The Ambivalence of Post COVID-19 Vaccination Responses in Humans

Abstract

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has prompted a massive global vaccination campaign, leading to the rapid development and deployment of several vaccines. Various COVID-19 vaccines are under different phases of clinical trials and include the whole virus or its parts like DNA, mRNA, or protein subunits administered directly or through vectors. Beginning in 2020, a few mRNA (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and adenovirus-based (AstraZeneca ChAdOx1-S and the Janssen Ad26.COV2.S) vaccines were recommended by WHO for emergency use before the completion of the phase 3 and 4 trials. These vaccines were mostly administered in two or three doses at a defined frequency between the two doses. While these vaccines, mainly based on viral nucleic acids or protein conferred protection against the progression of SARS-CoV-2 infection into severe COVID-19, and prevented death due to the disease, their use has also been accompanied by a plethora of side effects. Common side effects include localized reactions such as pain at the injection site, as well as systemic reactions like fever, fatigue, and headache. These symptoms are generally mild to moderate and resolve within a few days. However, rare but more serious side effects have been reported, including allergic reactions such as anaphylaxis and, in some cases, myocarditis or pericarditis, particularly in younger males. Ongoing surveillance and research efforts continue to refine the understanding of these adverse effects, providing critical insights into the risk-benefit profile of COVID-19 vaccines. Nonetheless, the overall safety profile supports the continued use of these vaccines in combating the pandemic, with regulatory agencies and health organizations emphasizing the importance of vaccination in preventing COVID-19's severe outcomes. In this review, we describe different types of COVID-19 vaccines and summarize various adverse effects due to autoimmune and inflammatory response(s) manifesting predominantly as cardiac, hematological, neurological, and psychological dysfunctions. The incidence, clinical presentation, risk factors, diagnosis, and management of different adverse effects and possible mechanisms contributing to these effects are discussed. The review highlights the potential ambivalence of human response post-COVID-19 vaccination and necessitates the need to mitigate the adverse side effects.

Keywords: Bell’s palsy; Guillain–Barré syndrome; adverse effects; allergy; autoimmunity; immune activation; long COVID; myocarditis; proinflammatory response; thrombosis.

Figure 1

Summary of host response to COVID-19 vaccines. The COVID-19 vaccination-induced host responses can be broadly divided into immediate or delayed hypersensitivity. While the former response elicits allergic reactions and anaphylaxis, the latter response results in mild, moderate, or severe adverse events. The immediate hypersensitivity response is caused either by a classical, IgE-mediated activation of mast cells and basophils or an alternative non-classical pathway involving IgG and other antibodies activating neutrophils and basophils. Autoimmunity due to COVID-19 vaccination can be caused by molecular mimicry, bystander activation of immune cells, viral epitope spreading, or adjuvant-mediated immune response. The overall magnitude and durability of immune response as well as adverse effects mediated by COVID-19 vaccination are determined by several factors, including the age, sex, genetic makeup, immune status, and underlying health conditions of the host as well as the nature of the vaccine used. Image created in Biorender.

Figure 2

Effects of COVID-19 vaccination-induced immunity. Following vaccination, the immune response against COVID-19 is mediated mainly by the development of Abs against SARS-CoV-2 proteins. The magnitude of immune response developed and its impact on the host protection is determined by the nature of Ab response elicited. An effective neutralizing Ab response neutralizes the virus, controls the infecting viral load and protects the vaccinated host against severe disease and/or death due to infection. However, a sub-optimal non-neutralizing Ab response leads to poor neutralization of the virus and ineffective control of viral load in the organs and may also contribute to Ab-mediated adverse effects (AE), which may enhance the disease manifestations. Image created in Biorender.

Figure 3

Key pathways of COVID-19 vaccine-induced adverse immune reactions. The COVID-19 vaccine is comprised of the SARS-CoV-2 S protein (either as mRNA or protein) combined with an adjuvant such as polyethylene glycol (PEG). In the classical pathway, internalization of the viral and adjuvant-derived antigens (Ag) in the vaccine by antigen-presenting cells (APC) results in the presentation of antigenic epitopes to the T helper (Th) cells, which produces cytokines and activates Ag-specific B cells to produce various antibodies, such as IgG, IgE, IgM, etc. The Ag-specific IgE Abs binds to the FcεR1 and activates basophils and mast cells to produce histamine, which leads to allergy and/or anaphylaxis reactions. In the non-classical pathway, the antigens were taken up directly by the MRGPRX2 receptor on mast cells, which results in the induction of histamine and allergic responses. In addition, the immune complex formation by the Ag-specific and/or anti-idiotypic IgG, IgE, IgM Abs activates the C3a and C5a complement components, which ultimately results in complement activation-related pseudo-allergic reaction (CARPA). Finally, in the alternative/additional pathway, the antigen–IgG complex is taken up by neutrophils through FcγRs, which activates these polymorphonuclear cells to produce reactive oxygen species (ROS), proteases such as neutrophil-elastases (NE), Protease-3 (PR3), cathepsin G (CatG), and the formation of neutrophil extracellular traps (NETosis). The combined action of these pathways may contribute to the overall allergy and anaphylactic response due to COVID-19 vaccination. Image created in Biorender.

Figure 4

Various mechanisms of adverse immune activation by COVID-19 vaccines. The viral S protein, either as mRNA or recombinant, adenovector-DNA, is endocytosed through Toll-like receptors (TLR) present on antigen-presenting cells (APCs). These endosomes trigger intracellular signaling pathways that result in the activation of Interferon regulatory factor-7 (IRF-7) and nuclear factor k B (NFkB) networks. Activated IRF7 and NFkB upregulate the production of proinflammatory cytokines IL-6 and TNFα. Alternatively, the viral components can escape from the endosome and trigger the cGAS signaling pathway, which activates STING/IRF3 network that ultimately results in the upregulation of proinflammatory type I interferons (IFN) response. Finally, the viral nucleic acids are translated into peptides and presented by the APC to activate T cells through the T cell receptor (TcR). Activation of naïve T cells results in the production of cytokines. Exposure to IL-4 skews the naïve T cells to an anti-inflammatory, Th2-type T cells that produce IL-3, IL-5, and IL-9, all of which can activate mast cells to elicit an allergic/anaphylactic reaction. In contrast, exposure to IL-12 and IFNγ polarizes the naïve T cells into Th1-type cells, which contributes to the proinflammatory response. Apart from the viral-derived molecules, vaccine adjuvants, such as CpG, can be recognized by TLR on the APC, with further activation of the NFkB pathway, leading to the production of inflammatory response. The viral nucleic acids also form a complex with platelet factor-4 (PF4) produced by the blood platelets. This complex activates Ag-specific B cells to produce anti-DNA/PF4 complex IgG, which binds with the FCγRIIa receptor on the platelets and activates these cells to form aggregates, leading to vaccine-induced thrombotic thrombocytopenia (VITT). Thus, both APCs and platelets play divergent roles in mounting immune dysregulation upon exposure to viral antigens and/or adjuvants. Image created in Biorender.