Life Research doi: 10.53388/life2021-0406-301 REVIEW History, epidemiology, vaccine and transmission of disease 2019 (COVID-19): a quick review

Rabia Altaf1 *, Asra Iftikhar2, Rabia Haq3, Bushra Zahoor2, Muhammad Zaini Asmawi4, Mohamed Khadeer Ahamed Basheer5

1Department of Pharmacy, The Green International University, Lahore, Pakistan. 2Department of Pharmacy, The University of Faisalabad, Punjab, Pakistan. 3Department of Family medicine, Agha Khan University Hospital, Karachi, Pakistan. 4School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. 5EMAN Research Ltd, Level 3/81 Flushcombe Rd, Blacktown NSW 2148, Australia.

*Corresponding to: Rabia Altaf. The Green International University, Bhobattian Chowk, Raiwind Road, Lahore, Pakistan; E-mail: [email protected].

Abstract Coronavirus belonging to family is a large group of viruses causing respiratory and gastrointestinal diseases. The outbreak of 2019- has created panic in the whole world after being transmitted from Wuhan, China in December 2019. A large number of people are affected throughout the world that forced a solitary situation in the affected areas confining common people to their homes to prevent its spread. Cellular receptors in humans for 2019-novel coronavirus are found to be same as for severe acute respiratory syndrome coronavirus, the first human pandemic of 21st century, however, 2019-novel coronavirus is highly contagious, virulent and mutable than the severe acute respiratory syndrome coronavirus. The most attractive site for vaccine development against 2019-novel coronavirus is the spike glycoprotein which is crucial for receptor binding, membrane fusion via conformational changes, virus internalization, and host tissue tropism or spike inactivation through antibody induced destabilization. First outbreak was in December 2019, later on at the end of 2020, the mortality ratio decreased that created a sigh of temporary relief in the globe. Summer season was considered as one of the sources combating infection and preventing spread of virus. However, for the last few months, suddenly a huge outrage of new variants of coronavirus disease 2019 are capturing attention of the entire population of earth endangering lives of people irrespective of their ages and communities. Researchers must focus on the inventions and discoveries of either preventive or therapeutic medicines that precisely target the spike proteins that enable the severe acute respiratory syndrome coronavirus-2’s entry into a host cell. In this article, we have highlighted various vaccines being approved for emergency use by Federal Investigating Agency to combat the disastrous effects of pandemic on humanity. Mutated variants have created an alarming situation for the health care workers, researchers and scientists to consider the possible mutants and their threat to humanity in the coming years. Further, we have tried to create awareness for developing a global internet community to promote a barrier-free connectivity among all corners of the world to facilitate humanity in case of a category 5 coronavirus disease-hurricane, a term used by researchers for future threats of pandemic. Key words: Pandemic, Severe acute respiratory syndrome coronavirus-2, Social distance, Respiratory illness, Epitopes, S-glycoprotein

Abbreviations: SARS, severe acute respiratory syndrome; MERS, Middle East respiratory syndrome; ACE2, angiotensin-converting enzyme-2; RBD, receptor binding domain. Competing interests: The authors declare that they have no conflict of interest. Acknowledgement: We would like to acknowledge the support of the Green International University, however no funding support has been provided by any organization. Citation: Altaf R, Iftikhar A, Haq R, Zahoor B, Asmawi MZ, Basheer MKA. History, epidemiology, vaccine and transmission of coronavirus disease 2019 (COVID-19): a quick review. Life Res. 2021;4(3):19. doi: 10.53388/life2021-0406-301. Executive Editor: Shan-Shan Lin. Submitted: 06 April 2021, Accepted: 05 June 2021, Online: 09 July 2021 © 2021 By Authors. Published by TMR Publishing Group Limited. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/BY/4.0/).

Submit a manuscript: https://www.tmrjournals.com/lr 1 doi: 10.53388/life2021-0406-301 REVIEW

