“Vitamin D supplementation and Covid‐19 outcomes: A systematic review, meta‐analysis and meta‐regression - Wiley” plus 3 more
“Vitamin D supplementation and Covid‐19 outcomes: A systematic review, meta‐analysis and meta‐regression - Wiley” plus 3 more |
- Vitamin D supplementation and Covid‐19 outcomes: A systematic review, meta‐analysis and meta‐regression - Wiley
- Respiratory Infection RSV Surges in South as Mask Use, Distancing Decline - Medscape
- The 1918 influenza and COVID‐19 pandemics: The effect of age on outcomes - Wiley
- Present variants of concern and variants of interest of severe acute respiratory syndrome coronavirus 2: Their significant mutations in S‐glycoprotein, infectivity, re‐infectivity, immune escape and vaccines activity - Wiley
| Posted: 27 Jun 2021 12:00 AM PDT 1 INTRODUCTIONSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to spread globally causing a pandemic and has become a major medical focus for the last couple of years. The pandemic has involved over 164 million confirmed cases, with more than 3.4 million deaths as of 23 May 2021.1 While some SARS-CoV-2 infections appear as mild upper respiratory symptoms and may be self-limiting, notable numbers of patients require hospitalizations and intensive treatment following progression into a more severe cases, varying from simple lower respiratory tract infections to acute respiratory distress syndrome (ARDS) and eventually may turn into multi-organ failure.2, 3 Individuals with comorbidities such as obesity, diabetes, chronic respiratory disease, cardiovascular disease and other immunocompromising conditions are facing higher risks in developing the severe form of SARS-CoV-2 infections.4-9 For the past months, medical therapies to treat Covid-19 have been growing and evolving rapidly, ranging from supportive care, antivirals, anti-inflammatory agents and possible supplementations such as vitamin D.10-13 Several studies have shown that vitamin D has antiviral properties and potential roles against acute lung injury or ARDS, making large interest on vitamin D has rapidly emanated even in the early beginning of pandemic.14, 15 Low vitamin D serum levels is associated with an increase in inflammatory cytokine levels and significant increase of risk to develop pneumonia and viral respiratory tract infections, which both contribute to the development of ARDS.16-18 The goal of this study is to provide evidence whether or not vitamin D supplementation is associated with improved outcomes of Covid-19 based on the available studies. 2 MATERIALS AND METHODS2.1 Eligibility criteriaThe protocol of this systematic review and meta-analysis study of the observational and clinical trial studies was registered in PROSPERO (CRD42021256117). Included articles were selected as potentially fulfilling the entry criteria: comply the PICO framework (P: Covid-19 patients; I: vitamin D supplementation in any form; C: a group of patients who did not receive vitamin D, only receive standard of care therapy or any other medications as control/placebo; O: intensive care unit [ICU] admission, the need for mechanical ventilation and mortality), cohort, case-control, cross-sectional and randomized or non-randomized clinical trial articles were included. All studies other than original research articles (review articles, letter to editor or correspondence), case-series or case report studies, studies reported other than in English language, studies focussing on populations below 18 years of age and pregnant women were excluded. 2.2 Search strategy and study selectionThe papers from three databases (PubMed, Europe PMC and ClinicalTrials.gov) were searched systemically. Search terms used include 'vitamin D' OR 'calcidiol' OR 'calciferol' OR 'calcifediol' OR 'cholecalciferol' OR 'calcitriol' AND 'SARS-CoV-2', OR 'coronavirus disease 2019' OR 'Covid-19' in a time range from 2019 until 8 May 2021 with English-language restriction. Our searching strategy details are listed in Table 1. Initial screening of titles and abstracts was conducted to identify eligible articles. Searches of potential articles were also done by analysing the list of references of eligible studies. The search strategy was presented in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram.
2.3 Data extraction and quality assessmentTwo authors (TIH and DI) performed the data extraction. An extraction form was developed to list the essential information about the study and its population characteristic (age, gender, hypertension, diabetes and corticosteroids usage/consumption), vitamin D dose, the number of patients receiving vitamin D and the control group, as well as the outcome of Covid-19 patients. The outcomes of interest are the rate of ICU admission, the need for mechanical ventilation and the mortality. The ICU admission rate is defined by the number of patients who were subsequently admitted into the ICU during the hospital stay. The need for mechanical ventilation is defined by the number of patients who need assisted ventilation. The total number of patients who were dead during the follow-up period with positive Covid-19 status was described as the mortality outcome. Two authors (JEH and HH) assessed the quality of each study included in this study independently. The quality of clinical trials was assessed using the modified Jadad scale assessment where the random allocation, allocation concealment, blindness and withdrawals and drop-outs of each study were evaluated. The studies were scored from zero to seven and a study ranked as a high-quality study if the score was >4.19 The quality of case-control and cohort studies were assessed using Newcastle–Ottawa Scale (NOS). The assessment reviews the selection, comparability and outcome of each study, then each study was assigned a total score from zero to nine. A study is graded as good quality if it scores ≥7. Cross-sectional studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for Analytical Cross Sectional Studies. 2.4 Statistical analysisThe meta-analysis was performed using the Review Manager 5.4 (Cochrane Collaboration) software and Comprehensive Meta-Analysis version 3. Mantel–Haenszel's formula was employed to calculate odds ratio (OR) and its 95% confidence interval (95%CI) for the ICU admission outcome and the need for mechanical ventilation outcome, while Inverse Variance method was used to obtain the OR and 95% CI for the mortality outcome. The heterogeneity was assessed by using the I2 statistic with a value of <25%, 26–50% and >50% were considered as low, moderate and high degrees of heterogeneity, respectively. Random effects meta-regression was performed using a maximum likelihood for pre-specified variables including age, gender, hypertension, diabetes and the use of corticosteroids. The qualitative risk of publication bias was assessed with funnel plot analysis, while the quantitative risk of publication bias was assessed by using the Begg and Mazumdar rank correlation test.20 3 RESULTS3.1 Study selection and characteristicsThe searches on the databases yielded 6038 studies. A total of 5128 records remained following the elimination of duplicates. Screening the titles and abstracts and matching the inclusion and exclusion criteria, 5063 studies were removed. Among 65 evaluated full-text articles for its eligibility, 46 articles were excluded due to unavailable of results (still recruiting or withdrawn), 4 articles had no control or comparison group, 3 articles did not mention the criteria of the outcome of interest and 1 article because the full-text was not in English. The meta-analysis included 11 studies21-31 with a total of 2265 Covid-19 patients (Figure 1). Out of 11 studies, one study was double-blind randomized clinical trial, one study was open-label randomized clinical trial studies, four were retrospective cohort studies, two were prospective cohort studies and three were cross-sectional studies. All of the vitamin D doses were administered orally, although the dosage varied between each of the included studies, ranging from 25,000 IU/month up to 200,000 IU/day for two consecutive days. The baseline characteristics and severity between the vitamin D group and the control groups were already controlled in each of the included studies, meaning that there is no significant difference between two groups' characteristics. Table 2 presents the characteristics of the studies.  PRISMA diagram of the detailed process of selection of studies for inclusion in the systematic review and meta-analysis
3.2 Quality of study assessmentJadad scale assessments suggested that one clinical trial study was graded high quality, while another study was graded moderate quality (Table 3). Quality assessment of cohort and case-control studies using NOS scale and cross-sectional studies using JBI Critical Appraisal checklist indicated all included studies had a good quality (Table 4 and Table 5). Altogether, all studies were acceptable to be further analysed using meta-analysis.
