Perspective Chapter: Tracking Trails of SARS CoV-2 – Variants to Therapy

Abstract

A virus when replicates itself from one generation to another, tends to change a little bit of its structure. These variations are called mutations. History says that SARS CoV-2 originated from the virus reservoirs of animals, specifically non-human mammals like bats and minks. Since then, there are evolutionary changes in its genome due to recombination in divergent strains of different species. Thus, making the virus more robust and smarter to sustain and evade immune responses in humans. Probably, this has led to the 2019 SARS CoV-2 pandemic. This chapter tracks the evolutionary trails of the virus origin, its pathogenesis in humans, and varying variants with the coming times. Eventually, the chapter overviews the available vaccines and therapies to be followed for SARS CoV-2.

1. Introduction

At the end of the year, 2019 a pandemic was caused by a new human infecting coronavirus, also called severe acute respiratory syndrome coronavirus 2 or SARS CoV-2. The first case of this novel virus was reported in Wuhan city of China and later it spread all over the globe. COVID-19 is the disease caused by SARS-CoV-2, which is characterized by different levels of severity and a range of signs and symptoms mainly fever, cough epidemic, sore throat, sudden onset of anosmia, shortness of breath, nausea, vomiting, and diarrhea [1]. This was announced a ‘public health emergency of international concern’ by the International Health Regulations (IHR) Emergency Committee of the World Health Organization (WHO) [2]. To date, more than 6 million deaths are caused by this disease around the globe (WHO, Coronavirus Disease COVID-19 Dashboard, accessed on 14/04/2022). Coronaviruses are positive-sense single standard RNA viruses that come under the family of Coronaviridae and Orthocoronavirinae subfamily. They are enveloped viruses having spherical, oval, or pleomorphic genomic shapes. The subfamily is further divided into four genera: Alpha, Beta, Gamma, and Deltacoronavirus [3]. Coronaviruses are not new to humans, and most of them cause minor respiratory infections in humans. They have also been known to infect domesticated animals for decades [4]. However, since the beginning of the twenty-first century, they have emerged as a major threat to the human population. There were six coronaviruses (CoV) known till now, among which severe acute respiratory syndrome CoV (SARS CoV) and Middle East respiratory syndrome CoV (MERS CoV) outbreaks took the life of a large number of people in 2002 and 2012, respectively. SARS CoV first appeared in China in 2002, infecting 8422 people followed by 916 deaths. MERS CoV afterward emerged in Arabian nations and infected around 1800 people. In 2019, the seventh CoV produced a large-scale outbreak that affected nearly every country on the planet. The new coronavirus was called SARS CoV-2 since it is closely related to SARS CoV. SARS CoV-2 is spreading quicker than SARS CoV and MERS CoV, with an increasing number of deaths [5].

2. History

Since the discovery of the virus in China in late 2019, the SARS CoV-2 pandemic has progressed through numerous stages. Patients with pneumonia-like symptoms were reported from various local health institutions in Wuhan city of China in December 2019. The reason was unknown, and the majority of the patients came from Wuhan’s sea/wet food market. The pathogen was identified and confirmed in the laboratory using real-time polymerase chain reaction, and next-generation sequencing. Because its genome did not entirely match any previously sequenced viral genome and the clinical signs were distinct from other recognized viral diseases, the virus was named 2019-nCov, where “n” stands for “novel” [5], and the disease was called COVID-19. The novel virus was classified as a Beta coronavirus based on the highly conserved protein-encoding open reading frame (ORF) 1a/1b sequence. As a result, the International Committee on Taxonomy of Viruses changed the nomenclature to SARS CoV- 2 [6].

3. Evolution

Based on mutation research, Li et al. [7] proposed that the virus appears to have emerged in late summer 2019 in China, and it may have invaded the West as early as October 2019. According to Dorp CH et al. [8], the illness spread globally most likely from the start of the epidemic. By Chaw SM et al. [9], SARS-CoV-2 spread cryptically well before the late 2019 outbreak in China, and Gambaro et al. [10] suspect the same for France. It is known that the SARS CoV-2 infection started in China, however, it is assumed that the virus arose in a mine in China in 2012, was collected in a laboratory, that may have escaped during manipulations in 2018 or 2019 [11]. This explanation might account for the virus’s circulation before the epidemic; during this early era, the virus could have undergone unnoticed mutations.