syndrome (MERS) which was diagnosed in Middle East Background countries especially Saudi Arabia in 2012 infected more than 2,428 individuals [4, 5, 11]. The initial symptoms History has taken turns changing its course at times due of MERS were mild upper respiratory injury leading to to occasional disease outbreaks ravaging humanity. severe acute respiratory syndrome (SARS) and acute Although pandemics are no new phenomena to lung injury [5]. It may not be highly infectious owing to mankind, currently world is facing a major disaster of a the fact that it binds to the CD26 receptor mainly pandemic named coronavirus-19 which has affected expressed in lower bronchi and may need prolonged as millions of people round the globe [1]. Clusters of well intense exposure to cause respiratory illness [12]. patients with pneumonia of unknown etiology were The first human pandemic in 21st century was reported in December 2019 in Wuhan, China which SARS-CoV that emerged in 2002–2003 in Southern spread to the whole world paralyzing the planet in less China (Guangdong) and spread worldwide causing than three months creating health, social, economic and fatalities [4, 13]. This virus had a link with handling of financial crisis. The novel virus outraged the classic exotic mammals for human consumption in wet markets indicators of reproduction rate and fatality rates of all of Wuhan, Hubei, a province in China bearing a the previous pandemics of 21st century including population of 14 million where live animals were sold influenza, severe acute respiratory syndrome [14, 15]. It was believed to be spread by international coronavirus (SARS-CoV) and Middle East respiratory air travel routes infecting 8,098 individuals causing 744 syndrome coronavirus (MERS-CoV) [2]. Coronavirus deaths in almost 33 countries of the world with is a large family of virus distributed among humans significantly high mortality rate [4, 5]. The outbreak (human coronavirus, HCoV) and animals. It belongs to was considered the sixth Public Health Emergency of family Coronaviridiae, subfamily Orthocoronavirinae international concern on January 30, 2020 [16]. in the order nidovirales comprised of four genera A novel virus which was never previously identified namely alpha-coronavirus, beta-coronavirus, in humans emerged in Wuhan, China in December 2019 gamma-coronavirus and delta-coronavirus affecting named as Wuhan Pneumonia or 2019-nCoV or Wuhan humans, mammals and birds [3–5]. Alpha-coronavirus coronavirus or SARS-CoV-2, belonging to genus and beta-coronavirus infect mammals and cause and sub-genus Sarbecovirus [4, 5, 17, respiratory illness [4, 6]. Coronavirus possess the 18]. The disease spread is considered to be the third largest known viral RNA constituted by ATPase human of 21st century [19]. helicase; S-protein (large surface glycoprotein), Genus coronavirus are enveloped RNA viruses that E-protein (small envelope protein), M-protein (a may cause disease in animals for example, murine membrane glycoprotein), N-protein (a neucleoprotein) virus, avian infectious bronchitis virus etc. and and an RNA-dependent RNA-polymerase [5]. humans as pneumonia in neonates, in Approximately one third of infections in immunocompromised patients, military recruits [20]. humans are the contribution of HCoV-229E, The reservoirs of SARS coronavirus were discovered HCoV-NL63, HCoV-OC43 and HCoV-HKU-1 which time to time on basis of evidence and found that initially are four of the identified six HCoVs. Other two are raccoon dogs, palm civets (in which viral RNA were SARS-CoV and MERS-CoV. HCoV-229E and found), then Rhinolophus bats (source of viral HCoV-NL63 are α-viruses whereas HCoV-OC43 and replication) were considered the primary and secondary HCoV-HKU1 are β-viruses [7]. hosts. The primary host for MERS was found to be camel and its pathogens were not observed in small History animals while SARS-CoV and SARS-CoV-2 both by mutation in spike glycoproteins infected animals which The history of coronavirus started in 1965 through may be considered to design suitable model for in-vivo discovery of a virus from nasal discharge of patients study of pathogen SARS-CoV-2 [5]. with common cold and was named B814 by Tyrrell and Bynoe [8]. Few human strains OC43 and 229E Epidemiology (Hamre’s virus) tended to be epidemic in three decades and infected children mostly. Further three new species The medium-sized RNA viruses with genomic size of coronavirus capable to attack humans were reported varying from 26–32 kilobase and 65–125 nm in namely human coronavirus NL63 (HCoV-NL63), diameter develop in cytoplasm of infected cells of human coronavirus-HKU1 (HCoV-HKU1) and humans. Distribution of cellular receptors for these MERS-CoV [9]. HCoV-NL63 was isolated from an CoVs are human aminopeptidase-N for group I infant with in 2004 while HCoV-HKU-1 coronavirus (229E), 9-o-acetylated neuraminic acid for was isolated from a patient with pneumonia in Hong strain organ culture 43 (OC43) and HCoV-HKU1, Kong in 2005 [10]. dipeptidyl-peptidase-4 for MERS-CoV, angiotensin A lethal zoonotic pathogen Middle East respiratory converting enzyme-II for SARS-coronavirus and

2 Submit a manuscript: https://www.tmrjournals.com/lr

Life Research doi: 10.53388/life2021-0406-301

HCoV-NL63 [4, 5, 21, 22]. spike inactivation through antibody induced SARS-CoV-2 infected 120,000 individuals in 109 destabilization [4, 6, 17, 21]. SARS-CoV-2 RBD countries with mortality rate 2.9% in such a short recognizes ACE2 receptors better than SARS-CoV duration from its emergence in December 2019 to date. RBD according to Jian, since SARS-CoV-2-receptor The same angiotensin-converting enzyme-2 (ACE2) binding motif has evolved strategies to neutralize the cell receptors are being used by SARS-CoV2 with charges on the lysine residues which is the key factor to much greater affinity due to mutation in N501T in facilitate the binding of coronavirus RBD to ACE2 [21, Spike glycoprotein [5]. The most attractive target for 23, 26]. COVID-19 binds to ACE2 that is expressed inhibitors and vaccines are spike (S)-proteins of largely on the surface of alveolar cells in lungs. The coronavirus comprising of S1 and S2 subunits in each adults and especially the adult men have higher plasma spike monomer providing sunlight based crown like concentration of circulating ACE2, so the elderly, shape to the virus protein and are oriented perpendicular health care workers, and anyone with underlying health to the cellular membrane [7, 23]. The positioning of conditions are at higher risk to get infected from the aromatic and hydrophobic domains to each other of disease [28]. SARS-CoV was found to be the key role player for its Several novel cytotoxic T-lymphocytes epitopes and entry into target cells as through receptor binding or vectors were found on SARS-CoV-2 which suggested membrane fusion [24]. the development of peptide based vaccine to prevent HCoVs gain entry into the host cell via endosomal, 2019-nCoV infection since it is closely related to non-endosomal and sometimes via combination of both predecessor SARS-CoV [6, 29, 30]. Remdesivir was pathways. A conformational change triggered in the S approved initially for emergency treatment of protein by the interaction between the S1 domain and its SARS-CoV-2 since it inhibits the RNA-dependent cognate receptor promotes the membrane fusion RNA polymerase of coronavirus which is being used between the viral and cell membranes through S2 for transcription of its genes and replication of its domain. These pathways are supported by certain genome [6, 31]. Chloroquine has been demonstrated to factors as low pH in cellular environment, certain act as an immunomodulator to enhance the antiviral proteases as cathepsin-L, transmembrane protease effect in vivo as well as interferes with ACE2 by serine 2 and airway trypsin like proteases [22]. HCoVs affecting at entry and post entry stages of 2019-nCoV induce apoptosis in intestinal mucosal cells, kidney which was later not found as much effective [3]. An tubular cells, neuronal dendritic cells and immune cells anti-neoplastic carmofur has been found to inhibit main suppressing the host innate and adaptive immune protease thereby inhibiting viral replication in cells responses [22]. SARS-CoV is highly contagious which giving way to development of new antiviral treatment crossed the species barrier and was enabled for human of COVID-19 [6, 32]. Immune enhancers, Chinese to human transmission [25]. It may get transmitted via herbs as well as intravenous gamma globulins were droplets in secretions as feces, urine, aerosols or found to improve the symptoms of corona virus. respiratory secretions while retaining its infectivity for Different experiments are being carried out in the 7 days [13]. whole world in different laboratories to search The RNA-recombination in S-glycoprotein among medicinal plants containing anti-viral phytochemicals the existing caused the emergence of that may inhibit the virus replication and to develop novel coronaviruses, e.g. 2019-nCoV from SARS-CoV, novel anti-COVID-19 therapeutic agents and vaccines which had an outbreak as a fatal pandemic spreading to prevent the attack of viruses [33–35]. To prioritize from Wuhan, Hubei province of China to almost whole the high-risk patients for COVID-19, an interpretable world. It was later named as SARS-CoV-2 [6, 11, 18]. mortality prediction model was being developed in Both SARS-CoV and SARS-CoV-2 share their gene China which uses lactic dehydrogenase as a biomarker content with each other as proteases (papain-like tool [6, 36]. Dexamethasone, a glucocorticoid was used protease and 3-C like protease), S-glycoprotein and the in few cases to reduce the death of patients of RNA-dependent RNA polymerase (Nsp12) [26]. COVID-19 by one third [37]. It is economical drug According to the serology and phylogeny, HCoV is available throughout the world previously being used as classified in four genera. Please refer to Figure 1 for the an anti-inflammatory as well as anticancer. illustration depicting the classification tree of HCoV. Convalescent plasma technique to boost up the immune Table 1 shows the chronology and pandemic details of system of patients of COVID-19 has been used to fight the different types of HCoVs [27]. off against virus with the help of antibodies in few trials The enhancement of cross-species transmission in during collaborative studies of different universities virus might be due to homologous recombination at [38]. S-glycoprotein of receptor binding domain (RBD) The clinical trials of newly developed drugs and region. This region is considered crucial site for vaccines are carried out. These clinical trials are receptor binding, membrane fusion via conformational comprised of three phases, the phase-1 trials and changes, virus internalization, host tissue tropism or phase-2 trials and phase-3 trials [39]. The trials carried

