Introduction

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused millions of deaths worldwide in the last three years since it was first identified in December 2019. So far, as of 28th May 2022, approximately, 527.8 million people were affected with SARS-CoV-2 and approximate deaths of 6.3 million worldwide, in which the greater numbers were reported from the United States of America with approximately 83.7 million affected and approximately 1.0 million deaths. In India, the number of people affected was approximately 43.1 million with approximately 0.52 million deaths (https://news.google.com/covid19/map?hl=en-IN&gl=IN&ceid=IN%3Aen). The estimated economic loss was approximately $8.5 trillion, thus causing huge public health and economic burden worldwide (https://www.un.org/en/desa/covid-19-slash-global-economic-output-85-trillion-over-next-two-years). Obesity and other non-communicable diseases, including type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer, and non-alcoholic fatty liver disease (NAFLD), have emerged as major determinants of severe COVID-19. Further, recent studies have found that other impaired metabolic determinants, specifically visceral obesity, hyperglycemia, hypertension, and subclinical inflammation, increase the risk of severity as well as found to be consequences of severe COVID-19 and might adversely affect the efficacy of COVID-19 vaccines [1].

SARS-CoV-2 is an enveloped, positive sense single-stranded RNA (ssRNA) virus of approximately 30 kb genome size belongs to the Cononaviridae family. The rod-shaped spike (S) protein present on the envelope binds to the angiotensin converting enzyme 2 (ACE2) receptors present on the host cell surface and mediates the viral entry into cells. The S protein is the main protein that determines the diversity of coronaviruses, host tropism responsible for virus antigenic properties [2]. The S protein contains two subunits S1 and S2. The S1 mediates the binding to the ACE2 while S2 catalyzes the fusion of cell membrane and viral membrane ensuring the virus entry through receptor-mediated endocytosis and release of the virion into the cytoplasm of host cells [3]. ACE2 expression is high in the lung, liver, heart, colon, ileum, kidney, and bladder [4]. Studies have also found that the small intestine, testis, thyroid, and adipose tissue have the highest ACE2 expression levels, while blood, spleen, bone marrow, blood vessels, and muscle have the lowest ACE2 expression. This indicates that SARS-CoV-2 can infect other tissues in addition to the lungs, including male tissues such as the testis and seminal vesicle [5]. The expression of ACE2 in various tissues and the lungs suggests that SARS-CoV-2 infection adversely affects other tissues’ functioning. Subjects with cirrhosis have higher hepatic decompensation and liver failure rates following SARS-CoV-2 infection. The possible pathogenesis involved is increased systemic inflammation, cirrhosis-associated immune dysfunction, coagulopathy, and gut dysbiosis, causing respiratory failure and death [6]. These results further indicate that impaired liver function may adversely affect the vaccine efficacy in subjects with liver cirrhosis.

ACE2 receptors are highly expressed on the apical surface of lung epithelial cells thus allowing them as a portal of entry for the virus. Once virion is released into the cell, viral RNA undergoes replication. Viral messenger RNA (mRNA) is used as a template for the synthesis of new viral proteins. Subsequently, new viral particles are packaged in the cell and released out of that host cell thus inducing the host cell lysis. The death of lung epithelial cells matches the fact that early lung injury is often observed in the distal airway [7, 8].

Following the lysis of host cells, the virus gets exposed to the innate immune cells including dendritic cells (DCs), and alveolar macrophages which get activated phagocytize the dying cells and present the viral antigen to the adaptive immune cells such as T lymphocytes which in turn mount the adaptive immune response. The immune response following the viral infection varies according to the immune status, age, disease severity, and presence of underlying comorbidities such as diabetes, cancer, etc., in subjects. Over a period of time, natural infection contributes to the development of herd immunity that subsequently helps in minimizing the spread of infection, hospitalization, and deaths against various viral diseases including SARS-CoV-2 and its variants including the delta found in India [9]. The herd immunity can be achieved either by natural infection or by artificially through vaccination. However, achieving herd immunity by natural infection in COVID-19 has been found to be risky and takes a longer duration [10]. The advancement in biomedical research has paved the way for the development and production of a number of COVID-19 vaccines including nucleic acid-based [Pfizer/BioNTech’s (BNT162b2), Moderna’s (mRNA-1273)] viral vector-based [Oxford-AstraZeneca vaccine and serum institute AZD1222 (ChAdOx1)], subunit [Novovax (NVX-CoV2373)] and inactivated whole virus [Bharat Biotech (Covaxin, BBV152)] vaccines [11].

