An overview of SARS-COV-2 epidemiology, mutant variants, vaccines, and management strategies

Background Over the last two decades, humanity has observed the extraordinary anomaly caused by novel, weird coronavirus strains, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). As the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has made its entry into the world, it has dramatically affected life in every domain by continuously producing new variants. The vaccine development is an ongoing process, although some vaccines got marketed. The big challenge is now whether the vaccine candidates can provide long-lasting protection or prevention against mutant variants. Methods The information was gathered from various journals, electronic searches via Internet-based information such as PubMed, Google Scholar, Science Direct, online electronic journals, WHO landscape, world meters, WHO website, and News. Results This review will present and discuss some coronavirus disease 19 (COVID-19) related aspects including: the pathophysiology, epidemiology, mutant variants vaccine candidates, vaccine efficacy, and management strategies. Due to the high death rate, continuous spread, an inadequate workforce, lack of required therapeutics, and incomplete understanding of the viral strain, it becomes crucial to build the knowledge of its biological characteristics and make available the rapid diagnostic and vital therapeutic machinery for the combat and management of an infection. Conclusion The data summarizes current research on the COVID 19 infection and therapeutic interventions, which will direct future decision-making on the effort-worthy phases of the COVID 19 and the development of critical therapeutics. The only possible solution is the vaccine development targeting against all variant strains to halt its progress; the identified theoretical and practical knowledge can eliminate the gaps to improve a better understanding of the novel coronavirus structure and its design of a vaccine. In addition, to that the long-lasting protection is another challenging objective that need to be looked into.


Introduction
Andrews and Gledhill in 1951 screened a hepatitis virus from mice which are now known as a single-stranded RNA coronavirus. Its diseases and cause have been recognized in animals and humans for over 50 years. 229E and OC43 were the first coronaviruses to cause very mild infections like common colds in humans. Later on, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) emerged from civet cats, camels, bats [1]. The family of coronavirus is called as Coronaviridae which comprises of two subfamilies, Coronaviridae and Letovirinae [2,3]. Pneumonia's initial diagnosis and unknown cause made the cluster of patients in China admitted into hospitals in December 2019. The reports confirmed the potential coronavirus outbreak, of coronavirus disease , and WHO gave it a name on February 11, 2020 [4]. In response to the outbreak, the center for disease control and prevention (CDC) conducted epidemiological and etio-logical investigations via Wuhan city's Health authorities. Nearly 1 billion cases per year and economic losses of hundreds of billions of dollars occur due to this zoonotic illness, demonstrating the importance of developing vaccine design strategies for virus families with pools of causing extensive zoonotic diseases. The transcriptional regulatory sequences (TRSs) mediates discontinuous transcription and transcribes sub genomic RNAs, which make up the structure of a virus particle [5,6]. Advances in understanding viral machinery, the role of various viral proteins, their genetic structure, host immune responses, and the ability to confer protection switch its way to developing a vaccine successfully. An additional challenge is conducting clinical trials in this pandemic loss by utilizing the current evidence and critical knowledge gaps to better understand the virus strategy to safeguard public health. This review, has focused and emphasized points on the COVID 19 pathophysiology, epidemi-ology, mutant variants, vaccine candidates, vaccine efficacy and strategies for disease management.