Submit a manuscript: https://www.tmrjournals.com/lr 3 doi: 10.53388/life2021-0406-301 REVIEW out on animals provide the data for phase-1 trials. formulating cell-culture-based vaccines, licensed vector Phase-1 trials are simply performed to establish the vaccines, recombinant protein vaccines, DNA-vaccines safety. The effect of dose on different biomarker and RNA-vaccine candidates in last decade. The key correlates with protection is examined in phase-2 trials target sites for vaccine development are enlisted to establish the desired protective efficacy. comprising spike proteins, spike RBD, spike Ultimately phase-3 trials critically evaluate the N-terminal domain, M-protein, E-protein and N-protein vaccine to achieve clinical end point, in this case, that etc. [41, 42, 43]. After passing through the clinical trial may be the protection against COVID-19 from phases, a number of candidate vaccines are brought for SARS-CoV-2 exposure [40]. Since the vaccine is a further considerations. biological preparation to protect humans from viral and bacterial infections, it is the crucial step taken by the Inactivated viral vaccines world’s scientists to develop vaccine against Food and Drug Administration (FDA)-approved COVID-19 to protect this world and next generations inactivated viral vaccines by Beijing Institute of from the lethal viral attack. The vaccine development Biological Products Company and inactivated technology has undergone great evolution by SARS-CoV-2 vaccine by Sinovac, a Chinese company.

Figure 1 Classification of human coronaviruses. HCoV, human coronavirus.

4 Submit a manuscript: https://www.tmrjournals.com/lr

Life Research doi: 10.53388/life2021-0406-301

Table 1 Comparison of different types of human coronaviruses Serial Human coronavirus Year of Receptor in humans Classification Incubation Outbreak in No. outcome period country 1 B814 1965 Human aminopeptidase-N Coronavirus 1–3 days England 2 HCoV-229E 1966 Human aminopeptidase-N α-coronavirus 2–5 days

3 Human coronavirus 1967 N-acetyl-9-O-acetyl β-coronavirus 2–5 days for organ culture-43 neuraminic acid 4 Severe acute 2003 Angiotensin converting β-coronavirus 2–11 days Guangdong, respiratory syndrome enzyme-2 China coronavirus 5 HCoV-NL63 2004 Angiotensin converting α-coronavirus 2–4 days Neitherland enzyme-2 6 HCoV-HKU-1 2005 N-acetyl-9-O-acetyl β-coronavirus 2–4 days Hong Kong neuraminic acid

7 Middle East 2012 Dipeptidyl peptidase-4/ β-coronavirus 2–13 days Arabian respiratory syndrome Adenosine deaminase Peninsula coronavirus complexing protein/ Cluster of differentiation 8 Severe acute 2019 Angiotensin converting β-coronavirus 3–6 days Wuhan, respiratory enzyme-2 China syndrome coronavirus-2 (coronavirus disease 2019) HCoV, human coronavirus.

