The initial outbreak of the unknown viral pneumonia-like disease in Wuhan, China, in early December 2019, rapidly spread across the globe within a short period. Nucleotide sequencing of the virus revealed it to be a novel strain of coronavirus belonging to the genus Beta coronavirus and was named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1]. By the end of January 2020, over ten countries from Asia, Europe, North America, and Australia were reporting cases of rising person-to-person transmissibility. The World Health Organization (WHO) soon declared a global health emergency on 31 January and a pandemic by 11 March 2020 ^[2][3][2,3]. As per the WHO data, 532,201,219 cases with more than 6 million mortality (until June 2022) have been recorded globally, making it the most significant global health crisis since the 1918 influenza pandemic. During the pandemic, several variants of SARS-CoV-2 emerged and spread rapidly with a few potent strains globally, and few of them have been responsible for the recurrent waves of the disease [4]. The global efforts to control and manage the pandemic were initially met with setback because of the highly transmissible and elusive nature of the virus-like alpha, beta, gamma, delta, and omicron variants that were subsequently identified as “variants of concern” [4]. However, a concerted approach to the pandemic resulted in the development of novel vaccines against COVID-19. By June 2022, the WHO reported 166 vaccine candidates under clinical phase development, out of which 33% are protein subunit vaccine candidates [5]. Different platforms for vaccine development have been explored and utilized by the researchers, including protein subunits, replicating and non-replicating viral vectors, DNA and RNA, inactivated viruses, virus-like particles, live attenuated viruses, as well as a bacterial antigen-spore expression vector. It is worth mentioning that vaccines’ ability to induce effectiveness, T cell responses, and neutralizing antibodies were observed to be different in respect to the different variants of the virus [6]. In December 2020, the US Food and Drug Administration (FDA), after rigorous review, allowed Pfizer-BioNTech-developed mRNA vaccine (BNT162) for emergency use authorizing it in the USA for the administration of mass vaccination [7]. This was the first instance of administrating mass COVID-19 vaccination in any country. As of June 2022, more than 11 billion doses of various vaccines against COVID-19 have been administered worldwide [8].

2. Complications during COVID-19

Given a wide range of clinical manifestations due to COVID-19, around 15% of the patients develop severe pneumonia, while approximately 5% exhibit acute respiratory distress syndrome (ARDS), multiple organ failure and septic shock ^[9][10][65,66]. Complications due to acute infections have been reported under respiratory, cardiac, haematological, and neurological symptoms ^[11][67]. Usually, these symptoms resolve within four weeks of infection. However, globally there have been reports of persistent and prolonged clinical presentations, including pulmonary, cardiovascular, haematological, neuropsychiatric and autoimmune in the post-acute phase of COVID-19 ^[12][13][68,69]. The pathophysiology of post COVID-19 complications is multifactorial and it is mostly speculated that SARS-CoV-2 infects a diverse range of human cell types making it a highly efficient infection. In fact, the virus receptor ACE2 is expressed in various tissues, such as the respiratory system, blood vessels, cardiomyocytes, brain endothelium and renal tissues among others, making it possible for multiple organ infections ^[14][15][70,71]. A number of recent studies have attempted to delineate the underlying mechanisms of COVID-19 related complications. Pulmonary complication: Studies have shown a high proportion of pulmonary complications among survivors of severe COVID-19 infections who were on mechanical ventilation ^[16][72]. A three-month follow-up of COVID-19 survivors revealed abnormal chest computerized tomography (CT) in 42% of the patients ^[17][73]. Characteristic ARDS followed by pulmonary fibrosis and injury of alveolar epithelial cells caused by direct viral entry are a hallmark of COVID-19 infection ^[18][74]. The dysregulated levels of inflammatory cytokines including IL-6 and TNFα along with VEGF, cause a cytokine storm leading to fibrosis and further secondary bacterial infections ^[19][75]. The cytokine storm also plays a critical role in coagulation dysfunction leading to thrombocytopenia and stimulates megakaryocyte production leading to thrombocytosis ^[20][76]. Cardiological complication: Multiple studies have associated cardiac complications with COVID-19 infections. Initial studies from Wuhan reported heart failure among 23% of the COVID-19 patients ^[21][77]. While a study from the United States reported cardiac arrest in 14% of COVID-19 patients admitted to Intensive Care Units ^[22][78]. Several mechanisms have been postulated for cardiac injury post SARS-CoV-2 infection including direct viral entry with the presence of viral RNA in heart tissues, the inflammatory response often leading to necrosis and structural myocardial damage ^[23][79]. Studies have revealed increased cytokine levels indicative of myocardial infarction, endothelial dysfunction and plaque instability ^[24][80]. Increased cytokines, e.g., IL-1, IL-6 and TNFα due to COVID-19 may also raise catecholaminergic state causing arrhythmias ^[25][81]. Neurological complication: There is substantial evidence for neurological indisposition as COVID-19 sequelae. Studies have documented 33.6–80% incidence of neurological or psychiatric manifestations after 6–12 months in COVID-19 hospitalized patients ^[26][27][82,83]. The possible mechanisms of neuropathology due to COVID-19 include direct viral injury, microvascular thrombosis and systemic inflammation ^[28][29][84,85]. Along with the detection of viral RNA in the brain, neural tropism has been recently described ^[30][86]. The effects of accumulated memory T cells and low levels of neuro-inflammation may play a role in COVID-19 persistence. Another hallmark of COVID-19 is the loss of olfactory and gustatory senses mainly due to olfactory epithelium cell injury by the virus ^[31][87]. The entry of the virus into the host nervous system has been hypothesized through the neural-mucosal border present in the olfactory mucosa. Renal complications post COVID-19 may be attributed to direct viral infection, acute kidney injury, fibrosis and systemic inflammation ^[32][33][88,89]. Additionally, the viral genome has also been detected in renal tissues during autopsies and biopsies ^[34][35][90,91]. Notably, many other COVID-19 related sequelae are being addressed and are coming into the picture with time, e.g., dermatologic, gastrointestinal, endocrine and genitourinary complications ^[36][92]. However, it is still not clear why a subset of SARS-CoV-2 infected individuals progress into disease severity while the resolution of disease and symptoms are observed in others. Few studies have illustrated that existing infection or previous exposure can substantially modulate the host immune response against SARS-CoV-2. In fact, it has been postulated that during COVID-19 related inflammation, existing pathogens concealed by SARS-CoV-2 may contribute to autoantibody generation which may continue to act after the resolution of acute phase infection leading to sequelae ^[37][93]. Reports of Guillain Barre syndrome, an autoimmune condition affecting the host neurological system, have been recorded in post COVID-19 patients ^[38][39][94,95].