4. Structure

Coronaviruses are members of the Coronavirinae subfamily of the Coronaviridae family, which includes four genera as mentioned earlier. CoVs have a single-stranded Positive-sense RNA genome (27–32 kb) which is bigger than any other kind of RNA virus. The capsid was formed outside the genome by the nucleocapsid protein (N), and the genome is further packed by an envelope that is associated with three structural proteins: membrane protein (M), spike protein (S), and envelope protein (E) [12]. After the virus was confirmed to be the member of the coronavirus family, the genome size of SARS CoV-2 which was sequenced which approximately was found to be 29.9 kb [13]. Other than the structural proteins, SARS-CoV-2 contains 16 non-structural proteins (nsp1 to nsp16). Majorly, to mention a few, Nsp1 mediates RNA processing and replication. Nsp2 modulates the survival signaling pathway of the host cell. Nsp3 is believed to separate the translated protein. Nsp4 is a transmembrane domain 2 (TM2) protein thus promotes alterations in the endoplasmic reticulum membranes. Nsp5 participates in the polyprotein process during replication. Nsp6 is a likely transmembrane domain. The presence of Nsp7 and Nsp8 boosted the combination of Nsp12 with template-primer RNA. Nsp9 is a protein that binds to ssRNA. Nsp10 is required for viral mRNA cap methylation. Nsp12 includes the RNA-dependent RNA polymerase (RdRp), which is required for coronavirus replication/translation. Nsp13 binds ATP and the zinc-binding domain for replication and transcription. Nsp14 is an exoribonuclease proofreading domain. Endoribonuclease activity of Nsp15 is Mn (2+) dependent. Nsp16 is a 2’-Oribose methyltransferase [14, 15]. According to one study, NSP-mediated effects on splicing, translation, and protein trafficking can suppress host defenses. When infected with SARS CoV-2, NSP16 binds to the mRNA recognition domains of the U1 and U2 snRNAs, suppressing mRNA splicing. NSP1 binds to 18S ribosomal RNA in the ribosome’s mRNA entry channel, interfering with mRNA translation. NSP8 and NSP9 bind to the 7SL RNA, which is found at the Signal Recognition Particle, causing protein trafficking to the cell membrane to be disrupted [16].

SARS CoV-2 virus contains a series of spike proteins on the surface. Microscopically, this virus appears like a crown, which gives rise to its name corona, which in Latin means crown [16, 17]. The structural and spike proteins are responsible for allowing the virus to attach to the membrane of the host cell. It contains a receptor binding domain that recognizes a specific receptor ACE-2 (Angiotensin Converting Enzyme- 2 Receptor), which is expressed in the lungs, heart, kidneys, and intestines [5, 18]. These proteins bind to the ACE-2 receptor with at least the same affinity and potentially as much as 20 times greater affinity than the SARS CoV-2 virus [6].

5. Pathogenesis

The structural proteins of this virion has specific roles for virus adhesion and invasion. The S glycoprotein mediates the viral particle’s entrance phases, which include adhesion to the host cell membrane and fusion. S protein is formed as a homotrimer and inserted in numerous copies into the virion membrane, giving it a crown-like appearance. Many viruses utilize these similar glycoproteins for host entry including HIV-1, Ebola virus, and avian influenza viruses. This is split into two subunits: extracellular and transmembrane in infected cells (that is, the cleavage happens before the virus is released from the cell that generates it). Similarly, some coronaviruses break their S protein into S1 and S2 subunits during biosynthesis in infected cells, whereas other coronaviruses cleave their S protein only when they reach the next host cell. SARS- CoV-2 and MERS- CoV, come under the first category: its S protein is cleaved in virus-producing cells by proprotein convertases such as furin [19, 20]. As a result, the mature virion’s S protein is made up of two non-covalently linked subunits: the S1 subunit binds ACE2 and the S2 subunit fixes the S protein to the membrane. The S2 subunit also contains a fusion peptide and other machinery required to promote membrane fusion during new cell infection.

Receptor interaction by viral entry glycoproteins, generally in conjunction with other triggers, causes substantial conformational changes in both subunits, bringing the viral and cellular membranes together and eventually forming a fusion hole that allows the viral DNA to access the cell cytoplasm. The cleavage of a second site internal to the S2 subunit, known as the ‘S2′ site, ‘is one such trigger for SARS-CoV-2. The virus exposes the S2′ location by engaging ACE2. Cleavage of the S2′ site by an enzyme called transmembrane protease, serine 2 (TMPRSS2) [21, 22, 23] at the cell surface or by cathepsin L in the endosomal compartment releases the fusion peptide, beginning fusion pore development. Because the viral genome requires access to the cytoplasm and can only do so when this hole develops and the viral and cell membranes merge perfectly, where each step of the procedure is essential.