The subunit vaccine candidates to design a vaccine Nanoparticulate subunit vaccines against MERS-CoV have used membrane protein and Protein, nucleic acid base vaccines and virus like spike glycoproteins that opens the window for particles are used as SARS-CoV-2 nanoparticulate recommendation of these vaccines against MERS-CoV subunit vaccine formulations. The subunit formulations as well as current pandemic COVID-19 [46]. ChAdOx1 often require co-administration of an adjuvant as nCoV-19, a viral vector vaccine has been given trial in aluminum salts (alum), combination of four randomized clinical trials to assess its safety and monophosphoryl lipid A and alum. efficacy against the novel coronavirus in Brazil, Britain and South Africa with quite positive outcome forming a Protein antigen recombinations basis for development of new vaccines against  A subunit vaccine with Trimer-Tag technology COVID-19 [47]. The new variants of COVID-19 have with a stabilized spike protein timer by Clover attacked children under ten years of age too so further Biopharmaceuticals Inc. in Australia. study is required to evaluate the potential risk factors  A vaccine candidate using spike protein trimer for the development of critical symptoms of COVID-19 with MF95 adjuvant by University of Queensland in children [48]. [44]. Some of the vaccines being used currently after  Vaccine candidate using RBD-dimer by Anhui clinical trials in a number of countries in different parts Zhifei Longcom Biopharmaceutical and the of the world are: Institute of Microbiology at the Chinese Academy  Pfizer/BioNtech (BNT162b2). An emergency use of Sciences. authorization for the vaccine was issued by FDA  Vaccine Pty Ltd with Medytox using recombinant on December 11, 2020 for a lipid spike protein as antigen and Advax as an adjuvant. nanoparticle-formulated, modified RNA particle The recombinant protein vaccine is considered encoding SARS-CoV-2 full length spike, more preferable than the RNA and viral vector BNT162b2. Almost at 150 sites worldwide, 43,448 vaccines due to its potent and effective nature [45]. patients were randomized in a 1:1 distribution  Vaccine candidate of a spike protein with double showing 95% efficacy 49. proline substitution by Medigen Vaccine  Moderna (mRNA-1273). Preliminary results Biologics corporation, the National Institute of showed the effectiveness of Moderna to be 94.1% Allergy and Infectious Disease, and Dynavax. against SARS-CoV-2. An emergency use

Submit a manuscript: https://www.tmrjournals.com/lr 5 doi: 10.53388/life2021-0406-301 REVIEW

authorization was issued by FDA on December 18, 2020 for Moderna to be given 0.5 mL, 2 doses-28 Developing an international internet society days apart. It’s a lipid nanoparticle containing A trustworthy continuous internet facility with strong mRNA encoding for spike proteins once absorbed end-to-end encryption is becoming the need of era in results in immune response development by spike near future. In such a pandemic crisis that has protein expression. implemented a long term social distance in general,  Novavax (NVX-CoV2373) (virus like particle current internet facility has made people to work from vaccine). An adjuvant is added to nanoparticles home, to gain uninterrupted online education, exchange coated with synthetic spike proteins, which of emotional values among isolated family members showed an efficacy of 89% (US/UK strain) with a during quarantine times. Still 50% of the world’s dose regimen of 2 doses-21 days apart. population could not have access to internet in remote  Sinopharm (BBIBP-CorV). Keeping all the and rural areas. Community-driven connectivity must proteins intact, the SARS-CoV-2 is chemically be made barrier-free by lawmakers and regulators to inactivated by beta-propiolactone, showed ensure easy access of each and every community to efficacy of 79% with 2 doses-3 weeks apart. uninterrupted internet as the best means of  Sputnik V (Gamaleya) (Sputnik communication [52]. V/Gam-Covid-Vac). Immune response is produced by spike proteins expressed by infected Clinical outcome, diagnosis and prevention cells showed 91% efficacy by 0.5 mL given in 2 doses-28 days apart. Human to human transmission  Oxford/Astrazeneca (ChAdOx1/AZD1222) The novel COVID-19 is found to be able to spread (Covidshield). Its also a viral vector vaccine that human to human by exposure to cough, sneeze, droplets, leads to immune response by spike proteins aerosols inhaled by mouth or nose, contact of subject expression showing efficacy of 82% with 2 with object infected with virus and transmission of virus doses-12 weeks apart. to nose or mouth of subject [5, 6, 14, 53]. In very few Factors that determine vaccines to be incorporated cases, it may have been the digestive route where ACE2 globally are: (a) complexity to find most effective was considered expressive in ileum and colon [53]. candidate; (b) storage requirements; as refrigerated Other routes of transmission as through breast milk, versus frozen; (c) requirement of a single or more sweat, semen or fecal etc. are still under review in injection for optimal immunity. different areas of the world to gain knowledge which may help to prepare its vaccine [1]. Health care policies for implementation of vaccination procedure and its future Animal to human transmission implementations Another route of transmission of coronavirus is considered to be through the intermediate hosts, that are Vaccination strategies and approaches through the animals. Undercooked meat of animals, The decision to get vaccinated or not is affected by a urine or milk consumption or through unknown wild number of factors around the world, as social norms, the animals are considered for a detailed knowhow. parent level of education, the socio-demographic context and the religious beliefs [50]. Approximately Transmission through Fomite exposure more than 180 vaccines are in production phase but still Since the deadly virus is considered to be viable for a conflict is there among the world’s population for who hours in the air and for days on surfaces of plastic, should receive the vaccine first. Young people must copper, steel and cardboard, it may be transmitted receive it initially to face the possible side-effects for through contaminated surfaces and aerosols. possessing better immunity than older ones, is the high talk now-a-days. A single-dose vaccination strategy is Transmission via environmental factors considered appropriate for high-exposure, low-risk The stability and transmission rate of SARS-CoV-2 individuals while two-dose regimen is considered varies with difference in environmental parameters as suitable for the high-risk populations and for older humidity, temperature and sunlight. The spread was adults. An increasing interest and trend in single-dose recorded least in African countries with high strategies has become the top trend to shift as many temperature and highest in cold areas of the world in people as possible to vaccination. Relaxed prevention, winter season especially when respiratory symptoms possibility of reinfection, virus mutation and worsen. vaccination delays are a combination of factors that may lead to long-haul COVID or long-COVID, literally Human to animal transmission a category 5 “COVID-hurricane”, that may cause The only reported evidence of coronavirus transmission infections that can linger for months [51]. from human to animal was in Bronx Zoo of USA, where