As vaccines induce the protective immune response by promoting the production of COVID-19 specific virus-neutralizing antibodies and immune memory cells, evidence from case studies and large observational studies suggests that the protective immune response lasts for approximately 6–12 months [12]. Further, emerging data, including evidence from breakthrough infections suggest that the effectiveness of the vaccine might be reduced significantly against emerging variants of concern such as “Omicron” and hence secondary vaccines will need to be developed to maintain herd immunity in addition to developing other antiviral drugs. Further, vaccine efficacy may also get adversely affected due to underlying comorbidities. Studies have found that diabetes, obesity, and other diseases associated with impaired metabolic health affect COVID-19 outcomes independently of each other. One of the studies done on a large community-based cohort (6,910,695 patients) from the UK reveals that high body mass index (BMI, > 23 kg/m²) in the age group of 10–39 years old was associated with adverse COVID-19 outcomes independently of several other COVID-19 risk factors including type 2 diabetes mellitus in patients [13]. Further, hyperglycemia was found to promote viral replication and cytokine production in monocytes, and glycolysis was found to sustain SARS-CoV-2-induced monocyte response and viral replication [14]. Similarly, studies have shown that pre-existing comorbidities such as overweight, type 2 diabetes, and cardiovascular disease were associated with vaccine breakthrough COVID-19 infections [15]. Further, it was found that vaccine efficacy drops down to 86% and 89% in individuals with three or more existing conditions, respectively, compared to 91% with documented infection and 93% with symptomatic illness following seven days post-vaccination with a second dose of the BNT162b2 mRNA vaccine [16]. Studies also indicate that a time-dependent decline in antibody levels might increase the risk of breakthrough infections [17]. These results suggest that comorbidities downregulate the COVID-19 vaccine efficacy, thus contributing to the risk of breakthrough infections. There are reports that the spread of some variants has been attributed to enhanced virus transmissibility and partial immune escape indicating that vaccines may offer reduced protection against some variants. There is little evidence to suggest that alpha evades vaccine-induced immune response and neutralization by post-vaccination sera is similar to wild type, and minimal differences in vaccine effectiveness have been observed [16]. However, studies report conflicting evidence against the beta variant [18]. There is also some evidence of a reduction in vaccine effectiveness against gamma and delta variants [19]. For the recent Omicron variant, reports suggest a greater reduction in vaccine effectiveness in fully vaccinated individuals after receipt of booster vaccine doses. However, the mild to moderate course of illness indicates that full vaccination followed by a booster dose still protects against the severity caused by the Omicron [20]. Further reports also suggest that the risk of hospitalization or death was lower for Omicron cases than delta cases [21].

On the other side, safety concerns have been raised following the administration of COVID-19 vaccines. Some of the common adverse effects include pain at the injection site, and non-specific systemic symptoms, such as fatigue, myalgia, headache, and fever. These symptoms may be observed soon after the vaccination and get resolved in a short period. However, recent reports from case studies have found vaccine-induced side effects in the form of unusual thrombotic events with thrombocytopenia, neurological effects, such as transverse myelitis, Guillain-Barre syndrome (GBS) following administration of COVID-19 viral vector vaccines [22]. This review provides a brief overview of host immune responses to the SARS-CoV-2 infection and vaccination, followed by vaccine efficacy, safety, immunogenicity, and their side effects.

Immune response to COVID-19 infection

COVID-19 infection induces a robust host humoral and cellular immune response. It has been found that COVID-19-specific immunoglobulin A (IgA) and IgG have been detected from both mucosal sites and serum of the COVID-19 infected persons [23, 24]. Also, the presence of IgM, IgA, and IgG was found in the blood sample of the infected person 5–15 days prior to the onset of symptoms [17]. In the very first week of the infected person, the IgM antibodies peak and then fall down until the detectable limit within 2–3 months after the infection [25, 26]. In the meantime, IgA antibodies also decrease gradually and become undetectable within the 3 months after infection while IgG antibodies are more stable. COVID-19-specific memory B cells and T cells will start to emerge within the first month following the infection [27, 28]. The degree of immune response after infection depends on multiple factors. Several studies reported that subjects infected with COVID-19 and who are symptomatic tend to have a higher antibody titer as compared to the asymptomatic person, also the person who is hospitalized tends to have higher antibody titers as compared to the outpatients. In subjects with severe COVID-19 infection, both binding and neutralizing antibody titers rise faster and reach the peak [25, 28, 29].