Pathophysiology
Coronavirus spike glycoprotein (S) with the expression of their subunits S1 and S2 binds to the host cell receptor's surface. S1 determines the cellular tropism and host range and helps attach the virus to the target cell. In contrast, the S2 subunit helps infusion with the host cells (mainly alveolar epithelial cells and small intestine enterocytes) with the aid of Angiotensin-Converting Enzyme-2 (ACE2) claw-like structure of the receptor by endocytosis [7,8]. When this S protein binds to the ACE-2 receptor, the transmembrane protein serine 2 (TMPRSS2), which is associated with the cell surface, mediates cleavage of S protein trimer, and the fusion mechanism is activated via endosomal acid proteases (cathepsin L) [9][10][11]. ACE2 is an 805 amino acid containing integral membrane protein consists of 3 domains that are a domain at the transmembrane side, a domain at the extracellular side and a domain at the cytoplasmic side, and the N-terminal peptide. The enzyme sheddase helps release soluble protein into the bloodstream by cleavage of the active carboxypeptidase domain from the transmembrane domain [12]. When there is a lysosome-mediated drop in pH, the endosome membrane fuses with the virus's envelope and releases a nucleocapsid in the cytoplasm. The cellular proteases degrade the capsid, and the positive sense RNA viral genome ranges between 27−32 kbp is left free. This viral genomic RNA consists of at least 6 open reading frames (ORFs). ORF1a and ORF1b are present at the 5 end, constitute a common fraction of the whole genome length RNAs, and are translated into pp1a and pp1ab proteins. Protease helps in cleavage of those proteins in to 16 non-structural proteins (NSP1 -NSP16) [13][14][15]. Some of these NSPs, like NSP3, encode for papainlike proteases (PLP) and NSP5 codes for 3CL-proteases. Both of these proteins form a polypeptide "Replication transcription complex" (RTC) and helps in innate immune response blockage via genomic transcription and translation process. NSP15 encodes for RNA helicase, whereas NSP12 for RNA dependent RNA polymerase (RdRp) and synthesis of subgenomic RNAs (sgRNAs) stand genomic RNAs occurs [16] (Fig. 1).
Other NSPs protein functions are listed below in Table 1 Four Structural proteins are coded by ORFs located on 3 end: 1) Membrane (M) shape the virions [17]. 2) Spike (S) recognizes the ACE2 receptor on the host cell surface [18]. 3) Envelope (E) helps in assembly and release of virions [19]. 4) Nucleocapsid (N) packages the genome in the virions, provides pathogenicity.
There are many other structural and accessory proteins that are specific to the different species. Membrane exocytosis helps budding of completed assembled SARS-COV-2 particles via endoplasmic reticulum in the endoplasmic reticulum-golgi intermediate compartment (ERGIC). It is currently known that interaction of mainly M protein with different structural proteins of virus E, S aids in the generation of the virion scaffold promoting assembly, budding, and release of mature virus particle by exocytosis. After the final phase of maturation, all the components of the virus fit together, the particle is infectious and ready to begin a new cycle [20][21][22][23].

Epidemiology
Coronaviruses which mainly infect birds and mammals, comprise a large family (Coronaviridae) of giant enveloped positive-strand RNA viruses, which can be a cause of upper and lower respiratory tract infections (RTI) manifest as pneumonia, bronchitis, MERS, SARS, COVID 19. These three new coronaviruses caused respiratory disease outbreaks with their unique features, but SARS and MERS are less infectious and have significantly higher fatality rates than SARS-COV-2. The following Table 2 demonstrates the fundamental difference between the three of them [57][58][59].

Origin
Disease spread globally over eight million after the emergence of many pneumonia-like cases in Wuhan, Hubei province China (Early December 2019).

Topological dispersal
On December 31, 2019, the Chinese government first confess the numerous cases of pneumonia of an unknown cause presumed to be a zoonotic illness that would later be called COVID 19. The first case of death was reported on January 11. The Wuhan city was locked down with over 11 million populations on January 23. A week later, thousands of cases were reported, and WHO immediately declared a global health emergency [60]. With the start of July 2020, there were approximately 8.6 million cases and 450,000 deaths due to COVID 19 [61].

Italy
Italy was the following unfortunate country after China experienced a significant outbreak and resulted in the highest death rate, 7.2%. Milan, the most dynamic city alone, represents 10% of the Italian economy, "The country's economic engine" was drastically slowed after Italy experienced a surge in coronavirus cases. Italy went from discovering the first official COVID 19 case to the prohibition of all movements and non-essential business activities in a matter of weeks (February 21- March 22). Around 3,949,517 cases and 119,021 deaths took place until 25th of April 2021 [61].