6 Submit a manuscript: https://www.tmrjournals.com/lr

Life Research doi: 10.53388/life2021-0406-301 the virus was transferred from asymptomatic zookeeper comparison of mask-off settings and mask-on settings to tiger, which gives an alarming situation. The issue is revealed a great rate of spread of the COVID-19 still under consideration [16]. clusters from one person to other. The extent of transmission was mitigated by universal masking Discussion phenomenon in the communities. It is still advisable wear the facial masks to avoid the transmission of virus The symptoms of COVID-19 range from asymptomatic from one person to another. Personal protection with conditions to flu, sneezing cough, myalgia, fever, the use of reusable masks, gowns and gloves is highly pneumonia, complicated dyspnea and more severe encouraged to combat the emerging infectious disease symptoms include acute lung injury, shock and acute [61]. kidney injury [54]. SARS-CoV-2 might target all The unpredictable challenges are being faced by both organs including lungs [55]. Since many pathogens are patients and specialists since the emergence of new present in saliva and nasopharyngeal secretions, any variants of COVID-19, especially by the patients with type of dental procedure may be considered an easy other pre-existing diseases as congenital heart failure or route of transmission of airborne contamination [56]. asthma [62]. A two-fold threat to human health may Real time PCR may be performed for the diagnosis of occur by the attack of novel viral pathogens in nucleic acid of SARS-CoV-2 in the samples of throat individuals with decreased host immunity due to swab, sputum and secretions of lower respiratory tract micronutrient deficiency. Certain micronutrients as zinc, [6, 53]. To overcome the accessibility and availability selenium, iodide, copper, iron and vitamins as vitamin of real time PCR, various serological tests including A, B, C, D and E present a supporting role on the host ELISA, immunoglobulin M, immunoglobulin G, immune response to viral infection. Their deficiency computed tomography and chromatographic tests are may become opportunistic approach for viral mutation being used for qualitative detection of SARS-CoV-2 through host cell permissiveness [63]. The role of host [57]. immunity and micronutrients to resist the attack by Mean incubation period of SARS-CoV-2 is infectious viral pathogens must be investigated more to suggested as 3–6 days with the interval of onset of get long-term benefits against future viral outbreaks symptoms and appearance of acute respiratory [64]. Special precautionary measures as avoiding crowd, distress syndrome of almost 6–7 days suggesting the maintaining social distance, usage of N95 respirators, consideration of 14 days for medical observation from protective suits and goggles, proper nutrition etc. must initial exposure [3]. Extreme rise in inflammatory be adapted by government and people themselves to cytokines as tumor necrosis factor alpha, and avoid the spread of disease. interleukins cause progression of pneumonia at the end After a dynamic study of transmission of the disease of 1st week causing death in some cases especially in from its origin to the whole world irrespective of elderly although all ages are susceptible [57]. Some climate, a number of articles came in press determining cohort studies reported gastrointestinal symptoms as the statistical analysis of transmission rate and anorexia, nausea, vomiting, diarrhea etc., whereby live strategies to assess its clinical severity including 2019-CoV were found in stool specimens, patients’s number of infected persons leaving the Wuhan state via with neurological manifestations including headache, different departure routes, number of patients infected dizziness, ischemic and hemorrhagic strokes, olfactory per day, time of onset of disease to death of patients, the and taste disorders as well as immune system disorders transmission route of disease from person to person or [26, 58]. object to subject and the symptomatic appearance of World Health Organization gave a detailed guideline disease etc. [65]. Breast feeding mothers and pregnant to use proper hygienic measures to prevent the spread of ladies require precautions to avoid transmission of virus disease from person to person and from infected objects to neonates since they remain at high risk for to subjects [59]. These guidelines included washing development of severe respiratory complications A hands properly with water and soap, using sanitizers (at study was carried out on almost 31 expecting mothers least with 60% alcohol) whenever touching any object, of which 2 died due to respiratory complications after use of certified respirators as non-oil mask with 95% delivery although none of them gave any evidence to efficiency (N95) and filtering face piece 2 (FFP2) while transfer the disease to neonates but still they claimed the performing aerosol procedures, covering face transfer of droplets while feeding the babies [66]. especially nose and mouth with face masks to avoid Vaccination transfers the immunity from mother to entry of airborne droplets through nose or mouth when infant as per reference to our history of vaccination for in social contact, using flexed elbow while coughing or pertussis and tetanus provides a great insight to adapt a sneezing, avoid touching nose, eyes or mouth vital public health measure to reduce preventable frequently, to stay at home and avoid any gatherings as mortality and morbidity for the mother, fetus and infant well as observe social distance to prevent spread of [67]. While developing a vaccine, a broad spectrum disease from person to person [6, 54, 60]. The cross protection approach must be considered to