6. Evolution of viral variants

Viruses are complex molecular structures with simple-looking morphology. They are just single-cell microorganisms containing genetic material either DNA or RNA [1]. That genetic material is made up of molecules that can be represented as a series of deoxy-ribonucleotides in the form of A = T (DNA), A = U (RNA), and G = C. Each part of this code contains instructions for how to make one specific protein that allows the virus to function. A virus has one goal that is, to make more of itself. But because it’s not so simple, it cannot do that on its own. So, it uses a host. Every time a virus infects a person, it uses its cells to make copies of itself replicating this complex code again and again [1, 24]. But eventually, it makes a mistake, sometimes it deletes or adds a letter. Sometimes it flips them around. This mistake is called a mutation, which changes the instructions for making a virus. This slightly altered virus is a variant. Since viruses are constantly going through this copying process, it’s normal for them to change over time [2, 25]. Most of the time mutations are harmless or even make the virus weaker, and they quietly disappear without making any notable difference. But when a series of mutations occur it gives the virus a slight edge over us. If a particular set of mutations makes a variant more successful, it might become more prominent than others and that’s when it gets noticed. That is how the scientists started to notice SARS CoV2, back in September of 2020 [3, 4]. oronaviruses are covered in spike proteins that they use to bind with and infect human cells. The thing is, that binding is not a perfect fit. So, it does not always get past the cell’s defenses. But the B.1.1.7 variant, which scientists later renamed the “Alpha” variant, has multiple mutations on the spike protein: Mutations that make it easier for the virus to bind with cells [5, 6, 26],help make the virus more transmissible. Which led it to become a dominant strain in many places around the world. But SARS CoV2 has been mutating all along. It’s important to remember that a virus does not make active decisions. It creates strategy within the cells [17]. Mutations are random errors. But the longer a virus is around, the more people it infects, the more it will change and the more those changes accumulate and the virus evolves into something more dangerous. Alpha, Beta, Gamma, Omicron, and Delta are five variants considered as “variants of concern” by the W.H.O. All have mutations on the spike protein [2, 3, 4]. Delta, the most recent addition to this list, has been referred to as a “double mutant,” because, while it has many different mutations, it has two significant mutations (L452R & E484Q). These two mutations seem to make the virus more transmissible. Variant strains of the virus make it easier for the virus to re-infect people who have already had Covid-19, meaning that variants may have evolved to dodge natural immune responses [17, 27]. The Omicron variant of COVID-19 is spreading more rapidly in comparison to other strains because it has more mutations majority of them on the spike proteins. The new omicron variant BA-2 appears to be about 50% more transmissible in comparison to the original omicron BA-1 and causes same severity of disease [2, 3]. BA-1 strain of omicron is more infectious in younger people and according to reports several people have been infected with omicron BA-1 and within a month infection with omicron BA-2. It appeared that this version of omicron was either highly infectious that it could overcome vaccine load or previous infection immunity, or it can evade immunity due to the mutation that it has evolved with [5, 27]. It was also more contagious compared to the Delta variants, as it quickly became the dominant strain in the US. W.H.O said it expects that people can spread omicron even if they are vaccinated or do not have symptoms [3, 6, 26]. Viruses multiply by copying their genomes over and over, but as an old photocopier, these copies are not always perfect. Each of these imperfect copies is a variant. Normally the imperfections or mutations do not change how the virus behaves and they can often make it less successful than the original strain [25, 28]. But very rarely mutations can change the virus in some important ways. The more a virus is allowed to replicate unchecked, the more chance it has to accumulate these rare beneficial mutations [2, 18]. That can occur when viruses are allowed to spread quickly through a population, or if they encounter an immune compromised host.

7. Coronavirus and its new variants

Epidemiologists may even decide to label it as ‘Variant of Concern’ (VOC), like the examples identified in Brazil, South Africa, and the UK. For months, scientists have been striving to work out what’s changed in these variants, and what those changes mean. Because a variant spreading does not necessarily mean that it has an advantageous mutation. For example, a small number of people could, by chance, move a variant from one region to another, like tourists traveling back from popular vacation spots. This could cause that variant to start spreading in a new location even though there may be no significant change to the biology of the virus. This is called the ‘Founder Effect’. On November 5th, 2020, the United Kingdom went into lockdown [4, 18]. But, despite having the same lockdown measures, infections in Kent, an area outside of London, were still rising. In early December, the overall drop in cases led the country to relax restrictions anyway and then this happened [5]. It was not until around this time that researchers realized that somewhere in Kent, the virus itself had changed. It was a new variant. It was more contagious and it was spreading. By the time scientists gave it a name called B.1.1.7, it had spread to most of southeast England [18]. Two months later it was in 30 other countries. Five months later, it was the most common form of the virus found in the United States [6]. Lately, more and more variants are emerging in various places around the world. XE is a new variant of omicron and it is first detected in the UK. After successful detection of the XE variant, W.H.O has issued a warning against XE. It has been suggested that the variant could be more transmissible than any Covid-19 strain so far. XE is a combination of recombinants of both sub-variants (BA.1 and BA.2) of Omicron. Understanding why a variant has emerged requires a combination of studies. Epidemiology can help detect and trace new variants and flag new or worrying patterns of infection. Meanwhile, lab studies can start to pinpoint how the mutations are changing the properties of the virus [5, 18, 25]. Some variants are faster spreading like the D614G mutation, known to virologists as Doug. It spread widely in the early days of the pandemic and can be seen in almost all variants [2, 17]. It affects the spike protein that coronavirus particles use to penetrate cells. N501Y also known as Nelly, is another spike protein mutation that appears to be associated with increased transmissibility. This mutation has been detected in the B.1.1.7, B.1.351, and P.1 strains - all variants of concern [5, 26]. The worry of so-called ‘immune escape’ has also been indicated with another spike protein mutation, E484K or Eek. Eek has been spotted in B.1.351 and P.1, the variants detected in South Africa and Brazil. Lab studies early in 2021 showed that the variant could evade some virus-blocking antibodies, while trials in South Africa suggested that the variant reduced the efficacy of several vaccines [28, 29]. Despite these worries, the coronavirus is mutating very slowly compared to something like influenza and it seems like the vaccines developed so far will remain at least partly effective. It is very important to monitor and trace the emergence of variants and that is not always simple to do [3, 18]. Organizations like the COVID -19 genomics UK consortium or COG-UK, have stepped up their efforts to combine fast sequencing with efficient data sharing. COG-UK has already sequenced over 400,000 SARS-CoV-2 genomes [3, 4, 5]. Next step for researchers is the need to look forward to how these mutated strains of SARS CoV-2 could affect global vaccination efforts. Existing vaccines can be redesigned and combinations of vaccines are also being tested but it could be difficult to perform reliable clinical trials amid the ongoing vaccination programmes. Public health policies such as track and trace, social distancing, and vaccine rollouts are powerful tools to interrupt, transmit and keep tabs on new variants [17, 28, 30]. After all, every time the virus is prevented from spreading, it’s also prevented from mutating, nipping new variants in the bud before they even have a chance to develop.