France and Germany
The "quick and dirty Sunday morning" analysis confirmed the trend of viral proliferation in France and Germany exceeds more than in Italy, South Korea, and Japan with a similar temperature. The study also suggests that intense containment measures as in Italy, South Korea, and Japan may help to slowdown proliferation [62]. France is 4th country affected and around 5,473,579 cases and 102,713 deaths took place until 25th of April 2021. Germany 10th leading country in COVID 19 cases and around 3,277,661 cases and 82,117 deaths took place until 25th of April 2021 [61].

Japan
Japan, though with a more significant percentage of the population, experienced a low mortality rate compared to Italy mainly because of their cluster-based testing approach and adoption of the "3C" method (avoidance of closed spaces, crowded spaces, close contact) (Bloomberg, 2020). Around 556,999 cases and 9854 deaths were reported in Japan until 25th of April 2021 [61].

United States
U.S reached the highest count of reported cases worldwide from the first known patient in late January to August 28th where there are 6 million cases and nearly 2 lakh deaths. About 32,766,119 cases   [55,56] have been reported and 585,449 deaths had took place on 25th of April 2021 and US is at the forefront [61].

Brazil
The second highest number of cases is found in Brazil, especially the Amazon state country's northwest, which has the highest mortality rate. Manaus, the state capital, and the bustling city make the potential hotspots for transmitting the virus (CDC, 2020).). Brazil is third affected country and around 14,238,110 cases and 386,623 deaths took place until 25th of April [61].

Russia
Russia was centered in Moscow's city, accounted for the highest number of cases measuring 257.7 thousand, followed by Moscow  Table 3 Variants of concern (VOC). Oblast with 67 thousand cases by August 24, 2020. It has registered ten folds of low mortality than Spain, Britain, Italy, and France despite having many cases. The country's well-funded healthcare system is to be appreciated for managing better than those in the U.S and Western European countries. Mass testing (has nearly 6 million tests carried out so far) helps people identify and isolate more people affected by the virus. They quickly convert hospitals and clinics to virus treatment centers. Russia is also at top leading in COVID 19 cases. Around 4,753,789 cases and 107,900 deaths took place until 25th of April 2021 [61].

India
India, among all other countries, has the lowest fatality rate (2.41%) as of July 23 in the World even though it stands third after the United States and Brazil for having a large number of cases in Asia. The first case of COVID 19 was reported in Kerala on January 30. By mid of May 2020, 6 major cities like Delhi, Mumbai, Kolkata, Chennai, Pune, and Ahmedabad accounted for around 50% of all cases reported in the country [65]. In India, there is progressive rise of COVID 19 and about 16,951,621 cases and 192,309 deaths are reported till 25th of April 2021 [61].

Etiology in different groups
The virus is transmitted via major routes such as droplets, contact, and aerosols. It has also been detected in the faecal samples of patients in the United States and China. Major risk factors include people more than 60 years of age, and even people underlying noncommunicable diseases (NCDs): diabetes, hypertension, chronic lung disease, cerebrovascular disease, cardiac disease, chronic kidney failure, immune-suppression and cancer patient. Due to immunosuppressive state and many other physiological adaptive changes pregnant women are more susceptible to RTI but currently evidence of SARS-CoV-2 transmission through the placenta to the new-born has not been observed. In one of the studies, the samples of amniotic fluid, blood obtained from the umbilical cord, throat swab of neonates, and maternal milk were collected from newborn babies whose mothers were SARS-CoV-2 positive. Still, none of the neonates were found to be positive [66].