3.3 Vitamin D and ICU admission of Covid-19 patientsFive studies (n = 772) reported the effect of vitamin D on the ICU admission of Covid-19 patients. Our pooled analysis showed that vitamin D supplementation was associated with reduction of ICU admission rate (OR 0.27; 95% CI: 0.09–0.76, p = 0.010, I2 = 70%, random-effect modelling; Figure 2a).  Forest plot that demonstrates the association of vitamin D supplementation with ICU admission rate (a), the need for mechanical ventilation (b) and mortality (c) outcomes 3.4 Vitamin D and the need for mechanical ventilationSix studies (n = 1516) reported the effect of vitamin D on the need for mechanical ventilation outcome. The pooled analysis suggested that vitamin D supplementation was associated with reduction of the need for mechanical ventilation (OR 0.34; 95% CI: 0.16–0.72, p = 0.005, I2 = 61%, random-effect modelling; Figure 2b). 3.5 Vitamin D and mortality of Covid-19 patientsTen studies (n = 2223) reported on mortality. The pooled estimate showed that vitamin D supplementation was associated with reduction of mortality from Covid-19 (OR 0.37; 95% CI: 0.21–0.66, p < 0.001, I2 = 50%, random-effect modelling; Figure 2c). 3.6 Meta regressionOur meta-regression suggested the association between vitamin D supplementation and mortality was affected by age (p = 0.027; Figure 3a), meaning that older people will gain more protective measures towards mortality in comparison with younger people. The association between vitamin D supplementation and mortality was not affected by gender (p = 0.191; Figure 3b), hypertension (p = 0.566; Figure 3c), diabetes (p = 0.608; Figure 3d), nor the use of corticosteroids (p = 0.070; Figure 3e).  Bubble-plot for meta-regression. Meta-regression analysis showed that the association between vitamin D supplementation and mortality outcome was affected by age (a), but not by gender (b), hypertension (c), diabetes (d) and the use of corticosteroids (e) 3.7 Publication biasFunnel plot analysis showed an asymmetrical inverted-plot for the ICU admission outcome (Figure 4a) and the need for mechanical ventilation outcome (Figure 4b), showing some indication of publication bias. Funnel plot analysis showed a relatively symmetrical inverted-plot for the mortality outcomes (Figure 4c). Begg and Mazumdar rank-correlation test were not statistically significant for ICU admission (p = 0.086), the need for mechanical ventilation (p = 0.060) and mortality outcome (p = 0.371), showing no indication of publication bias. However, because the number of included studies in the ICU admission and mechanical ventilation outcomes are fewer than 10 studies, the funnel plots and statistical tests for detecting publication bias are not very reliable when compared with larger numbers of included studies in each outcome.32, 33  Funnel plot analysis for the association of vitamin D supplementation with ICU admission (a), the need for mechanical ventilation (b) and mortality (c) outcomes 4 DISCUSSIONAccording to our pooled analysis, vitamin D supplementation had an association with a reduction of ICU admission rate, reduction in the need for ventilators and reduction of mortality from Covid-19. This meta-regression reveals that age affects the association between vitamin D supplementation and Covid-19 mortality. There are some explanations how vitamin D could affect the prognosis of Covid-19 patients. The interaction of SARS-CoV-2 infection and vitamin D are presented briefly in Figure 5. Both innate and adaptive arms of the immune system, triggered by SARS-CoV-2 infection, cause a destructive inflammatory reaction, resulting in local and systemic complications. The host immune or the inflammatory reaction is one of many severity-determining variables as proven by significant association between inflammatory proteins/indicators and disease severity.34, 35 Exhaustion markers (e.g., CD8+ T cells, NK cells, NKG2A) are increased during acute symptomatic period of Covid-19 and then return to normal in the convalescent period. Cytotoxic lymphocytes and natural killer cells aid control of viral infection, and both may serve as a predictor in determining the severity of the disease. Throughout the course of Covid-19 infection, Natural killer and cytotoxic lymphocytes will eventually reach functional exhaustion, as indicated by reduced total number.36 Severe Covid-19 patients have high levels of various inflammatory proteins such as C-reactive protein, D-dimer and cytokines, including IL-6, IL-1β, TNF-α, also known as cytokine storm.37 IL-6 can be used as a good indicator of poor outcome in Covid-19 patients who suffer ARDS.38, 39 Cytokine storm leads to a severe pulmonary infiltration by neutrophils and macrophages that causes severe alveolar injury with hyaline membrane formation and alveolar wall thickening.38 The cytokine storm increases inflammatory mediators and oxidative stress, while concomitantly reducing endothelial nitric oxide synthase. All these processes result in systemic inflammation and endothelial dysfunction, and ultimately cause hemodynamic instability, tissue injury and multiple organ failure.40  The role of vitamin D in suppressing the nuclear factor kappa B (NF-κB) signalling pathway (a) and the proposed potential therapeutic effect of vitamin D for COVID-19 and induced acute respiratory distress syndrome (b) There are three main mechanisms through which vitamin D may reduce the risk of infection: enhance physical barriers, cellular innate immunity and adaptive immunity. Vitamin D strengthens cellular immunity by induction of antimicrobial peptides, including human cathelicidin LL-37, and through 1,25-dihydroxyvitamin D and defensins.41 Cathelicidins are known to have direct antimicrobial effect towards a variety of pathogens comprising both Gram negative and positive bacteria, non-enveloped and enveloped viruses, and fungi.42 Cathelicidins also promote the chemotaxis of cellular immunity to the site of infection and its expression was upregulated by vitamin D especially in respiratory epithelial cells, which play a major role in host defenses.42 Furthermore, on the cellular level, vitamin D also stimulates gap junction genes, tight junction genes and adherens genes (e.g., E-cadherin) to strengthen cellular junction integrity and improve cell to cell communication, therefore maintaining the intercellular junctions to prevent further invasion of microorganisms, including viruses, which may lead to further inflammation and tissue damage.43, 44 The vitamin D receptor (VDR) is possessed by the majority of immune cells including macrophages, B and T lymphocytes, neutrophils and dendritic cells. VDR activation leads to downstream cell signalling that produces immunomodulatory, anti-proliferative, and pro differentiative effects.42 Vitamin D helps to reduce pro-inflammatory T helper 1 (Th1) cytokines, TNF-α and interferon (IFN)-γ and helps the production of Th2 lymphocyte cytokines which indirectly suppress Th1 cells.41, 45 Additional evidence that supports immunoregulatory function of vitamin D is that 1,25(OH)2D3 or calcitriol, the active form of vitamin D, is able to induce monocyte differentiation into macrophage-like form.42 VDR expressed by monocytes sensitizes them to the differentiating effects of calcitriol (autocrine mechanism for cell maturation). Vitamin D modulates macrophage response, and thus prevents overproduction of inflammatory cytokines and chemokines.42 Calcitriol downregulates granulocyte-macrophage colony stimulating factor but stimulates the immunosuppressive prostaglandin E2 production by the macrophages.41 Importantly, vitamin D deficiency impairs macrophage maturation.41 Several studies have shown that the risk of Covid-19 increases in people with vitamin D deficiencies; furthermore, lower concentration also contributes to the development of ARDS.46, 47 Aside from that, vitamin D has also been known to induce the production of type I IFNs, which able to suppress and keeping viral replication under control causing the prevention of further inflammatory response.48, 49 Several studies have reported that severe form of Covid-19 is frequently related with increased hypercoagulable state, which could be worsen by excessive inflammation