The hotspots and the mechanism of replacement of amino acids that bring about mutations at specific points in the SP’s and NSP’s have been shown in Figure 1. S1 and NSPs are thus considered hotspots for mutations that may have high clinical relevance in terms of virulence, transmissibility, and host immune evasion. NSPs are mostly biocatalyst or catalytic proteins or enzymes that induce viral replication and methylation and may play a critical role in host responses to infection. These genes are encoded in two important groups, namely ORF1a (NSP1-11), and ORF1b (NSP12-16). NSP1 is a principal protein to antagonizes type I interferon induction in the host and benefits the replication of the virus itself. The variants of concern (VOCs) have impacted the global health significantly, especially in the later year of 2020. The major ones are Alpha variant (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa and Delta (B.1.617.1 and B.1.617.2) (Table 1). Figure 1 also tries to depict the important mutations in these VOCs, for example, the Alpha variant has an N501 mutation, N asparagine has been replaced with Y tyrosine, as well as K417 where the lysine K is replaced with asparagine N (Figure 1). Another emerging variant derived from B.1.1.7 also carries E484 mutation where the glutamic acid E is replaced with lysine K. Both Beta and Gamma variants have more substitutions other than N501. The Beta variant has E484, while the Gamma variant has the E484 and the K417 mutations. The latest variants Delta, and Kappa share two mutations E484 (glutamic acid E substituted by glutamine Q) and L452 (leucine L altered by arginine R). Other than the two mutations above, Delta also harbors a unique mutation, T478 (threonine T replaced by lysine K) (Figure 1) [31].

Figure 1.

Diagrammatic representation of mutations in different regions of SARS CoV-2 giving rise to different variants. Amino acid substitutions are depicted in both structural and non-structural proteins of SARS CoV-2, which modify their affinity to ACE2 receptors, thus making them VOC.

Variants and their name according to W.H.O	Scientific Name	Canonical Mutations	Country, where first documented	References
Alpha	B.1.1.7	N501Y, 69/70; deletion, P681H	South-eastern England	[3, 6, 7, 8, 13]
Beta	B.1.351	K417N, N501Y, E484K	South Africa and Nigeria	[2, 3, 4, 7, 13]
Gamma	P.1	K417T, E484K, and N501Y	Brazil	[2, 5, 7, 13]
Delta	B.1.617.2	L452R, T478K, D614G and P681R	India	[3, 6, 7, 8, 13]
Omicron	B.1.1.529	N679K, H655Y, and P681H	South Africa	[4, 5, 10, 13]
Epsilon	B.1.427 and B.1.429	S13I, W152C, L452R. D614G	USA	[6, 7, 13]
Theta	P.3	—	Philippines	[7]
Zeta	P.2	—	Brazil	[7, 8]
Mu	B.1.621	—	Colombia	[5, 7]
Eta	B.1.525	—	Nigeria	[3, 7]
Iota	B.1.526	—	USA	[7]
XE	—	—	UK	—

Table 1.

Different variants of coronavirus with scientific names.