SARS-CoV-2 enters the host cell through S protein by receptor-mediated endocytosis. The virus replicates and gets packaged and gets released out of the target cell and infects new cells. Following the release out of the cell, the virus comes in contact with the innate immune system [30]. Epithelial cells, DCs, and alveolar macrophages form the main cellular components of the innate immunity in the airway [31]. DCs and macrophages function as innate immune cells to fight against viruses till adaptive immunity is mounted. During the initial phase of infection, DCs and macrophages phagocytize virus-infected epithelial cells and present the viral antigen through class II major histocompatibility complex (MHC) to T helper (Th) cells. SARS-CoV-2 can also infect DCs through DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) and furin and DC-SIGN-related (DC-SIGNR) protein in addition to the ACE2 and transmembrane protease serine 2 (TMPRSS2) [32]. Th cells in turn activate B-cells and induce their differentiation into plasma cells that produce antibodies thus mounting the humoral response, while cytotoxic T cells can kill the virus-infected cells thus activating the adaptive response to SARS-CoV-2 infection. Further, the innate immune response also gets activated through pattern recognition receptors (PRRs), such as C-type lectin-like receptors, NOD-like receptor(NLR), Toll-like receptor (TLR), and RIG-I-like receptor (RLR). The COVID-19 virus induces the expression of numerous inflammatory factors, and the synthesis of type I interferons [IFNs; IFN-γ, IFN-α, interleukin-1β (IL-1β), IL-6, IL-12, IL-18, IL-33, tumor necrosis factor-α (TNF-α), transforming growth factor beta (TGF-β), C-C motif chemokine ligand 2 (CCL2), CCL3, CCL5, C-X-C motif ligand 8 (CXCL8), CXCL9, CXCL10, receiver operating characteristic (ROC)], which limit the spread of viral and accelerate macrophage phagocytosis of the viral antigens resulting in the clinical recovery [33–37]. However, the nucleocapsid (N) protein of COVID-19 helps the virus to escape from the immune responses. A schematic representation of the immune response against COVID-19 is presented in Figure 1.

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Figure 1. 

The picture depicts the overview of host immune response to COVID-19 infection or COVID-19 vaccine. SARS-CoV-2 enters the host cell through its S protein by receptor mediated endocytosis. Inside the host cell, virus replicates and new viral particles are released causing target cell lysis. Antigen presenting cells recognize the virus infected cells and phagocytize them. Process the viral antigen and present to the Th cells via class II MHC. In the case of vaccine, following the vaccine injection, antigen presenting cells, process the S protein (in case of viral vector vaccines and nucleic acid vaccines) or process the antigen from the inactivated whole virus vaccine, and present to the Th cells as above. Th cells recognize the viral antigen and activated and secrete cytokines which in turn activate B cells. Activated B cells differentiate into plasma cells and memory B cells. Plasma cells secrete antibodies which neutralize the viral antigen. As disease progress pathogenic CD4⁺ secrete higher amounts of proinflammatory cytokines such as IL-6, monocyte chemoattractant protein 1 (MCP-1), TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), etc., which in turn cause infiltration of neutrophils and tissue macrophages, lymphocytes leading to tissue and organ failure. Memory cells formed due to vaccine or infection, following the repeat encounter of the same antigen or virus gets activated and differentiated into antibody producing plasma cells. CD4: cell differentiation 4; ↓: decrease; ↑: increase