3. Effect of COVID-19 Vaccine on Host Immunity

The mRNA-based vaccines of COVID-19 induce maturation of CD4⁺ and CD8⁺ T lymphocyte and the vaccinated individuals tend to possess memory-based T-lymphocyte responses ^[40][107]. Individuals vaccinated with the second dose of mRNA-based vaccine show developed B-lymphocytes and high levels of IgM and IgG antibodies eight weeks post second dose of vaccine ^[41][108]. The vaccine induced memory B and T cells remain stable for up to 3–6 months post vaccination. Oxford AstraZeneca (AZD1222/ChAdOx1) and Sputnik V (gram-COVID-Vac-rAD26/rAD5) elicit receptor binding domain specific IgG and neutralizing antibody responses at >20 days after the first dose and further induction of responses takes place after second dose ^[41][108]. The S protein’s prefusion conformation has been targeted as the immunogen for vaccine formulation as it has significant epitopes against which neutralizing antibodies are made ^[41][108]. Delaying the interval between the first and the second dose of mRNA-based vaccines such as Oxford AstraZeneca (AZD1222/ChAdOx1) and Pfizer-BioNtech (BNT162b2) between 6 and 14 weeks results in higher neutralizing antibody levels than those of three-week intervals tested for clinical trials during vaccine licensing ^[42][43][98,109]. However, longer time intervals dampen the T-cell responses which might be attributed to the fact that longer time interval results in more S-specific T-cell response upon re-exposure to S-protein ^[44][45][110,111]. Recent reports suggest that COVID-19 vaccines boost the neutralizing antibody titers up to 10- to 45-fold higher in individuals with a history of infection compared to those without any past infection history after the first dose of vaccination ^[46][47][112,113]. However, the neutralizing antibody titers decline after six months of vaccination with a second dose as the vaccine induced plasma cells are short-lived compared to those acquired during natural infection ^[48][49][114,115]. Waning effectiveness: Prior to the outbreak of the Omicron variant, a few studies have evaluated the effectiveness of COVID-19 vaccines and observed that 7 months after a booster dose, the effectiveness declined for BNT162b2, mRNA-1273 and ChAdOx1 nCoV-19 plus an mRNA vaccine ^[50][116]. A few data also suggest that vaccine effectiveness relatively declined after 5 months of vaccination among older aged (above 55 years) and individuals with risk factors ^[51][52][53][117,118,119]. Therefore, administration of booster dose is assumed to reduce the risk of infection and restore the waning effect. A recent study in Israel evaluated the effect of fourth booster dose of BNT162b2 vaccine for effectiveness against the Omicron variant. The rate of infection considerably lowered for a short period while the elicited immunity did not wane for severe disease ^[54][55][120,121]. Another study found ‘viral load decrease effectiveness’ significantly declines after booster dose of BNT162b2 vaccine. It suggests a fast waning of effectiveness of vaccine’s booster dose possibly affecting community level infection ^[56][122]. With respect to the emerging variants of the virus, COVID-19 vaccines have been demonstrated to elicit protection against severe infection. However, variability in vaccine effectiveness is seen for protection against symptomatic infections. For example, data suggest that vaccine effectiveness against symptomatic infections caused by the Delta variant is lower than the wild type and Alpha variants ^[57][58][123,124]. The waning effectiveness post two and three doses of mRNA vaccines have been described during the Delta and Omicron variant pandemic wave further underscores the importance of additional doses to sustain protection against different variants of SARS-CoV-2 ^[59][125]. Breakthrough infections: As no vaccine is 100% effective, there are instances of infection even after receiving vaccination which are known as breakthrough infections. For COVID-19, there is a higher risk of breakthrough infection with Delta and Omicron variants but the risk of severe infections is low among individuals who received vaccine booster doses ^[60][61][126,127]. The first breakthrough infection with omicron was detected in fully vaccinated German individuals with mRNA vaccine and exhibited mild to moderate illness ^[62][128]. A recent study from the USA suggested that individuals with breakthrough infections showed a lower risk of fatality and post-acute sequelae as compared to unvaccinated individuals ^[63][129]. Moreover, it is indicative from the available data that the risk of breakthrough infections is higher among vaccinated immuno-compromised patients and individuals with existing comorbidities ^[62][64][128,130]. Recently, many retrospective cohort studies have been conducted among healthcare workers which show the association between COVID-19 vaccination and asymptomatic infections. Studies observed that individuals vaccinated with two doses of the BNT162b2 mRNA vaccine exhibited lower incidence rates of asymptomatic infection. However, these findings are limited by observational designs ^[65][66][131,132]. Similarly, a research letter from St. Jude’s Children’s Research Hospital reported that the vaccination greatly reduced the symptomatic and asymptomatic infections in employees compared with their unvaccinated contemporaries. However, an exact association with the asymptomatic infection remains unclear ^[67][133]. The impact of vaccine on the onset of asymptomatic infection depends on the efficacy of the specific vaccine. The reduction in the asymptomatic infection is also likely to be affected by the timing of the vaccine doses ^[68][69][100,134].