8. Variants and their effects on pathogenesis

Coronavirus is a large family of viruses, which are found in humans and animals [32, 33]. These viruses have had two large-scale outbreaks in the past two decades the SARS virus in 2002 and the MERS (Middle East Respiratory Syndrome) virus in 2012 [34, 35, 36]. It’s generally been considered that these coronaviruses could cause future disease outbreaks because they are known to be able to evolve with animals and then jump to humans as an intermediate host in SARS. Palm civets and raccoon dogs were identified as the intermediate [37, 38]. According to the current mortality index total cases worldwide are found at 52.3 Cr and deaths confirmed at 62.7 L [34, 39]. The top five nations in terms of deaths in order are the US, India, Mexico, Brazil, and Russia. The UK has a much smaller number of deaths in comparison to these five countries. The highest number of cases are found in the US approximately 8.29 Cr and deaths confirmed 10 L. Coronavirus spreads mainly by respiratory droplets, cough, and sneezing. The aerosol-carrying virus allows it to travel into nasal or all cavities and it can live on surfaces for hours and even up to a few days on some surfaces [32, 35]. Infected touch can transfer the virus to mucous membranes in the eyes, mouth, nose, and upper airway [34, 35]. With that, symptoms arise like the common cold, stuffy nose, headache, sore throat, and fever [40, 41]. It is within the mucosal epithelium of the upper GI tract where primary viral replication is thought to occur similar to SARS CoV-2 is able to get further into the human respiratory system and lung’s epithelial cells [38, 42]. ACE-2 receptor interaction with SARS CoV-2 binds S protein to the ACE-2 receptor, this mechanism of binding is followed t in the same way in airway epithelial cells [37, 43, 44]. The host cells have proteases that break down proteins and these cleave spike protein, this process activates a protein to trigger the process of membrane fusion before injecting the viral genome into the host cell [45, 46]. This mechanism is similar to direct cellular entry that facilitates cell entry in the influenza virus. The virus may also enter the cell via endocytosis, where it is engulfed and surrounded by an area of the cell membrane [39, 47]. Further down it forms a vesicle inside the host cell where specific RNA and proteins are synthesized within the cytoplasm [46, 48]. Viral proteins are assembled with the blueprint of information contained within viral RNA using hosts cellular machinery specifically ER and Golgi apparatus with specific processes to form envelope glycoproteins [40, 48]. New variants are assembled by fusing to plasma membranes and released as vesicles via exocytic secretory processes. The stress is placed on cells by a viral infection and the interaction of the immune system with viral antigens presented by infected host cells leads to cell death [47, 49, 50]. During this process of cell death, multiple inflammatory mediators are released and create an inflammatory response leading to a buildup of mucus. Thickening and hyperplasia of cells within airways this inflammation causes irritation of cells lining airways, which leads to cough [42, 51, 52]. In the lower respiratory tract, the virus acts within the lungs to get into the trachea or windpipe this branch is further bifurcated into the left and right main bronchi these bronchi branch into lobar bronchi. Bronchi have three sub-branches here one on the right and two on left, these branches are further segmented into segmental bronchi [49, 51, 53]. The segmental bronchi further branches into respiratory bronchiole and after that respiratory bronchiole culminate in tiny alveoli. COVID-19 infection may lead to inflamed alveolar walls, that get thickened and fill the alveolus with fluid, which can impair their ability to exchange gases [29, 40]. This can lead to the symptom of shortness of breath in some people infected with COVID-19 [38, 39]. Viruses can lead to an exaggerated immune response with a huge release of proinflammatory mediators causing, which is known as a cytokine storm or cytokine release syndrome. Cytokines are small proteins involved in cell signaling and crucial in mediating immune responses [39, 52]. The cascade of inflammatory mediators causes an uncontrolled systemic inflammatory response, which leads to acute respiratory distress syndrome or ARDS is the rapid and widespread inflammation of the lungs [47, 48]. ARDS causes epithelial and endothelial cells of the lungs to secrete inflammatory mediators, which fill the alveoli and allow these inflammatory signaling cells to recruit other cells of the immune system into the alveoli [50]. It further amplifies the problem and systemic inflammatory state causing increased capillary permeability, resulting in more fluid entering in alveoli causing pulmonary e dema [39, 50, 54]. Compounding the problem overall this pathological process severely impairs the ability of the lungs to exchange oxygen and carbon dioxide. This whole cycle of SARS CoV-2 invasion in general, pathogenesis, disease outcome, and current therapy has been illustrated in Figure 2.

Figure 2.

A summarized cycle of SARS CoV-2 depicting (a) different parts of SARS CoV-2 virus (S = spike, M = membrane, E = envelope, viral mRNA, N = nuclear material) being represented on antigen presenting cells (APC) and T helper cells, (B) further initiating the immune responses in the human body that may be cell-mediated or antibody-mediated/innate or adaptive immunity (C) shows the potential immune evasion mechanisms. This shows a common evasion shared by all three respiratory viruses (SARS-CoV, MERS-CoV, and SARS-CoV-2). (1 and 2) shows hindrance created by coronaviruses during RNA sensing, starting the innate immune response and interferon (IFN-1) production. (3) shows the STAT1/2 activation leading to downstream activation of IFN/IFNAR (4) as sown by blocking marks. This blocking or oppression results in the decrease of interferon production thus impacting the adaptive immune response. Thus, helping the persistence of the virus in the host cells thus aggravates immune responses which may lead to immune exhaustion and immune suppression. (D) Shows the type and severity of disease manifestations inside the human host (E) indicates vaccine as the only available therapy which is helping in controlling this fatal viral infection.