Submit a manuscript: https://www.tmrjournals.com/lr 7 doi: 10.53388/life2021-0406-301 REVIEW develop a vaccine that may be applied to exert its Siddique R. COVID-19 infection: origin, protective effects in case of similar viral diseases in transmission, and characteristics of human humans or animals in future [12]. coronaviruses. J Adv Res. 2020;24(1):91–98. Available: 10.1016/j.jare.2020.03.005; https://dx. Conclusion doi.org/10.1016/j.jare.2020.03.005 6. Kumar S, Maurya VK, Prasad AK, Bhatt MLB, The pandemic has spread throughout the world in no Saxena SK. Structural, glycosylation and time infecting almost 145 million people round the antigenic variation between 2019 novel globe. Many have been recovered by keeping coronavirus (2019-nCoV) and SARS coronavirus themselves socially distant, in quarantine. Half of the (SARS-CoV). Virusdisease. 2020;31(1):13–21. countries have been through severe lock down to Available: 10.1007/s13337-020-00571-5; https:// prevent the spread of disease through borders. Few are dx.doi.org/10.1007/s13337-020-00571-5 back to their normal living and few are still suffering 7. Parameshwar K, Pamu S, Sandeep K, Suresh C. A that has created a huge economic crisis leaving a large review novel coronavirus. Asian J Pharm Clin population unemployed. A huge responsibility falls on Res. 2020;13(4)12–17. Available: 10.22159/ medical personnel, health care professionals, doctors, ajpcr.2020.v13i4.36982; https://dx.doi.org/10.221 pharmacists, scientists to make collaborative efforts to 59/ajpcr.2020.v13i4.36982 develop vaccine for 2019-CoV to counteract its 8. Kahn JS, McIntosh K. History and recent hazardous effects in coming generations. Although advances in coronavirus discovery. Pediatr Infect vaccine development is a need of the day but following Dis J. 2005;24(11 Suppl):S223–227. Available: all the procedures for vaccine development including 10.1097/01.inf.0000188166.17324.60; https://dx. clinical trials, it would also be quite time demanding to doi.org/10.1097/01.inf.0000188166.17324.60 let each and every human on globe to be vaccinated for 9. Woo PC, Lau SK, Chu CM, et al. Characterization the novel coronavirus [68]. Meanwhile, implementation and complete genome sequence of a novel of specific preventive measures, provision of quarantine coronavirus, coronavirus HKU1, from patients facilities worldwide, maintenance of social distance, with pneumonia. J Virol. 2005;79(2):884–895. campaigns for awareness of hygiene as well as the Available: 10.1128/JVI.79.2.884-895.2005; https: knowledge of symptoms of the disease to prevent its //dx.doi.org/10.1128/JVI.79.2.884-895.2005 spread are few of the unavoidable liabilities on the 10. Jonsdottir HR, Dijkman R. Coronaviruses and the government bodies of each country to combat human airway: a universal system for virus-host aftereffects of the pandemic. At the same time, a serious interaction studies. Virol J. 2016;13:24. Available: focus is to be advocated for people to stay mentally 10.1186/s12985-016-0479-5; https://doi.org/ healthy and augment the focus on resilience and on 10.1186/s12985-016-0479-5 strategies to improve it [69]. 11. Iwasawa T, Sato M, Yamaya T, et al. Ultra-high-resolution computed tomography can References demonstrate alveolar collapse in novel coronavirus (COVID-19) pneumonia. Jpn J 1. Haleem A, Javaid M. Effects of COVID-19 Radiol. 2020;38(5):394–398. Available: pandemic in daily life. Curr Med Res Pract. 2020; 10.1007/s11604-020-00956-y; https://doi.org/ 10(2):78–79. Available: 10.1016/j.cmrp.2020.03. 10.1007/s11604-020-00956-y 011; https://doi.org/10.1016/j.cmrp.2020.03. 011 12. Contini C, Di Nuzzo M, Barp N, et al. The novel 2. Peterson E, Koopmans M, Go U, et al. Comparing zoonotic COVID-19 pandemic: an expected SARS-CoV-2 with SARS-CoV and influenza global health concern. J Infect Dev Ctries. pandemics. Lancet Infect Dis. 2020;20(9): 238– 2020;14(3):254–264. Available: 10.3855/jidc. 244. Available: 10.1016/S1473-3099(20) 30484-9; 12671; https://doi.org/10.3855/jidc.12671 https://doi.org/10.1016/S1473-3099 (20)30484-9 13. Franks TJG, Jeffrey R. Coronavirus. In: Fraire AE, 3. Xue L, Li J, Wei L, Ma C. A quick look at the Woda BA, Welsh RM, Kradin RL. ed. Viruses and latest developments in the COVID-19 pandemic. the Lung: Infectious and Non-infectious J Int Med Re. 2020;48(9):1–8. Available: Viral-linked Lung Disorders. Springer-Verlag 10.1016/j.cub.2015.04.020; Berlin Heidelberg;2014:Chapter 13:109–116. https://doi.org/10.1177/0300060520943802 14. Zhu H, Wei L, Niu P. The novel coronavirus 4. Bhattacharya S, Sharma P, Mathur H, et al. outbreak in Wuhan, China. Glob Health Res Recent apprise on coronavirus and its terrible Policy. 2020;5:6. Available: 10.1186/s41256 insinuations. Virusdisease. 2020;31(2):1–7. -020-00135-6; https://doi.org/10.1186/s41256 Available: 10.1007/s13337-020-00582-2; https:// -020-00135-6 dx.doi.org/10.1007/s13337-020-00582-2 15. Institute of Medicine (US) Forum on Microbial 5. Shereen MA, Khan S, Kazmi A, Bashir N, Threats. Learning from SARS: Preparing for the