Mutations and severity of infection
Before SARS-CoV-2 other viruses also mutate themselves. There are different mutant variants of SARS-CoV-2 that have reported and increased the severity of infections. In UK, new and emerging respiratory virus threats advisory group (NERVTAG) published a paper with the result outcome from many preliminary analyses of B.1.1.7 [67]. One of the variants was detected in England and was highly transmissible and got dispersed to several other countries. This variant contains seventeen mutations in the genome in which 8 are on S protein which is main antigenic target of 3 SARS-CoV-2 vaccines that have been licensed in England [67]. The NERVTAG proposed that infections by B.1.1.7 have high chances of death, as compared to parent virus. The other highly infectious variant P.1 in Brazil was reported in the mid-2020. This variant has increased the rate of infections, severity of the disease and the Manaus city, in Brazil where the health department is totally in a collapsed position. Today Brazil is third leading country in the SARS-CoV-2 infection globally because of these variants [67].
The B.1.351 variant was first identified in South Africa in 2020. The vaccines manufactured by Moderna claimed on Jan 25, 2021 that our vaccine is effective against both B.1.1.7 and B.1.351 variants. However, the claim was based on an in vitro study. In addition to that, a South African variant was having decreased levels of neutralizing antibody titers. The company Pfizer has claimed that our vaccine will work against B.1.1.7 variant because of their investigations in laboratory, although these studies have not been peer reviewed [67]. As long as the variants emerged, the more havoc it will create, vaccines will not work and the severity of the disease will be more. In India, more than three hundred thousand cases hit each day as on 25th of April 2021 because of the double and triple mutant variants [61]. There should be big focus on the drug development against SARS-COV-2 rather than whole focus on the vaccines. Such as in cases of other viral diseases which have been controlled by drugs not by vaccines like HIV. Vaccines may be effective against a single variant but drugs might work against many variants as is evidenced by many antiviral drugs. There are three CDC established classifications for multiple variants of the virus in collaboration with SIG. They are: variant of concern (VOC), variant of interest (VOI), and variant of high consequences (VOHC).

VOHC's
These variants have clear evidence that medical counter measures (MCMs) or measures for prevention reduced the effectiveness significantly compared to the previous variants. Fortunately, there are no SARS-CoV-2 variants observed so far at this high level of consequences [68].

VOC's
There is a clear evidence of transmissibility, severity, and immunity which require efforts to control the virus spread, CDC reporting, health actions of public, test and research to evaluate the vaccine effectiveness [68]. List of variants are given in Table 3.

VOI's
These variants have genetic markers which are specific which changes the binding of receptor, treatment efficacy reduction, has a clear evidence of transmissibility, severity, neutralization reduction by previously generated infection or vaccination. These variants require health actions of public, increased laboratory  [2]. List of variants of interest are given in Table 4.

Variants under monitoring
Through genomic variant rules-based screening, preliminary scientific evidence, epidemic intelligence these variants are detected as signals. There is a weak evidence which is not been assessed by European centre for disease prevention and control (ECDC) that they show similar properties as of VOC (Table 5).

Cough management
Sixty percent of COVID 19 positive cases report dry cough with zero phlegm production due to inflammation or irritation in your respiratory tract, which can get better with steam, humidifiers, honey consumption, cough suppressants, saltwater gargle, codeine phosphate, morphine sulfate as per the severity of infection [72,73].

Fever management
Fever after five days of infection is the most common in 99% of cases as your body's normal immune response tries to kill a virus. Advising the patients to consume a large number of fluids and to take paracetamol or ibuprofen can help to manage fever. Still, the use of ibuprofen use has marked a question of concern as the adaptive immune response will interfere with the release of prostaglandins, suppressing the fever response also leads to an increase in activity of lymphocyte, hyperemic response, and organ tissues oxygenation, causing failure of multiple organs [74,75].