and may accelerates upcoming thrombogenic events. Vitamin D has the potential role to promote antithrombin and thrombomodulin gene expression to suppress that hypercoagulable state, causing significant protection during the course of severe form of Covid-19.49-51 Vitamin D supplementation and serum levels above 50 ng/ml have been observed and may help in reducing severity and the course of viral diseases including Covid-19.41 Another role of vitamin D in the pathogenesis of Covid-19 is through its ability to inhibit the RAS and nuclear factor kappa B (NF-κB) pathway. Because ACE2 has a protective role against lung injuries, interference with that receptor by SARS-CoV-2 might be linked with ARDS. Lung injury caused by ischaemia and reperfusion are promoted by the increased expression of ACE/Ang II l and reduced levels of ACE2/Ang-(1-7). ACE2 plays its protective function to the lung through Ang-(1-7)/MasR pathway and prevents activation of NF-κB pathway/extracellular signal-regulated kinase.52 The 1α,25(OH)2D3, the biological active form of vitamin D, contributes its protective role and reduces lung injury by regulating RAS biosynthesis (renin, ACE/Ang II/AT1R axis and ACE2/Ang-(1-7) axis stimulation).53 The VDR and calcitriol also prevent lung, liver and kidney fibrosis through the downregulation of RAS and the inhibition of NF-κB and wnt/β-catenin.54, 55 A cohort study that investigates the influence of genetic variation in vitamin D pathway found that three SNP in VDR (rs4334089, rs11568820 and rs7970314) are associated with increased risk of upper respiratory tract infection.56 A systematic review and meta-analysis study which evaluates the association between VDR polymorphism and severe Respiratory Syncytial Virus (RSV)-bronchiolitis supports the association between FokI polymorphism and severe RSV infection. This study also examines the role of six VDR polymorphisms (Cdx, A1012G, FokI, BsmI, ApaI and TaqI) on infection susceptibility to enveloped virus found that a polymorphism at locus rs2228570 (FokI) is associated with viral infections.57 The TT genotype and T allele were reported to be risk factors for infections with enveloped viruses, including RSV.58, 59 Being an enveloped virus, it may be the same case for SARS-CoV-2. The mechanism that explains the association of FokI polymorphism with increased viral infection is that the FokI polymorphism creates a shorter VDR proteins that causes higher rate of transcription driven by the NF-κB, increased IL-12 and higher lymphocyte proliferation.56 Therefore, supplementation with vitamin D may help in ameliorating those potentially negative effects from viral infection. All of these properties and roles might explain the benefit of vitamin D on the outcomes of Covid-19. This study has some limitations. Significant heterogeneities were identified on most of the outcomes of interests included in this study. This was probably caused by the difference in the given vitamin D doses and co-administered medications with vitamin D as Covid-19 treatment. Importantly, we have made rigorous efforts to ensure that only sound studies were included, and several pre-print studies were included to minimize the risk of publication bias. 5 CONCLUSIONOur meta-analysis indicates that vitamin D supplementation had an association with favourable outcomes of Covid-19, compromising reduction in the rate of ICU admission, reduction in mechanical ventilation usage and reduction of mortality rate from Covid-19. This study suggests that vitamin D might be a potential therapeutic agent for the management of Covid-19 to give better outcomes for the patients. However, more randomized clinical trial studies are still necessary and should be done to confirming the results of our study. Finally, vitamin D might be considered as an essential drug for future Covid-19 therapy models. CONFLICT OF INTERESTThe authors declare that there is no conflict of interest. AUTHOR CONTRIBUTIONConceptualization, methodology, formal analysis, data curation, writing-original draft, visualization, writing-review and editing: Timotius Ivan Hariyanto. Conceptualization, methodology, formal analysis, data curation, writing-original draft, writing-review and editing: Denny Intan. Conceptualization, validation, supervision, writing-review and editing: Joshua Edward Hananto. Conceptualization, validation, supervision, writing-review and editing: Harapan Harapan. Conceptualization, validation, supervision, writing-review and editing: Andree Kurniawan. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory Infection RSV Surges in South as Mask Use, Distancing Decline - Medscape Posted: 28 Jun 2021 12:23 PM PDT  Doctors in Georgia and other Southern states have seen since April an unusual surge of a common respiratory virus that affects children and older adults. The spike in cases of respiratory syncytial virus (RSV) at this time of year is linked, at least in part, to children and others no longer widely wearing masks or social distancing to prevent COVID-19 infection, experts say. When masks began coming off, "we knew we'd see a really bad RSV season,'' said Dr Stephen Thacker, a pediatric infectious disease specialist in Savannah."Kids are getting infected at the same time.'' Thacker said the virus swept through his own household, starting with his youngest child. "I got it, too,'' he told GHN on Thursday. The CDC this month issued an advisory about the rise of RSV, which can lead to severe disease in young children and older adults. It's primarily spread via respiratory droplets when a person coughs or sneezes, and through direct contact with a contaminated surface. RSV is the most common cause of pneumonia and bronchiolitis (inflammation and congestion of the small airways in the lungs) in children under a year old in the United States. Each year in the US, the virus leads to an average of about 58,000 hospitalizations, with 100 to 500 deaths among children younger than 5 years old; and 177,000 hospitalizations with 14,000 deaths among adults aged 65 years or older. The virus is generally a leading cause of hospitalization for children in the nation. The risk is worse for children born prematurely and those with heart conditions or immune system problems, Thacker added. Fortunately, most people who get it, including infants, develop only mild symptoms like those of a common cold, such as congestion, runny nose, and coughing, the American Lung Association in Georgia said. Compared with previous years, RSV activity remained relatively low from May 2020 to March 2021, the CDC said. But since then, the infections have surged. Dr Flavia Rossi, a Tifton pediatrician, told GHN last week that her practice is seeing a substantial rise in RSV cases, and she linked the increase to masks no longer being worn as frequently. Health officials have seen an increase in RSV cases in Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, New Mexico, North Carolina, Oklahoma, South Carolina, Tennessee, and Texas. More children and adults in the population may not have been exposed and infected while people were physically distancing and not mixing, said Dr Andi Shane, pediatric infectious disease physician at Children's Healthcare of Atlanta. Shane also noted that "some countries in the Southern Hemisphere, notably Australia and South Africa, also saw an interseasonal increase in children with RSV during their late spring and early summer of 2020-21, which like some parts of the Southeastern US may correspond with increased mixing of people as communities reopen and people travel." The Lung Association urges parents to watch for symptoms of RSV in their children, which include:
"Parents know their children best, and if they feel that their child is having problems breathing, refusing to drink, and is not acting as they usually do, they should be brought to medical attention," Shane said. "Children with underlying medical conditions are more likely to require hospitalization when they have an infection with RSV as well as other respiratory viruses such as influenza and SARS-CoV-2, the virus that causes COVID-19." Almost all children will have had an RSV infection by their second birthday, the CDC says. And most RSV infections go away on their own in a week or two. There is no specific treatment for RSV infection, though researchers are working to develop vaccines and antivirals (medicines that fight viruses). Due to reduced circulation of RSV during the winter months of 2020-2021, older infants and toddlers might now be at increased risk of severe RSV-associated illness. That's because these children have likely not had typical levels of exposure to RSV during the past 15 months, the CDC said. Thacker added that "the smaller you are, the smaller the nasal passages are, and a little mucus causes a lot of problems.'' A drug called Synagis can be used as a preventive measure against RSV in high-risk children, though insurers have at times balked at coverage of the medication, Thacker said. As a general preventive measure, he recommended practicing good hand hygiene, including frequent handwashing. Among recommended steps to relieve symptoms:
Symptoms in adults are typically consistent with upper respiratory tract infections, including a runny nose, a sore throat, coughing, headaches, fatigue, and fever. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The 1918 influenza and COVID‐19 pandemics: The effect of age on outcomes - Wiley Posted: 27 Jun 2021 12:00 AM PDT  The 1918 'Spanish' influenza pandemic and the current coronavirus disease 2019 (COVID-19) pandemic have been caused by two distinct respiratory viruses. The similarities and differences between each pandemic are summarized in Table 1. While the exact origins of the 1918 event have not been defined, it was caused by a founder influenza A virus strain of the H1N1 subtype.1 Early reports described transmission of this influenza virus strain in the US army camps and the American Expeditionary Forces were involved in spreading the virus to Europe via maritime routes. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of the COVID-19 pandemic, was first associated with human disease in Wuhan, China, in late 2019 and rapidly disseminated by air travel. Both pandemics spread globally with multiple waves of infection. It is estimated that 500 million people, or almost one-third of the world's population, experienced symptomatic disease during the 1918 pandemic, with possibly 50–100 million deaths.2 The latest figures for COVID-19 (15 June 2021) list 176 million infections or approximately 2% of the world's population and 3.8 million deaths.3 It is important to acknowledge that infection rates based on positive swab testing may be an underestimate of COVID-19, particularly in some countries with low testing rates.
Mortality associated with infection from circulating seasonal influenza virus strains generally follows a 'U-shaped' curve with high death rates in the very young and very old. In contrast, the 1918 pandemic produced a 'W-shaped' mortality curve with a high death rate in healthy young adults, which was responsible for most of the excess influenza deaths.1 However, the mortality associated with COVID-19 is very different, where the vast majority of deaths have occurred in people over the age of 70 years.3 Death in young children infected with SARS-CoV-2 is very rare. Therefore, age is a major determinant of clinical disease outcome following infection with the two respiratory viruses associated with these different pandemics. Age has a profound effect on the susceptibility of individuals to infection, but this is an area which is still not well understood.4 Neonates are born with limited immunity, with protection provided from maternal antibodies. The innate immune response in children develops before the adaptive response. Young adults (approximately 20–40 years) have well-developed and effective immunity. In older people, the immune system becomes less effective. Immune senescence occurs with increasing age.4, 5 The ageing immune system has decreased tolerance to self-antigens, which predisposes to the development of auto-immune disease. The adaptive immune response becomes dysregulated in the elderly with changes in the number and function of T- and B-cell compartments. Macrophage and neutrophil function decreases with age. Finally, inflamm-ageing is characterized by the increased production of inflammatory mediators with age.4, 5 The leading cause of excess mortality in healthy young adults in the 1918 pandemic was secondary bacterial pneumonia.1 Lung autopsy specimens have demonstrated severe bronchopneumonia with epithelial necrosis, haemorrhage, oedema, thrombosis and variant pathology from which pathogenic bacteria could be cultured.1, 6 Why there was such a high death rate in healthy young adults is not understood. It is possible that an inappropriately strong immune response may have contributed to poor outcomes; however, the published data supporting this proposition are limited. Damage to the bronchial epithelium and alveolar endothelium from direct viral cytopathicity and vigorous innate immunity7 may predispose to opportunistic pulmonary infection with pharyngeal bacteria such as Streptococcus pneumoniae. A 'cytokine storm' may occur in severe influenza with contributions from both innate and adaptive immune cells resulting in lung damage,8 but there are no specific human studies published in reference to the 1918 influenza outbreak. This is because the H1N1 influenza A virus that caused the 1918 pandemic was not known to be the aetiological agent at the time, with influenza A viruses only first isolated in the 1930s. While the strain causing the 1918 pandemic has since been recovered and reconstructed,9 the viral virulence and host response factors that contribute to its severe pathogenicity remain under investigation today. A proportion of patients with COVID-19 develop lung disease, such as pneumonia or acute respiratory distress syndrome, which may result in progressive respiratory failure. Mortality overwhelmingly occurs in adults over the age of 70 years. Post-mortem findings in COVID-19 demonstrate diffuse alveolar damage including capillary congestion, pneumocyte necrosis, interstitial and alveolar oedema and widespread thrombi.10 In contrast to the 1918 influenza virus, SARS-CoV-2 infection is not generally associated with secondary bacterial pneumonia. A cytokine storm may occur in COVID-19; whether this is an appropriate response to severe infection or contributes to lung pathology has been controversial.11 However, mild pharmacological immune suppression with dexamethasone has been clearly demonstrated to be beneficial.12 Whether immune senescence or inflamm-ageing is involved in poor outcomes is currently under investigation. Young children, including those less than 2 years of age, appear to be protected against significant clinical disease with COVID-19 and surprisingly have the best outcomes of any age group. Young children typically have no or minimal symptoms with SARS-CoV-2 infection, suggesting that they control and clear the infection very early. There are likely to be a variety of mechanisms responsible for this effect,13 although at this stage definitive studies are lacking. Airway macrophages are the immune cells that rapidly respond to viruses in the respiratory tract. It is possible that macrophages could play a key role in determining the outcome of SARS-CoV-2 infection, particularly in children, but this is an area in which there are little published data. Age appears to be a primary factor in the outcomes of both the 1918 influenza and COVID-19 pandemics, but the mechanisms responsible remain unclear. Studies that directly compare immune responses between different age groups may provide important insights as to why this occurs and have potential implications for treatment. CONFLICT OF INTERESTThe authors have no conflict of interest in this work. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Posted: 27 Jun 2021 12:00 AM PDT Abbreviations