4. COVID-19 Vaccine-Related Complications

Millions of COVID-19 vaccine doses have already been administered worldwide and various health authorities that monitor vaccine safety, e.g., the WHO, CDC, United States Food and Drug Administration (USFDA) etc., as well as stakeholders, have repeatedly emphasized the safety of the vaccines in use. Although severe adverse events are extremely rare, anaphylactic events have been reported for around five cases per one million administered vaccine doses ^[70][135]. Anaphylaxis reported for COVID-19 vaccines includes cardiovascular, haematological, neurological and autoantibody related events. Cardiovascular: As of June 2021, 1226 reports of myocarditis cases had been registered in the United States after the administration of more than 290 million doses of the COVID-19 mRNA vaccine ^[71][136]. Similar reports of myocarditis after vaccination have been reported from the Philippines, England and Israel ^[72][137]. Following the administration of two doses of mRNA-1273 (Moderna vaccine), BNT162b2 (Pfizer vaccine) and NVX-CoV2373 (Novavax vaccine), young males were reported with the occurrence of myocarditis and pericarditis ^[71][73][74][136,138,139]. Mostly mild myocarditis has been reported globally after a week of mRNA vaccine administration with speedy resolution of clinical symptoms ^[75][140]. Hematological: Around 0.0031% and 0.0045% of thrombotic events have been reported in the United Kingdom and Singapore, respectively, after administering mRNA vaccines ^[76][141]. Rare vaccine-related thrombosis and thrombocytopenia have been observed in five individuals of more than 1,30,000 cohort at around 7–10 days of first dose of the AstraZeneca vaccine (ChAdOx1 nCoV-19/AZD1222). The researchers proposed this adverse event as a spontaneous immune thrombotic thrombocytopenia induced by vaccine ^[77][142]. Of the approximately seven million doses of Ad26.COV2.S (Johnson & Johnson) vaccine administered, similar venous thrombosis with thrombocytopenia events have been recorded in 12 individuals by April 2021 after a single dose of vaccination. Fatal outcomes were recorded in 3 individuals ^[78][143]. The mRNA vaccines from Pfizer and Moderna also have shown the implications of triggering rare immune thrombocytopenia. A study observed 20 individuals with thrombocytopenia within 23 days of vaccination with two doses of the mRNA vaccines ^[79][144]. Although careful monitoring for symptoms post-vaccination is efficiently ongoing for such adverse events, vaccine regulatory bodies have reiterated the benefits of these COVID-19 vaccines in the population which outweigh rare risk events. Neurological: Emerging reports of neurological symptoms as rare adverse events have been recorded post COVID-19 vaccination. A study from Hong Kong reported Bell’s palsy cases post Vaccination with the first dose of CoronaVac (Sinovac Biotech, Hong Kong, China) and BNT162b2 vaccines. They found 28 cases after CoronaVac vaccination of more than 4.5 million individuals while 16 cases were reported post BNT162b2 vaccination of 5.3 million individuals ^[80][145]. An increased risk of Bell’s palsy and Guillain Barre syndrome with 1.38 and 2.9 incidence rate ratio, respectively, was also observed after vaccination with the first dose of ChAdOx1 nCoV-19 ^[81][146]. After administration of more than 13 million doses of Ad26.COV2.S vaccine, around 130 cases of Guillain Barre syndrome cases have been reported after a single dose vaccination in the US ^[82][147]. Although the mechanism is still unclear, researchers have hypothesized the role of autoimmune response through stimulation of inactive autoreactive T cells or vaccine antigen mimicking host cells ^[83][148].