9. Available therapy

COVID-19 is one virus that causes serious breathing difficulties other than common flu-like symptoms. Patients who have trouble breathing may be given supplemental oxygen, if the oxygen alone is insufficient to help the patient breathe then the patients are put on mechanical ventilation such as BiPAP, and in some situations, they may need to intubate and oxygenate the patient through conventional ventilators [37, 53]. Individual treatment depends heavily on their health condition and the resources available at a time. Remdesivir is an antiviral drug, which disrupts the virus’s ability to replicate and spread within the body [55]. Remdesivir specifically is recommended for patients, who have been hospitalized and require oxygen but are not on mechanical ventilation. Globally remdesivir is in short supply and many health institutions have very limited quantities of it. Dexamethasone is a corticosteroid drug that makes adjustments to how the immune system regulates itself [55, 56]. Dexamethasone or other glucocorticoids similar to it can be used in patients, who need oxygen and can be used on patients who are on mechanical ventilation or non-mechanical ventilation [57]. However, patients who are not on supplemental oxygen are not recommended to take dexamethasone as the side effects of the drug may worsen their condition [41, 54, 58]. There have been some proposed treatment solutions like the use of blood plasma of patients, who have recovered from COVID-19 also called convalescent plasma [58, 59]. But this therapy could not find much success in seriously sick patients with COVID-19. In the spring of 2020, there was a lot of news coverage regarding the use of chloroquine and hydroxychloroquine to treat severe covid-19 patients [23, 60]. In August of 2020, the National Institute of Health issued a statement that recommended against using these drugs as initial trials in Covid-19 had either shown no benefit at all or had led to worst outcomes for patients due to drugs with dangerous side effects [59, 61, 62]. In 2021 India has begun to roll out an antibody cocktail drug therapy for COVID-19 patients and a similar therapy was used to treat former US president, Sir Donald Trump. This was a cocktail of two drugs, casirivimab and imdevimab [63]. The cocktail therapy claims to reduce hospitalization and death in Covid-19 patients by 70%. Each patient’s dose is 1200 mg (600 mg of casirivimab and 600 mg of imdevimab) and the price of each patient’s dose will be around 60,000 rupees [63, 64, 65, 66]. Majority of these drugs are a recipe of monoclonal or artificial antibodies that are generated by cloning a unique white blood cell [67]. These amalgamated antibodies are designed in such a way that they can well bind to the spike protein of SARS CoV-2 and fight against the infection. But the effectiveness of these antibodies is limited to Covid-19 patients with mild to moderate symptoms [64, 65, 68]. Its effectiveness shows best when given during the first seven days of the infection when the virus is multiplying. Thus the viral entry at this time point is ceased. This therapy is not advised for severe Covid-19 patients, who require oxygen therapy [54, 56, 68].

10. Vaccine against SARS CoV-2 and its efficacy

Researchers are racing towards the goal of delivering a safe and effective vaccine that could curb COVID-19 [69]. Production and scale-up for some of the vaccines have already started. New technologies are genetic vaccines and viral vector vaccines [70]. A lot of investment in them has especially focused on their potential to combat emerging infectious diseases and COVID-19 is putting that potential to test [15, 71]. Scientists developed a successful influenza vaccine was in 1953 where they injected viruses into fertilized eggs, which were then incubated to allow viral replication within the eggs [72]. These replicated viruses are then explored for developing two classical vaccine formulations, where the virus is either weakened (Live attenuated virus) or killed (Whole inactivated virus) live attenuated and whole inactivated virus vaccines. These are [34, 70, 72]. These approaches are still in use today, although different cell cultures have replaced the use of eggs. At the current time, vaccinology has introduced multiple other approaches to develop vaccines [71]. This has been summarized in Figure 3. Major types of vaccines being deployed against COVID-19 are genetic vaccines, protein subunits, virus-like particles, viral vector vaccines, live attenuated viruses, and whole inactivated virus vaccines [70, 73]. Because of previous research on SARS and MERS, researchers only focus initial attention on the S protein of the SARS CoV-2 virus that is necessary for viral entry into human cells [35, 74]. So, a vaccine that exposes the immune system to just a spike should induce a protective response and that is the strategy behind the majority of COVID-19 vaccines. A comparison between conventional vaccines (that contain the whole virus) and genetic vaccines is interesting. Researchers can take genetic material either as m-RNA or DNA, that codes spike protein and explore this for vaccine development [75]. Two types of genetic vaccines are being investigated for COVID-19, i.e. m-RNA and DNA vaccines. mRNA needs to reach the cytoplasm of host cells, while DNA needs to enter the nucleus. Then this genetic material gets taken up by cell machinery, and cells express spike protein [74, 75]. These spike proteins are recognized by the immune system, hopefully stimulating a protective response. Naked mRNA cannot easily cross cell membranes passively, and it’s very susceptible to degradation [32, 43]. In vaccines, mRNA coding for the spike is encased in small carrier molecules called lipid nanoparticles [44, 75]. The goal is to induce immunity against the target antigen, the added genetic cargo. But these vaccines may also induce immunity to the vector itself and viruses used as vectors are attenuated or weakened, so they cannot cause disease. A lot of different viruses have been developed as vectors, and they can be broadly categorized into two types, replication-defective and replication-competent [74, 76]. A very popular choice among potential COVID-19 vaccines is adenoviruses as these viruses are common pathogens that typically cause mild cold or flu-like symptoms [77]. Lots of vaccines with adenovirus vector carries DNA coding for the spike to host cells., but it does not display on its surface. Once the virus infects a host cell, it delivers DNA to the nucleus, cells machinery expresses spikes using this DNA which is to genetic vaccines [77, 78]. Adenovirus vectors are replication defective, after the virus infects a cell no more viruses are produced [78]. Replication competent virus vectors used recombinant vesicular stomatitis virus. The wild-type VSV is usually asymptomatic in humans or it causes a mild flu-like illness. Scientists attempted to replace part of the RNA sequence with spike coding RNA of the virus genome [32, 40, 77]. Once the virus (rVSV) infects the host cell, cell machinery starts expressing a spike. This phenomenon mimics a real viral attack more closely [44, 78]. Adenovirus vectors, which are much further ahead in COVID-19 trials, have never been used in an FDA-approved vaccine and there are likewise no FDA-approved DNA or RNA vaccines.