1 INTRODUCTIONThe devastating effects of the COVID-19 pandemic have brought noteworthy health crises throughout the globe. The pandemic has generated significant social problems and even has shut down communities in different countries throughout the world.1-4 In addition, the world is facing an economic crisis, creating a vulnerable condition in developing world countries. As of 11 June 2021, COVID-19 has infected 174,502,686 peoples as per World Health Organization (WHO) data. Meanwhile, 3,770,361 peoples have died from this disease so far. The scientists are putting their best efforts into searching the different therapeutic and development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).5-8 The rise of infections and death cases has been observed in several world regions after the spread of novel SARS-CoV-2 variants. Due to a new variant, COVID-19 cases gradually increased in the UK in November 2020. The country has to go through a lockdown to contain the spread of variants.9 Similarly, due to the spread of a novel SARS-CoV-2 variant, a steady rise of COVID-19 cases was noted in India. The spread of the variant has created a second wave of infection of COVID-19 cases in the country. The country has currently imposed lockdown partially in several regions of the country.10 Newly emerging variants are now a threat to global public health gain. The genome sequence data of SARS-CoV-2 were first provided by the Chinese researcher, Professor Zhang, and his colleagues at Fudan University in the first week of January 2020. The team deposited the sequence into the GenBank for the use of further studies.11, 12 After the SARS-CoV-2 detection in China, it was observed that several SARS-CoV-2 new variants came into existence with time and different geographic locations as a consequence of genetic evolution (Figure 1). SARS-CoV-2 new variants genome sequences are submitted quickly to the global initiative on sharing all influenza data (GISAID) and GenBank databases. Around the world, most scientists are submitting their genome sequences of the variants into the GISAID database, and it is a well-known database for the genome sequences for this virus. As of 12 June 2021, 1,938,109 sequences have been submitted to the GISAID database. Utilising this database, scientists are trying to delineate several vital factors of the new variants, such as mutations, pathogenicity, virulence, transmissibility and antigenicity.  A timeline depicting the origin time of some significant variants of SARS-CoV-2. The variants of concern are marked into the red box and variants of interest marked into the violet box. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 It has been observed that mutations in the genome sequence have generated a definite change, giving rise to the new variants of the SARS-CoV-2.13, 14 Mutations are prevalent in the viral genomes. Mutations occur due to the consequences of viral replication.15 In general, higher mutation rates are recorded in RNA viruses compared to DNA viruses.16 However, fewer mutations are noted in the coronaviruses than in RNA viruses because the virus can produce an enzyme with proof correction machinery. This enzyme corrects several errors that occur during replication.16 Nevertheless, it has been observed that this virus has made several single mutations throughout the genome compared to the wild type (genome from the Wuhan strain in China, which was sequenced in the first week of January 2020).17, 18 Several factors are associated with the generation of viral mutations. One of the significant causes is the intervention of the human immune system. The machinery involved in the immune system can cause interference in the genome to introduce viral mutations. Another important cause of mutation in the genome of this virus is the rapid transmission and quick spread rate. Moreover, RNA viruses are prone to rapid mutations as compared to DNA viruses. These factors provide considerable opportunities for SARS-CoV-2 with natural selection, which generates favourable and rare-acted mutations (Figure 2).19, 20 Significant studied SARS-CoV-2 mutations in the S-glycoprotein are K417T/N, L452R, E484K, N501Y and D614G, responsible for generating different kinds of significant variants.  Fundamental factors and the processes associated with the SARS-CoV-2 mutation. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 During the last one and half years, several variants of this virus came into existence. Some of the significant variants are B.1.351 (South Africa), B.1.1.7 (UK), P.1 (Brazil/Japan), B.1.427 (USA), B.1.617 (India) and B.1.429 (USA).10, 21-23 Among these variants, WHO, Centers for Disease Control and Prevention (CDC) (USA) and European Centre for Disease Prevention (ECDC) (Europe) has entitled some variants as significant variants and termed them as variants of concern (VOCs) and variants of interest (VOIs). VOC has appeared as a worry for various countries as they emerged as a greater threat to public health with superior infectivity and transmissibility. At the same time, these variants harm the COVID-19 epidemiology blueprint and have an increased virulence pattern. Thus, VOC can alter the COVID-19 clinical manifestation. Even, it may reduce the efficacy of available vaccines and therapeutics and may obstruct the present ability of reverse transcription polymerase chain reaction (RT-PCR) assays to detect variants.24, 25 Similarly, VOI appeared due to amino acid alterations associated with increased community transmission, and these variants have been detected in various countries.24, 25 In this manuscript, we have discussed the alarming appearance of these variants throughout the world. The article also discusses the properties of the significant VOCs and VOIs, important mutations for the VOCs, and VOIs such as K417T/N, L452R, E484K, N501Y, D614G and P681R. Consecutively, we have illustrated the transmissibility, infectivity, re-infectivity immune escape, vaccine activity and vaccine escape of new variants. 2 APPEARANCE OF VARIANTS OF SARS-CoV-2 IS ALARMING THROUGHOUT THE WORLDSeveral SARS-CoV-2 variants have appeared as a global threat throughout the world (Figure 3). It has raised various major questions among scientists about the nature of the variants and their consequences. One of the significant variants is the B.1.1.7, which originated in the UK.26 Frampton et al. found that the disease was augmented due to the transmissibility of the variant. Using a cohort study in the UK hospital, the researchers concluded that the variant was not associated with the severity of the disease in the hospitalised cohort.27 Another lineage that was found spreading throughout South Africa was B.1.351 variant.28 Zhou et al. found that this variant has immune escaping abilities and can escape from the neutralisation of monoclonal antibodies due to the E484K mutation.29 At the same time, P.1 variant of SARS-CoV-2 was identified from the genome sample collected from the Manaus city in Brazil. This variant was genome sequenced from the collected sample and was found associated with re-infection in Manaus.30, 31 At the same time, the other two variants (B.1.429 and B.1.427) were detected from Colorado, USA. Both of these variants spread throughout the USA and are now a public health concern in USA.32 Jacobson et al. found these two variants re-infected the healthcare personnel even after vaccination. The phenomenon was observed in the medical centre in Northern California, USA. Among the infected samples, N501Y mutation and E484K mutation were observed.33 Some other significant variants are B.1.525 (UK/Nigeria), B.1.617 (India), P.2 (Brazil), P.3 (Philippines/Japan) and B.1.616 (France), which are affecting public health and hindering the efforts to contain this pandemic.  The origin, distribution and transmission of newly emerging SARS-CoV-2 variants. (a) Origin of variants of concern and variants of interest. (b) Distribution and transmission of newly emerging variants of SARS-CoV-2. The figure focused on Asia – subsampling which was developed using the Nextstrain server on 10 June 2021. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 Acquisitions of several mutations give rise to several significant variants, and natural selection determines the fate of a newly generated mutation. Therefore, natural selection is the determinantal factor about the existence and the consequence of the variants. 3 PROPERTIES OF THE SIGNIFICANT VOCsFive SARS-CoV-2 variants are regarded as VOCs by the WHO and the CDC (USA) as of 27 May 2021 (Table 1). The most significant variants are as follows.