8 Submit a manuscript: https://www.tmrjournals.com/lr

Life Research doi: 10.53388/life2021-0406-301

Next Disease Outbreak: Workshop Summary. SARS coronavirus spike glycoprotein: refinement Knobler S, Mahmoud A, Lemon S, Mack A, of the requirements for SARS coronavirus cell Sivitz L, Oberholtzer K, ed. Washington: National entry. Virol J. 2009;6:230. Available: Academies Press;2004. 10.1186/1743-422X-6-230; https://doi.org/10. 16. Rabaan AA, Al-Ahmed SH, Muhammad J, et al. 1186/1743-422X-6-230 Role of inflammatory cytokines in COVID-19 25. Antia R, Regoes RR, Koella JC, Bergstrom CT. patients: A review on molecular mechanisms, The role of evolution in the emergence of immune functions, immunopathology and infectious diseases. Nature. 2003;426(6967): 658– immunomodulatory drugs to counter cytokines 661. Available: 10.1038/nature02104; https:// storm. Vaccines. 2021;9(5):436. Available: 10. dx.doi.org/10.1038/nature02104 3390vaccines9050436; https://doi.org/10.3390 26. Cevik M, Bamford CGG, Ho A. COVID-19 vaccines9050436 pandemic-a focused review for clinicians. Clin 17. Wang C, Li W, Drabek D, et al. A human Microbiol Infect. 2020;26(7):842–847. Available: monoclonal antibody blocking SARS-CoV-2 10.1016/j.cmi.2020.04.023; https://doi.org/10. infection. Nat Commun. 2020;11(1):2251. 1016/j.cmi.2020.04.023 Available: 10.1038/s41467-020-16256-y; https:// 27. Ye ZW, Yuan S, Yuen KS, Fung SY, Chan CP, Jin dx.doi.org/10.1038/s41467-020-16256-y DY. Zoonotic origins of human coronaviruses. Int 18. Boulos MNK, Geraghty EM. Geographical J Biol Sci. 2020;16(10):1686–1697. Available: tracking and mapping of coronavirus disease 10.7150/ijbs.45472; https://doi.org/10.7150/ COVID-19/severe acute respiratory syndrome ijbs.45472 coronavirus 2 (SARS-CoV-2) epidemic and 28. Gallego P, Ruperti-Repilado FJ, Schwerzmann M. associated events around the world: how 21st Adults with congenital heart disease during the century GIS technologies are supporting the coronavirus disease 2019 (COVID-19) pandemic: global fight against outbreaks and epidemics. Int J are they at risk? Rev Esp Cardiol (Engl Ed). Health Geogr. 2020;19(1):8. Available: 2020;73(10):795–798. Available: 10.1016/j.rec.20 10.1186/s12942-020-00202-8; https://doi.org/ 20.06.016; https://doi.org/10.1016/j.rec.2020. 10.1186/s12942-020-00202-8 06.016 19. Asrani P, Hasan GM, Sohal SS, Hassan MI. 29. Sarkar B, Ullah MA, Johora FT, Taniya MA, Araf Molecular basis of pathogenesis of coronaviruses: Y. Immunoinformatics-guided designing of a comparative genomics approach to planetary epitope-based subunit vaccines against the SARS health to prevent zoonotic outbreaks in the 21st Coronavirus-2 (SARS-CoV-2). Immunobiology. century. Omics. 2020;24(11):634–644. Available: 2020;225(3):151955. Available: 10.1016/j.imbio. 10.1089/omi.2020.0131; https://doi.org/10.10 2020.151955; https://doi.org/10.1016/j.imbio. 89/omi.2020.0131 2020.151955 20. Peiris JS, Lai ST, Poon LL, et al. Coronavirus as a 30. Lim HX, Lim J, Jazayeri SD, Poppema S, Poh CL. possible cause of severe acute respiratory Development of multi-epitope peptide-based syndrome. Lancet. 2003;361(9366):1319–1325. vaccines against SARS-CoV-2. Biomed J. Available: 10.1016/s0140-6736(03)13077-2; https: 2020;44(1):18–30. Available: 10.1016/j.bj.2020. //dx.doi.org/10.1016/s0140-6736(03)13077-2 09.005; https://doi.org/10.1016/j.bj.2020.09. 005 21. Shang J, Ye G, Shi K, et al. Structural basis of 31. Hillen HS, Kokic G, Farnung L, Dienemann C, receptor recognition by SARS-CoV-2. Nature. Tegunov D, Cramer P. Structure of replicating 2020;581(7807):221–224. Available: 10.1038/s41 SARS-CoV-2 polymerase. Nature. 2020; 586-020-2179-y; https://doi.org/10.1038/s415 584(7819):154–156. Available: 10.1038/s41586 86-020-2179-y -020-2368-8; https://doi.org/10.1038/s41586- 22. Lim YX, Ng YL, Tam JP, Liu DX. Human 020-2368-8 coronaviruses: a review of virus-host interactions. 32. Jin Z, Zhao Y, Sun Y, et al. Structural basis for the Diseases. 2016;4(3):26. Available: 10.3390/ inhibition of SARS-CoV-2 main protease by diseases4030026; https://doi.org/10.3390/ antineoplastic drug carmofur. Nat Struct Mol Biol. diseases4030026 2020;27(6):529–532. Available: 10.1038/s41594- 23. Lan J, Ge J, Yu J, et al. Structure of the 020-0440-6; https://doi.org/10.1038/s41594- SARS-CoV-2 spike receptor-binding domain 020-0440-6 bound to the ACE2 receptor. Nature. 33. Qamar MT, Alqahtani SM, Alamri MA, Chen LL. 2020;581(7807):215–220. Available: 10.1038/ Structural basis of SARS-CoV-2 3CL(pro) and s41586-020-2180-5; https://doi.org/10.1038/s anti-COVID-19 drug discovery from medicinal 41586-020-2180-5 plants. J Pharm Anal. 2020;10(4):313–319. 24. Corver J, Broer R, van Kasteren P, Spaan W. Available: 10.1016/j.jpha.2020.03.009; https://dx. Mutagenesis of the transmembrane domain of the doi.org/10.1016/j.jpha.2020.03.009

Submit a manuscript: https://www.tmrjournals.com/lr 9 doi: 10.53388/life2021-0406-301 REVIEW