As the disease progresses in some patients, there is a reduction in peripheral blood T cells (lymphopenia) as determined by the elevated expression levels of checkpoint receptor transmembrane domain 3 (Tm3)⁺ programmed cell death protein 1 (PD-1)⁺ in the cluster of CD4⁺ and CD8⁺ T cells and elevation of NK group 2 member A (NKG2A) in CD8⁺ T cells [38]. Further, it was observed that activated CD4⁺ cells express higher levels of proinflammatory cytokines including IL-6, IL-10, granulocyte-colony stimulating factor (G-CSF), MCP-1, macrophage inflammatory protein 1α (MIP1α), and TNF-α [39]. The severity is correlated with the levels of IL-6. The elevated expression levels of CD69, CD38, and CD44 indicate the hyperactivation of CD4⁺ and CD8⁺ cells. The aberrant pathogenic CD4⁺ cells co-express IFN-γ and GM-CSF [40]. GM-CSF though helps in the differentiation of innate immune cells and activates T cells, but it can initiate tissue damage in excess [41]. GM-CSF⁺IFN-γ⁺CD4⁺ cells were found at substantially higher levels in autoimmune encephalomyelitis (EAE) models that secreted higher amounts of IL-6. Additionally, SARS-CoV-2 infected cells also secrete higher amounts of IL-8, which is a chemoattractant for neutrophils and T cells. Infiltration of a large number of inflammatory cells was observed in severe COVID-19 patients [42, 43], and these cells presumably consist of a group of neutrophils and T cells. Neutrophils in large numbers induce lung injury [44–46]. Considering the reduction in circulating T cells, infiltrating T cells, similar to neutrophils, can kill the virus and also cause lung injury when present in excess at the tissue level [47]. Additionally, a large number of monocytes (CD14⁺CD16⁺) were also found to infiltrate into the lung tissue and these cells secrete higher levels of IL-6, which is likely to accelerate the progression of systemic inflammatory response. Together, aberrant expression of chemoattractant and proinflammatory factors by CD⁺ cells cause huge infiltration of both nonspecific and adaptive immune cells causing tissue damage and failure.

Immune response to COVID-19 vaccine

Vaccination is the best way to protect oneself against the COVID-19 infection, as it may train one’s immune system to respond quickly and effectively to the virus infection, thereby preventing severity of the illness. The vaccine works with the immune system and builds immune memory T and B-lymphocytes for the COVID-19 and can protect for a long time after receiving both doses of the vaccine.

Different types of vaccines work in different ways to offer protection. Following the vaccination, the Th cells will detect the S protein and activate other immune cells followed by the killer T cells that seek out the S protein. B cells will recognize the S protein and will create an antibody against the virus. Vaccination will induce the production of anti-S and anti-receptor-binding domain (RBD) binding and neutralizing antibodies in the blood and similar to an infection, vaccine results in early production of the serum IgA, IgM, and IgG antibodies, and also induce long-lasting memory B-cell and T-cell responses [48–50]. Second dose vaccine which is mostly administered 4–8 weeks later will train the immune system further and strengthen the response and will create an immune memory for the virus. The immune system will be ready to fight quickly and effectively against COVID-19 in the future, thereby preventing the infection and controlling the spread of the pandemic [51].

The various study supports the vaccination concept which has the potential to prevent COVID-19 infection. In one of the studies, it was found that vaccination of primates protects against viral challenges, and the development of functional neutralizing antibodies, thereby protecting against severe illness. Similarly, epidemiologic studies in humans have also suggested that neutralizing antibodies is associated with protection from infection [13, 52, 53].

Vaccines against COVID-19 that evoke protective immune responses are crucial to the prevention and mitigation of the morbidity and mortality caused by SARS-CoV-2 infection. Many reports suggest that balancing humoral and Th1-directed cellular immune response might be an important aspect of protecting against COVID-19 and also avoiding the vaccine-enhanced diseases [54, 55]. Considering this, several vaccines have been developed and tested which include nucleic acid vaccines, inactivated virus vaccines, protein/peptide subunit vaccines, live attenuated vaccines, and viral vectored vaccines [56, 57]. Each vaccine has its own advantages and disadvantages. By the end of 2020, many vaccines had been developed and made available for use in different parts of the world. Out of these vaccines, the World Health Organization (WHO) has approved 7 vaccines to fight against COVID-19.

Conclusions

The COVID-19 pandemic has caused significant devastating effects on public health and a huge economic burden worldwide. As new drugs and other treatment modalities and vaccines are being developed, the virus uses an alternative strategy in the form of mutants to evade the effect of drugs and vaccines to survive and propagate in susceptible hosts. Despite adverse effects particularly for viral vector vaccines have been reported, at this hour of public health crisis worldwide, vaccines still form the potent weapons that induce a protective immune response to keep the transmission of the SARS-CoV-2 virus under control, minimize the hospitalization and case fatality rate. Further, a thorough understanding of the interaction between host and viral proteins, viral evasion of the immune response, viral mutations, etc., will help in designing novel antiviral targets to counter viral pathogenesis. Additionally, based on age, type of vaccine, presence of comorbidities, individual variation in response to the vaccine, dwindling antibody levels over a period of time, evolving of viral mutants, new vaccines, and new strategies such as booster dosing or annual vaccination have to be debated and adapted based on scientific studies.