3.1 B.1.1.7 (Alpha) variantThe B.1.1.7 variant is also defined as 20I/501Y.V1, as described by the Nextstrain database, and GR/501Y.V1, as described by the GISAID database. Hence, 20I/501Y.V1 and GR/501Y.V1 are known as Nextstrain clade and GISAID clade, respectively. However, both are similar identity of the B.1.1.7 variant. B.1.1.7 variant was identified in a clinical sample collected in the UK during September 2020. This variant was responsible for the augmented infection in different parts of England, especially the eastern and south-eastern parts of England. The variant was even found responsible for the infection in other regions of the London municipality. Due to the rapid spread of this variant, the daily mortality rate was increased in the country. The highest mortality was noted during January 2021.26 Afterwards, B.1.1.7 variant spread to other 30 countries and was detected in the USA between 29 December 2020 and 12 January 2021. Galloway et al. have predicted that the transmission of the B.1.1.7 variant might threaten the USA healthcare prospects.34 High transmissibility of this variant in comparison with non-VOC was reported by Volz et al. They have concluded that B.1.1.7 variant may have considerable transmission gain compared to non-VOC. However, more infection cases were observed among the patients below the 20-years age group than non-VOC lineages.35 Several significant mutations accumulated in this variant throughout the genome. Various vital mutations in the receptor-binding domain (RBD) region of this strain are E484K, S494P and N501Y (Figure 4a). Other than the mutations in the RBD region, other major mutations in S-glycoprotein are 69del, 70del, D614G, 144del, A570D, S982A, P681H, D1118H, T716I and K1191N.36 Graham et al. observed that this variant is resistant to neutralisation through the neutralising antibodies (nAbs).37  The schematic diagram showing the position of the significant mutations in the receptor-binding domain (RBD) region in variant of concern (VOC) and variant of interest (VOI). The diagram depicts the position of significant mutations in the RBD in VOC. (b) The diagram depicts the position of significant mutations in the RBD in VOI 3.2 B.1.351 (Beta) variantThe B.1.351 variant is also defined as 20H/501Y.V2, as described by the Nextstrain database, and GH/501Y.V2, as described by the GISAID database. Therefore, 20H/501Y.V2 and GH/501Y.V2 are known as Nextstrain clade and GISAID clade, respectively. The variant was detected from South Africa in December 2020 and was traced in the Eastern Cape region. After that, it was detected from the KwaZulu and Western Cape regions.38 The variant was even detected from Zambia, located in the southern part of Africa,39 indicating circulation of this variant throughout the country. Simultaneously, the variant also got transferred to various countries. Yadav et al. reported that the variant was detected in India, imported through a traveller.40 In March 2021, the variant was identified in Germany through a rapid antigen test.41 During January–February 2021, the clinical laboratory identified the variant from Maryland, USA.42 It was observed that this variant has more hACE2 binding affinity. The researchers showed that the variant has 4.62 times more RBD-hACE2 binding affinity than the RBD of SARS-CoV-2.43 The variant is also associated with public health hazards such as re-infections. Staub et al. found that B.1.351 accounted for four re-infection cases in Luxembourg, Europe.44 Several mutations have accumulated in the genome of this variant. Among them, one deletion mutation and 12 non-synonymous mutations are significant in comparison with the Wuhan strain. The mutations in the RBD region are K417N, E484K and N501Y (Figure 4a). Other than the RBD, S-glycoprotein mutations are D80A, D215G, 241del, 242del, 243del, D614G and A701V. Some variants demonstrate escape from neutralising monoclonal antibodies due to mutations like K417N, E484K and N501Y. It was observed that this variant could escape from vaccine-induced sera and natural sera.29 One clinical trial was conducted in South Africa to understand the protection or efficiency of the AstraZeneca COVID-19 vaccine (AZD1222) against the B.1.351 variant in infected individuals. The trial evaluated the vaccine protection due to the infection of this variant in COVID-19 patients with mild to moderate symptoms. During the evaluation process of the clinical trial, two-dose regimen of this vaccine was selected. No protection was observed in the patients (mild-to-moderate patients) due to the infectivity of this variant.45 3.3 P.1 (Gamma) variantP.1 variant, defined as B.1.1.28.1, belongs to B.1.1.28 lineage. It is a significant variant worldwide, first identified in Brazil (late 2020 to January 2021) from the clinical genome sequence.21, 46 This variant is responsible for generating the second wave in Brazil with high infection rate.31 The P.1 variant is also known as 20J/501Y.V3, as described by the Nextstrain database, and GR/501Y.V3, as described by the GISAID database. Therefore, 20J/501Y.V3 and GR/501Y.V3 are known as Nextstrain clade and GISAID clade, respectively. Thus, both are the similar identity of the P.1 variant. The variant is responsible for re-infections in the Amazonian area of Brazil.47 The variant is also accountable for the re-infection of the São Paulo State.48 The variant got transmitted outside Brazil and circulated in different countries throughout the world. Di Giallonardo et al. observed that the P.1 variant was transmitted to several parts of Italy.49 At the same time, the variant was also detected in Uruguay and Japan.50, 51 The researchers found three significant mutations from the genome sequence of this variant, which are E484K, K417T and N501Y.51 Several mutations have accumulated in the genome of the P.1 variant. Some significant mutations are found in the S-glycoprotein, ORF1ab, ORF8 and N protein. The S-glycoprotein of this variant gathered the highest number of mutations compared to the Wuhan strain. About 12 mutations in the S-glycoprotein of this variant have been reported. The mutations in the RBD region are K417T, E484K and N501Y (Figure 4a). Other than RBD, the S-glycoprotein mutations are T20N, R190S, D614G, P26S, D138Y, H655Y, L18F and T1027I. Due to these mutations, the P.1 variant shows augmented resistance to nAbs.51, 52 3.4 B.1.429 (Epsilon) and B.1.427 (Epsilon) variantsThe B.1.427 variant was detected from California, USA. The variant was described as VOC by CDC, USA, but it is entitled as VOI by the WHO. The B.1.427 variant is also known as 20C/S:452R as defined by the Nextstrain database. Some significant mutations were found in the S-glycoprotein. One mutation in the RBD region is L452R (Figure 4a). Another primary mutation in the S-glycoprotein other than the RBD is D614G. The B.1.429 variant was also identified from California, USA. The variant was described as VOC by CDC, USA, but it is entitled as VOI by the WHO. The B.1.429 variant is also known as 20C/S:452R as defined by the Nextstrain database. Some significant mutations were noted in the S-glycoprotein. The one considerable mutation is located in the RBD (L452R) (Figure 4a). S-glycoprotein mutations, other than the RBD, are S13I, W152C and D614G. After continuous surveillance during January–March 2021, these two variants were identified from Colorado, USA, and were found highly contagious. These variants are accountable for more severe illness.32 Another study found post-vaccination infections among healthcare workers by these variants in the northern part of California.53 Conversely, McCallum et al. reported the immune escape properties of these two variants.54 4 PROPERTIES OF THE SIGNIFICANT VOIsThere are 11 VOIs according to the WHO and the CDC (USA) as of 27 May 2021 (Table 2). The significant variants are as follows.
