effects account for IFN-I-administered symptoms remains unclear.

The notion that effective immune responses to SARS-CoV-2 and other pathogens depend on IFN-I raises questions about how vaccines induce immunity. In addition to recognizing TCRs for antigens (MHC-binding peptides) on DCs, T cells need a “second signal” to induce an effective immune response; This signal is the result of contact of T-cell CD28 molecules with CD80 and CD86 molecules on the DC. Without such stimulation, the T-cell response may lead to tolerance rather than immunity. Therefore, a required feature of successful vaccines is that, in addition to providing an antigenic source, the vaccine must contain an “adjuvant” to induce a strong upregulation of co-stimulant molecules on the host DC. owner (9

). Like IFN-I, adjuvant stimulates DC by binding to PRR on these cells, signaling the cells to become activated and regulating co-stimulatory molecules. Many components of the pathogen have adjuvant activity, especially mRNA and DNA. Furthermore, adjuvant activity was conspicuous for Poly(I:C), a synthetic analogue of double-stranded RNA; CpG oligodeoxynucleotides, which are short single-stranded synthetic DNA molecules; and Freund’s Complete Adjuvant (CFA), a suspension of whole dried mycobacteria in mineral oil. It is noteworthy that these and other nucleic acid-containing adjuvants have no effect on IFNAR .^-/- mice, suggesting that these adjuvants act by stimulating IFN-I production (10). Indeed, IFN-I itself is a powerful adjuvant.

From the foregoing, it is very likely – although unproven – that the adverse events of the COVID-19 vaccine are simply a by-product of a short course of IFN-I concurrent with induction of effective immune response. Notably, adverse events varied significantly with the age and sex of the recipient, with effects being more severe in females than in males and in younger adults than in the elderly (11). The point to emphasize here is the striking correlation with IFN-I production. Thus, in parallel with the intensity of typical immune responses, the IFN-I generation is essentially stronger in females than in males and in younger than in older adults.

For SARS-CoV-2 infection, it was mentioned earlier that low levels of IFN-I reflect resistance to the virus. In contrast, IFN-I levels are often high in cases of influenza infection (3). This difference may explain why “flu-like” symptoms are prominent in influenza but are often mild with SARS-CoV-2 infection. However, it is worth noting that the current COVID-19 vaccine only leads to selective expression of the mutant protein, which cannot antagonize IFN-I. Therefore, vaccine-induced IFN-I production may be significantly higher than after SARS-CoV-2 infection, which may explain why young people tend to have significant adverse events. for the COVID-19 vaccine but are asymptomatic during SARS-CoV-2 infection. Having direct data on this is of obvious interest.

For this reason, fatigue and headache after COVID-19 vaccination should be viewed positively: as a necessary first step to an effective immune response. The side effects of vaccination are almost always mild and transient, and the vaccine alone is doing its job of stimulating the body’s production of interferon, the body’s built-in immune stimulant.

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Source: https://pubmed.ncbi.nlm.nih.gov/34158390/

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Translator: ToanTran.