Figure 3.

The diagrammatical representation shows the different types of vaccines against COVID-19.

11. Vaccines and their efficacy

A lot of viral evolution just comes down to statistics and a particular mutation that may confer the ability of the virus to make more copies of itself or to be stickier to cells. After that over time, it becomes more predominant in the population, because of that selective advantage it has and this is exactly what has happened with variants being detected around the globe [71, 79]. The variants reported are usually designated by their regions or locations where they were first found (B.1.17, B.1.351, P.1, and B.1.427/B.1.429). For example, some detected in California, South Africa, etc. [38, 80] (summarized in Table 2). But some variants were simultaneously found in many locations at the same time like a variant was first detected in the UK, South Africa, and Brazil which were already circulating in the US. This dilemma is still unanswered and may dampen the effectiveness of available vaccines [46, 66, 81]. When researchers talk about vaccine efficacy, a lot of attention is paid to antibodies, specifically neutralizing antibodies. The leading COVID-19 vaccines all induce neutralizing antibodies, which bind to the virus at a few different sites on spike proteins called epitopes [43, 81]. These neutralizing antibodies thus block the virus attachment to cells but to contrary, the evolving mutations in the virus are most worrisome in terms of vaccines, as they affect neutralizing antibody binding sites on spikes [81]. So, the first step in understanding how a variant will impact vaccine effectiveness is to analyze where the mutations are. But while this provides important clues, it does not give the full picture. Table 2 below summarizes the available vaccines till now and their efficacy.

Vaccine Name	Clinical trial Number	Manufacture	Phage	Number of Participants	Immunity response	Efficacy
mRNA-1273	NCT04470427	MODERNA/NIAID	3	30,000	CD4+ T-cell activation reported (Th1 skewed phenotype	94.10%
BNT 162b2	NCT04368728	BioNTech/Pfizer	3	44,000	Virus specific Th1 and CD8+ T cell responses reported	95%
Ad5-nCoV	NCT04526990	CanSino Biological	3	40,000	T-cell responses were observed in 88% of the participants	—
AZD1222	NCT04540393	AstraZeneca	3	30,000	T-cell responses were observed in all participants	62.10%
Sputnik V	NCT04530396	Gamaleya Research Institute	3	40,000	CD4+ and CD8+ T cell responses were observed in all participants	—
JNJ-78436735	NCT04505722	Janssen Pharmaceutical	3	90,000	CR4+ T cell responses in 80% of the participants	—
CoronaVac	NCT04456596	Sinovac Research & Development Co.	3	8870	Not Reported	—
BBIBP-CorV	NCT04560881	Beijing Institute of Biotechnology	3	63,000	Not Reported	79.38%
BBV152	CTRI/2020/11/028976	Bharat Biotech	3	26,000	Virus -specific CD4+ and CD8+ T cell responses Reported	—
NVX-CoV2373	NCT04611802	Novavax	3	45,000	CD4+ T cell activation in all tested participants	—
CoVLP	NCT04636697	Medicago	3	30,612	Not Reported	—

Table 2.

Advanced SARS-CoV-2 vaccine candidates.

12. Testing variants against serum

Researchers and physicians have also explored different components of blood for imparting immunity to the Covid-19 affected patients. Serum, a component of blood that contains antibodies was taken from a vaccinated individual and combined with the virus in the lab, to see if antibodies contained in the serum block virus from infecting cells [82, 83]. There is currently no centralized system for testing all different vaccine sera against all different variants. Most studies have been small, and have primarily focused on mRNA vaccines [82, 84]. B.1.1.7 variant was first detected in the UK; and the B.1.351 variant was detected in South Africa, where serum testing showed a reduction of about six-fold in antibody sensitivity [85]. The other variants of concern currently identified by the CDC are P.1, which was first detected in travelers from Brazil, and two variants first detected in California B.1.427 and B.1.429 [85, 86]. Fewer studies are available on these variants, but current data indicate that the reduction in antibody sensitivity is somewhere between B.1.1.7 and B.1.351 [85]. Overall researchers need more laboratory data. But even when larger studies become available on all different variants and vaccine sera, these data may prove inconclusive [83]. Testing against serum samples has limitations. A big one is that antibodies are only one part of the immune response. In serum, the patient will not have our T cells, the patient will not even have our memory B cells or plasma cells that might be important just for antibody response [87, 88]. So, a lot is missing and that makes it hard to determine how a decrease in antibody sensitivity of 6 fold, in the lab, translates to vaccine effectiveness in the real world [86, 89]. Given these limitations to laboratory testing, it is of paramount importance to collect data on the ground. One example of such data would be sequencing variants infecting people, who become seriously ill with COVID-19 despite being vaccinated [84]. Another source of ground data is ongoing and recently completed vaccine clinical trials. ChAdOx1 nCoV-19 derived vaccine did not fare well in South Africa, where B.1.351 variant dominated, and South Africa halted its distribution in February [89, 90]. ChAdOx1 nCoV-19 derived vaccine is close to filling for authorization in the US and this vaccine is already being distributed elsewhere, including in the UK, and Europe by WHO [89]. Another vaccine that was tested in South Africa is from protein subunit vaccine, this vaccine is not yet being distributed, but it is getting close to filling for authorization in the UK, the US, and elsewhere. The most recent update read out of data suggests that while the protein subunit vaccine was almost 90% effective in the UK, it was much less effective in South Africa about 49 or 55% depending on whether or not people include participants infected with HIV [74, 90, 91]. A vaccine made by a piece of a modified virus is now being distributed in the US, reports a similar trend. This vaccine was 72% effective at preventing moderate to severe disease in US 28 days after vaccination. In South Africa, that number was only 64% [90]. But importantly this vaccine’s efficacy against the severe disease was similarly high across regions [74, 84]. The currently available data indicate that while variants do pose a real threat to vaccine effectiveness, the available vaccines remain potent tools in fighting the pandemic. But researchers and public health experts also stress, that there will be more SARS- CoV-2 variants [92]. This underscores the importance of a global approach to surveillance, tracking, and vaccine development. But CDC Director Dr. Rochelle Walensky has emphasized the need to scale up surveillance across the US. In early January 2021, there were 250 samples a week that were being sequenced. In addition, CDC, NIH, vaccine procedures, and other groups are already discussing and collecting data on various vaccine strategies for combatting variants [92]. One potential strategy is a booster shot that would expose the human body to viral spike protein from the newer, resistant variant. This would stimulate the immune system to produce antibodies specific to the new variant in addition to an extra protective cushion for protection against other variants as well [88, 93, 94]. Studies evaluating both booster approaches have already started. Other strategies may also be like a bivalent vaccine, which induces an immune response to two different antigens with one shot. Such a vaccine could induce immunity to two different variants or two viral proteins from the same variant [79, 95]. But while such strategies are important to evaluate, the most significant way to mitigate the threat posed by variants is to reduce the community spread of SARS CoV-2. The way to decrease the amount of virus circulating is to get as many people vaccinated as possible, as quickly as possible, and to continue preventive measures like mask wearing and physical distancing [84, 95].