4.1 B.1.525 (Eta) variantB.1.525 variant was found in the UK and also in Nigeria. The B.1.525 variant is also known as 20A/S.484K, as defined by the Nextstrain database. Similarly, the name G/484K.V3 is given by the GISAID database. Therefore, 20A/S.484K and G/484K.V3 are known as Nextstrain clade and GISAID clade, respectively. This novel variant has got transmitted to different parts of the globe. Pereira et al. reported that the identification of the variant had created a challenge for public healthcare personals in Brazil.55 Similarly, the B.1.525 was also reported from Nigeria.56 Significant mutations are reported in the S-glycoprotein (A67V, 69del, 70del, 144del, D614G, Q677H and F888L). Other than S-glycoprotein, one considerable mutation is noted in the RBD (E484K) (Figure 4b). 4.2 B.1.617 variant and its sublineages (B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3)This variant was first detected from the Maharashtra state in India. The B.1.617 variant is also known as G/452R.V3, as defined by the GISAID database, hence G/452R.V3 is known as GISAID clade. Presently, this variant is circulating throughout India. It is accountable for the sudden surge in infections and resulted in a second wave of infections in India during April 2021.10, 57 WHO described this variant as VOI.53 At the same time, ECDC defined this variant as VOC during May 2021.58 Some significant mutations are found in the S-glycoprotein of this strain. The one considerable mutation is located in the RBD (L452R). However, mutation (E484K) was observed in the RBD of some samples, while it was found absent in others.53 Other than the RBD, important mutations in the S-glycoprotein are D614G and P681R. Using clinical isolates of this variant, Yadav et al. investigated the neutralisation of B.1.617 using covaxin (BBV152) vaccine sera. The analysis is underway, and the results are yet to be published.59 Presently, three sublineages have been observed for this variant which are B.1.617.1, B.1.617.2 and B.1.617.3. These all sublineages are described as VOC by ECDC during May 2021.58 In B.1.617.1, RBD mutations are E484Q and L452R. Other than the RBD, important mutations in the S-glycoprotein are T95I, D614G, E154K, P681R, G142D and Q1071H. In B.1.617.2, RBD mutations are L452R and T478K (Figure 4b). Similarly, other than the RBD, major mutations in the S-glycoprotein are T19R, G142D, D614G, P681R, 157del, R158G, 156del and D950N. Conversely, in B.1.617.3, RBD mutations are L452R and E484Q. Similarly, other than the RBD, major mutations in the S-glycoprotein are T19R, G142D, D614G, P681R and D950N. Yadav et al. determined the neutralisation antibody titer from the sera of the covishield (AstraZeneca and Serum Institute of India) vaccinated individuals. They found that the persons were protected from the B.1.617.1 variant regarding severity and mortality after 4 weeks of second dose vaccination.60 4.3 P.2 (Zeta) variantP.2 variant was first identified in Brazil in April 2020. It is also known as B.1.1.28.2, belonging to B.1.1.28 lineage. It is now circulating in several countries throughout the world. Recently, the variant was detected in Uruguay.50 The P.2 variant is also known as 20B/S.484K, as defined by the Nextstrain database. Therefore, 20B/S.484K is also known as Nextstrain clade. Significant mutations are found in the S-glycoprotein of this strain (F565L, D614G and V1176F). Other than S-glycoprotein, one considerable mutation has been observed in the RBD (E484K) (Figure 4b). 4.4 P.3 (Theta) variantP.3 variant was identified in Japan and the Philippines during February 2021. It is also known as B.1.1.28.3, corresponding to B.1.1.28 lineage. Several significant mutations are found in the S-glycoprotein (141/143del, D614G P681H, E1092K, H1101Y and V1176F). Other than S-glycoprotein, two significant mutations are located in the RBD, which are E484K and N501 (Figure 4b). At the same time, the immune evasion characteristic of this variant was reported by Ferraz et al. The study analysed the immune evasion through the model generation of the electrostatic surface potential of RBD.61 4.5 B.1.616 variantB.1.616 variant was identified in France during January 2021. Fourati et al. described the variant as Clade 19B.62 However, the Nextstrain server describes it as the 20C clade. Transmission of this variant is low because the variant does possess a mutation that is not associated with the transmission. Several important mutations are reported in the S-glycoprotein (141/143del, D614G P681H, E1092K, H1101Y and V1176F). The two significant mutations are located in the RBD (E484K and N501Y) (Figure 4b). 5 SIGNIFICANT MUTATIONS FOR THE VOCs AND VOIsSeveral significant mutations are observed in the VOCs and VOIs (Figure 5a and 5b). We also noted the country-wise significant mutations for the VOCs and VOIs in Table 3. Some important mutations are described below.  Position of some significant mutations in the S-glycoprotein. (a) Position of some crucial mutations in the 3D structure of S-glycoprotein. (b) Position of some essential mutations in a schematic diagram of S-glycoprotein
5.1 K417T/N mutationsThe two mutations, K417T and K417N, are significant mutations that are found in the RBD region. K417T is noted in the P.1 variant and the K417N in the B.1.351 variant. K417T mutation is associated with a conformational change of S protein. At the same time, K417N is also related to a conformational change of S protein. Both of these two mutations are responsible for the antibody escape characteristic of the virus.63, 64 Specifically, these two mutations are associated with the hACE2 biding of the virus. The affinity of binding to hACE2 increases the infectivity of new SARS-CoV-2 variants.65 5.2 L452R mutationThis mutation is associated with the change in the RBD region of VOC B.1.429 and B.1.427 variants from the USA. Similarly, the mutation is also noted in the RBD region of the B.1.617 variant and its sublineages (B.1.617.1, B.1.617.2 and B.1.617.3). It is also found in the VOI B.1.427 variant which is originated from USA. This mutation is associated with increased infectivity, higher transmission and a reduction in neutralisation by specific therapeutic antibodies. Researchers found that it is associated with more than 18%–24% higher transmissibility. At the same time, a 20-fold reduction was observed in neutralising titers from vaccine recipient individuals and convalescent patients.66 5.3 E484K mutationThis mutation is associated with the change in the RBD region of VOC B.1.1.7, B.1.351 and P.1 variants. Likewise, the mutation is also noted in the RBD region of VOI P.2, P.3, B.1.525, B.1.526 and sublineages B.1.617.1 and B.1.617.3 of B.1.617 variant. This mutation is related to the hACE2 biding of the virus and is reported for the augmented infectivity of new variants.65 Lohr et al. reported that the immune escape phenomenon during Bamlanivimab therapy in patients infected with a new variant (B.1.1.7) was because of E484K mutation.67 Jangra et al. reported that this mutation influences the binding of nAbs and thus reduces antibody neutralisation.68 The mutation is also associated with the re-infection, as noted in the SARS-CoV-2 re-infected patients in Brazil.69 5.4 N501Y mutationThis significant mutation is associated with the change in the RBD region of VOC B.1.1.7, B.1.351 and P.1 variants. At the same time, the mutation is also noted in the RBD region of the VOI P.3 variant. Zhao et al. evaluated the variant-specific case fatality ratio (CFR) using a statistical framework of time-varying representation and calculated changes in CFR. They concluded that N501Y substitution is associated with a possibility of case fatality for COVID-19 patients.70 Using Monte Carlo sampling and molecular dynamic simulations, Ali et al. found that this mutation confirms a sturdy binding resemblance to ACE2. This mutation is accountable for the superior electrostatic interactions in the interaction site and is responsible for a powerful hydrogen bond formation between residue T500 of S-glycoprotein and residue D355 of ACE2 near the mutation site. Finally, they concluded that the molecular association