GI disturbances
Pain in the abdomen (3.6%), looseness of the bowels (10.1%), Emesis (3.6%) is joint in COVID 19 patients due to its ACE2 receptor, which is expressed highly in gastrointestinal intestinal epithelial cells. Also, its viral RNA has been found in stool specimens of patients. A cohort endoscopy study of 95 COVID 19 patients reported six additional cases and identified viral RNA in the stomach, esophagus, intestinal duodenum, and rectum from 2 severe cases. Treatment relies on supportive care, antiemetics, proton pump inhibitors (PPI), antidiarrheals, promethazine, ondansetron, metoclopramide, adequate hydration, fresh ginger boiled in water added with honey can also treat nausea and weakness can reduce vomiting. If loose motions persist, stop the diet and consume coconut water (John Wiley, 2020), (Lipi Roy, 2020).

Vaccines
Acute viral infections remain a leading cause of morbidity andmortality. This novel coronavirus pandemic has triggered unprecedented global health researchers and scientists to find a safe, effective vaccine against this virus. Extensive research can be done by gaining the knowledge from SARS and MERS vaccines development strategies and knowing the key targets such as receptor-binding domain (RBD) of spike protein, nucleotide identification, immunization route, suitable animal model utilization, production facility scalability, are some of the essential parameters to be considered [78]. There are seven COVID 19 vaccines in the third phase of clinical trials. Out of which four are from China, two of the candidates are from China National Biotec Group (CNBG) [79]. On August 27, Sputnik V advanced Russia vaccine trials of Sputnik V announced COVID 19 vaccine trials for over six months in forty thousand volunteers (Table 8).

COVID 19 vaccine efficacy
The vaccines were marketed in short span of time after the deadly pandemic. The most important thing was whether these vaccines have good efficacy in neutralising the SARS-CoV-2 virus or there is long term protection by generating memory B-cells and T-cells. In Table 7 we have discussed various marketed vaccines and their efficacy like the dosage regimen, antibody response, T cell response, and effectiveness. There are many vaccines which have received emergency approval in many countries. As of April 2021, 28 vaccines which have entered phase III clinical trials, and other 5 reported showed efficacy in the submitted reports to the peerreviewed regulatory authorities for their emergency use through literature and/or through detailed publicly reports are available. For minimal protection 2 doses of vaccines are required for most of the them. Only 2 mRNA vaccines have shown efficacy at first dose after the detection of moderate TH1 cells and non neutralizing antibodies (Nabs). Induction of antibody dependent effector mechanisms, T-cell response, virus neutralization suggests that T cells, innate immune mechanisms, NAbs low levels and other immune effector mechanisms are involved which helps in easy identification of protection mechanism and further understanding of immune system involvement for further development of vaccines.

Conclusion
SARC-CoV-2 is a novel strain of coronavirus that is liable for causing the global pandemic. This has challenged all the crucial factors like the global economy, medical infrastructure, and public work life, particularly the variant strains are causing havoc. The impact of this pandemic is so severe that it has shaken most countries' economies. Since the tremendous advancement has been achieved in understanding the condition, shortly there seems a strong possibility of some of the therapeutic interventions to combat the SARS-COV-2 pandemic; till then, the only trusted intervention which is currently viable and proven to control is the following of strict quarantine measures, but to reach that intervention to all the affected groups there is a need of a more extensive set of randomized trials and fast testing of the condition to combat the disease effectively. However, this comprehensive review can provide some of the references for the follow-up medical studies. The spread of coronavirus trajectory across the World is difficult to predict as one country's problems will become global. The only possible solution is the vaccine development targeting against all variant strains to halt its progress, the identified theoretical and practical knowledge, current evidence, international alliances, ini-tiatives, and ideas based on the values of cooperation, inclusiveness, and equity can eliminate the gaps to improve better understanding of the novel coronavirus structure and its design of a vaccine.

Author's contribution
TF and JAM contributed equally in data collection and drafting the article. AHM, TA and KA contributed in data analysis and interpretation, and drafting the article. SA supervision and critical revision. All authors approved the final version of the article.

Funding
No funding sources.