13. Future predictions of COVID-19

The continuous emergence of different variants of SARS CoV-2 has shown us that this coronavirus has high replication potential than other RNA viruses, due to which with every transmission and spread, the rate of mutation increases. Though predicting the future of an ongoing pandemic can never be explained with confidence and surety, still, possible future scenarios of COVID-19 can be explained [96, 97, 98, 99].

1. The most important apprehension regarding this pandemic is that this will not end up with a sudden break in the coming times. Mini waves will keep coming, where we will face manifestations from severe disease, with high levels of infection to milder disease symptoms. Though the recent COVID-19 infection in the past 3 years and vaccination will provide herd immunity, still the diagnostic surveillance should go on.

2. As discussed earlier the other possible scenario of this pandemic in the near future can be its transition to the epidemic, where it will follow the story of the Influenza virus. It has been seen in the past years that 2% of the annual global deaths (out of which 2/3rd of the people above the age of 65) are because of respiratory illness which majorly includes flu. And if this is compared with SARS Co V-2 infection, the availability of vaccine and effective monoclonal antibody therapies (70–85% effective), gives an optimistic view of COVID-19 infections in the future. There is still high scope of more effective therapies against COVID-19 coming down the lane, thus keeping a positive approach towards decreasing SARS CoV-2 infections in the approaching times.

3. The other future scenario of SARS Co V-2 can be its transition from a pandemic to an endemic. As seen in the past with other coronaviruses like MERS and SARS, which got restricted to different pocket areas of the world and people of different ethnicity. Though there is limited data that supports the above information, it is therefore not possible to predict with confidence what adaptation SARS CoV-2 will take with time.

   These future predictions of SARS CoV-2 virus spread and recurrence of COVID-19 will depend on one or all of these important facts: 1. Epidemiological tracking (updated data on continuous surveillance of the disease and its global spread); 2. Updated data on its pathogenicity, virulence, and variation in disease severity globally; 3. A continuous inflow of funds worldwide for more research in the development of efficient targeted therapies for COVID-19 [100].

14. Conclusion

The world has witnessed the recent pandemic of SARS CoV-2 and it is difficult to see that the world will return to pre-covid life any time soon. Although the global vaccination drive has brought this fatal respiratory infection under control, still SARS CoV-2 trajectory is yet to form a plateau. It is anticipated that with the transition of this pandemic to an endemic, uncertainties will remain with the human population. The persistence of this endemic virus in different pockets of the world may rise as a seasonal epidemic flu with some susceptible individuals who might succumb to its infection if immunocompromised or with waning levels of immunity.

We all share a beautiful world and as wisely said by “Sir Mahatma Gandhi”, “Unity to be real must stand the severest strain without breaking”. This pandemic has taught the world to be unanimous, be it in fighting against this disease by imposing national and international lockdowns to cease the spread of the disease or helping each other by providing daily bread and needs to the jobless migrants and affected people. Furthermore, the inflow of funds among different nations for rapid and continuous research led to the development of globally effective vaccines in the shortest time. The whole world stands together and looks forward to their respective contributions to keep an eye on the trajectory of COVID-19 so that we can reach the plateau with more effective strategies to combat COVID-19 and any more such pandemics in the near future if any.