during binding might contribute above 40% of the binding energy of total binding energy.71 By utilising whole genome sequencing and Swiss-wide diagnostic screening, researchers established that this mutation is associated with the transmission and rapid spread of the new variants in Switzerland.72 5.5 D614G mutationThis significant mutation is found in the S-glycoprotein protein outside the RBD region. The mutation is noted from all the reported VOC variants (P.1, B.1.427, B.1.1.7, B.1.429 and B.1.351). At the same time, the mutation is also noted in the S-glycoprotein outside the RBD region of all the reported VOI (B.1.525, B.1.526 (sublineage B.1.526.1), B.1.617 (all sublineages like B.1.617.1, B.1.617.2 and B.1.617.3), P.2, P.3, B.1.616 and B.1.427). Therefore, it is a very significant mutation in the newly appearing SARS-CoV-2 variants. Mansbach et al. described that this rapid transition of a variant with G-form carried an amino acid substitution D614G. This mutation with G-form provides a favourable environment for an open conformational state of S-glycoprotein. Through the in vitro experiments, researchers observed that G-form is highly infectious and is related to higher viral loads in the upper part of the airway in the respiratory tract.72 Similarly, this S-glycoprotein mutation is associated with the transmissibility of the new variant.73 Furthermore, scientists found that this mutation causes a 1.7 to 2.4-fold reduction in SARS-CoV-2 nAb, elicited through the BNT162b2 vaccination.74 5.6 P681R mutationThis significant mutation is also found in the S-glycoprotein protein outside the RBD region. It is located in the VOI B.1.617, and it is all sublineages such as B.1.617.1, B.1.617.2 and B.1.617.3. The mutation was observed adjoining to the furin cleavage site. It might have a consequence on the cleavage of the S1/S2 region and thereby in virus cell entry. The mutation might also have an effect on the infectivity of this variant.75 6 NEW VARIANTS AND THEIR IMPACT ON TRANSMISSIBILITY, INFECTIVITY AND RE-INFECTIVITYSeveral models have been developed to assume improved transmissibility of new variants. Scientist calculates the basic reproduction number (R0), evaluates the peak viral load and the viral shedding time to understand the transmissibility. Graham et al. tried to find the cause of the increased number of infections with the B.1.1.7 variant. They observed the augment in the effective reproduction number (Rt) of the UK variant (B.1.1.7). Due to national and regional lockdowns, the Rt value can be decreased. Even the increase in the rate of re-infection can be lowered.76 However, re-infection can be prompted by the new variants. Romano et al. noted the re-infection cases by the P.1 variants in São Paulo city of Brazil.48 At the same time, four re-infection cases by the B.1.351 were recorded in Luxembourg.44 Researchers reported that a higher transmission rate was noted in B.1.1.7 with 43%–82%.77 Similarly, a 2.6 times higher transmission rate was found in the case of P.1.78 The significant mutation D614G is associated with the increased transmissibility of the new variants.79 This mutation is found in the S-glycoproteins of all VOC and VOI with amplified transmissibility. In addition, Hou et al. have validated that the D614G mutation is responsible for enhanced transmission in an animal model.80 7 NEW VARIANTS AND THEIR IMPACT ON DIAGNOSTICSNew variants may possess an amplified risk of likely probe/primer mismatch. This probe or primer mismatch could obstruct the capability of present RT-PCR assays to detect the new variants.81 For that reason, Jain et al. has recorded 132 probe or primer sequences from different public literature using about 5862 distinctive variants. In addition, they observed about 286 genomic regions with low variability. These genomic areas are the continuous stretch of ≥20bps.82 However, more research will be required to search for the new probe/primer to identify the new variants by RT-PCR assays. At the same time, other rapid diagnostic assays should be developed to detect the newly evolving variants. 8 NEW VARIANTS AND THEIR IMPACT ON IMMUNE ESCAPE, VACCINES ACTIVITY, AND VACCINE ESCAPEImmune escape is a concern for the new variants. Several exponents have been noted for the immune escape characteristic. To understand the affinity between antibody and variants (especially VOCs), Ferraz et al. developed a model of electronic surface in RBD. The study observed the cross-reactivity between the VOCs and elicited nAbs. Due to lower cross-reactivity between the VOC and the elicited nAb, the VOC can escape from the immune system, a phenomenon possessed by the new variants with their significant mutations.61 Conversely, Garcia-Beltran et al. illustrated that the numerous variants of SARS-CoV-2 could escape different vaccines such as mRNA 1276 and BNT162b2 due to several mutations in RBD (K417T/N, E484K and N501Y).83 It has been noted that B.1.1.7 gained a significant and critical mutation (E484K). Due to the mutation, the immune sera from a human subject with Pfizer/BioNTech vaccination (mRNA-based vaccine) modestly reduced in neutralising titers against the UK variant (B.1.1.7) compared to wild-type pseudoviruses.84 At the same time, only 10% protection was observed by the ChAdOx1 vaccine from AstraZeneca against COVID-19, infected with another variant (B.1.351), as observed in South Africa. Researchers found that a two-dose vaccine regime cannot protect individuals re-infected with COVID-19 with mild-to-moderate symptoms due to the B.1.351 variant.85 The same vaccine showed 75% protection against the UK variant (B.1.1.7).86 Likewise, an analysis from Israel noted that mRNA-based vaccine BNT162b2 (Pfizer/BioNTech) was less effective against B.1.351 than other emerging variants.87 From the significant mutations analysis, Wang et al. developed a model where they hypothesise that mutations in RBD might disrupt antibody recognition abilities, which may be a threat to the current COVID-19 vaccines. Thus, these mutations may be entitled as vaccine escape mutations.88 We also recorded the vaccine escape mutations of the new variants in Table 4.
However, the development of a next-generation vaccine for COVID-19 may be one solution for vaccine escape. This next-generation vaccine should posse alternative epitopes from the different emerging variants. Bhattacharya et al. developed a vaccine using alternative epitopes from the significant variants of SARS CoV-2 and Wuhan strain through immunoinformatics approach.95 However, more research data are needed in this direction. 9 CONCLUSIONThe development of emerging variants, especially VOCs and VOIs, is now a global challenge. Due to new variants, different countries are facing massive COVID-19 surges and a drastic rise in mortality. New variants are capable of more rapid transmission and immune escape. Some mutations, such as D614G, E484K and N501Y, are advantageous to viral survival. On the other hand, every county has started a COVID-19 vaccination program to end the pandemic. Therefore, first, every country should understand the efficacy of the available vaccines against these new variants. There is a knowledge gap about the VOI in the area of transmissibility, infectivity, re-infectivity, immune escape and vaccine activity. Thus, intense research strategies are required in these directions. Moreover, healthcare and hospital preparedness are compulsion for every nation to fight against the emerging variants. ACKNOWLEDGEMENTSThe authors are grateful to the authorities of Adamas University, India, Fakir Mohan University, India and Hallym University, Republic of Korea. CONFLICT OF INTERESTThe authors declare no conflict of interest. AUTHOR CONTRIBUTIONSConceptualization, methodology, data curation, writing, supervision: Chiranjib Chakraborty. Validation, formal analysis: Manojit Bhattacharya. Formal analysis, review and editing: Ashish Ranjan Sharma. All authors reviewed and approved the final version of the manuscript. The authors confirm that the data supporting the findings of this study are available within the article.
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