34. Xu B, Gutierrez B, Mekaru S, et al. of severe acute respiratory syndrome coronavirus Epidemiological data from the COVID-19 2 in India and vaccine impact. Indian J Med outbreak, real-time case information. Sci Data. Microbiol. 2020;38(2):210–212. Available: 2020;7(1):106. Available: 10.1038/s41597-020- 10.4103/ijmm.IJMM_20_303; https://doi.org/ 0448-0; https://doi.org/10.1038/s41597-020-0 10.4103/ijmm.IJMM_20_303 448-0 44. Gupta P. A review: epidemiology, pathogenesis 35. Anand AV, Balamuralikrishnan B, Kaviya M, et al. and prospect in developing vaccines for novel Medicinal plants, phytochemicals, and herbs to coronavirus (COVID-19). Indian J Tubercul. combat viral pathogens including SARS-CoV-2. 2020;68(1):92–98. Available: 10.1016/j.ijtb.2020. Molecules. 2021;26(6):1775. Available: 10.3390/ 09.021; https://doi.org/10.1016/j.ijtb.2020. 09.021 molecules26061775; https://doi.org/10.3390/ 45. Almond J, Hacker J, Harwood C, et al. molecules26061775 Development of vaccines at the time of 36. Yan L, Zhang HT, Goncalves J, et al. An COVID-19. microLife. 2020;1(1):uqaa003. interpretable mortality prediction model for Available: 10.1093/femsml/uqaa003; https://dx. COVID-19 patients. Nat Mach Intell. doi.org/10.1093/femsml/uqaa003. 2020;2(5):283–288. Available: 10.1038/s42256- 46. Kyriakidis NC, López-Cortés A, González EV, 020-0180-7; https://doi.org/10.1038/s42256- Grimaldos AB, Prado EO. SARS-CoV-2 vaccines 020-0180-7 strategies: a comprehensive review of phase 3 37. The RECOVERY Collaborative Group, Horby P, candidates. NPJ Vaccines. 2021;6(1):1–17. Lim WS, et al. Dexamethasone in hospitalized Available: 10.1038/s41541-021-00292-w; https:// patients with Covid-19. N Engl J Med. dx.doi.org/10.1038/s41541-021-00292-w 2021;384(8):693–704. Available: 10.1056/NEJM 47. Voysey M, Clemens SAC, Madhi SA, et al. Safety oa2021436 https://doi.org/10.1056/NEJMoa and efficacy of the ChAdOx1 nCoV-19 vaccine 2021436 (AZD1222) against SARS-CoV-2: an interim 38. Bartsch SM, O’Shea KJ, Wedlock PT, et al. The analysis of four randomised controlled trials in benefits of vaccinating with the first available Brazil, South Africa, and the UK. Lancet. COVID-19 coronavirus vaccine. Am J Prev Med. 2021;397(10269):99–111. Available: 10.1016/S 2021;60(5):605–613. Available: 10.1016/j.amepre. 0140-6736(20)32661-1; https://doi.org/10.10 2021.01.001; https://doi.org/10.1016/j.amepre. 16/S0140-6736(20)32661-1 2021.01.001 48. Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk 39. Rab S, Afjal, Javaid M, Haleem A, Vaishya R. An factors for severity in children with coronavirus update on the global vaccine development for disease 2019: a comprehensive literature review. coronavirus. Diabetes Metab Syndr. Paediatr Clin North Am. 2021;68(1):321–338. 2020;14(6):2053–2055. Available: 10.1016/j.dsx. Available: 10.1016/j.pcl.2020.07.014; https://dx. 2020.10.023; https://doi.org/10.1016/j.dsx. doi.org/10.1016/j.pcl.2020.07.014 2020.10.023 49. Zhu N, Zhang D, Wang W, Li X, et al. A novel 40. Batty CJ, Heise MT, Bachelder EM, Ainslie KM. coronavirus from patients with pneumonia in Vaccine formulations in clinical development for China, 2019. N Engl J Med. 2020;382(8): 727– the prevention of severe acute respiratory 733. Available: 10.1056/NEJMoa2001017; syndrome coronavirus 2 infection. Adv Drug https://doi.org/10.1056/NEJMoa2001017 Deliv Rev. 2021;169:168–189. Available: 50. Baumgaertner B, Carlisle JE, Justwan F. The 10.1016/j.addr.2020.12.006; https://doi.org/ influence of political ideology and trust on 10.1016/j.addr.2020.12.006 willingness to vaccinate. PloS One. 2018;13(1): 41. Kaur N, Singh R, Dar Z, Bijarnia RK, Dhingra N, e0191728. Available: 10.1371/journal.pone.01917 Kaur T. Genetic comparison among various 28; https://doi.org/10.1371/journal.pone.01917 28 coronavirus strains for the identification of 51. Syrek R. Trending clinical topic: single-dose potential vaccine targets of SARS-CoV2. Infect vaccination. https://reference.medscape.com/ Genet Evol. 2020;89:104490. Available: viewarticle/946524. Published March 05, 2021. 10.1016/j.meegid.2020.104490; https://doi.org/ Accessed March 05, 2021. 10.1016/j.meegid.2020.104490 52. Abuhammad S. Barriers to distance learning 42. Ita K. Coronavirus disease (COVID-19): current during the COVID-19 outbreak: a qualitative status and prospects for drug and vaccine review from parent’s perspective. Heliyon. development. Arch Med Res. 2020;52(1):15–24. 2020;6(11):e05482. Available: 10.1016/j.heliyon. Available: 10.1016/j.arcmed.2020.09.010; https:// 2020.e05482; https://doi.org/10.1016/j.heliyon. dx.doi.org/10.1016/j.arcmed.2020.09.010 2020.e05482 43. Jacob JJ, Vasudevan K, Veeraraghavan B, 53. Adhikari SP, Meng S, Wu YJ, et al. Epidemiology, Iyadurai R, Gunasekaran K. Genomic evolution causes, clinical manifestation and diagnosis,

10 Submit a manuscript: https://www.tmrjournals.com/lr

Life Research doi: 10.53388/life2021-0406-301

prevention and control of coronavirus disease nu12010236; https://doi.org/10.3390/nu120102 36 (COVID-19) during the early outbreak period: a 64. Katona P. The interaction between nutrition and scoping review. Infect Dis Poverty. 2020;9(1):29. infection. Clin Infect Dis. 2008;46(10): 1582– Available: 10.1186/s40249-020-00646-x; https:// 1588. Available: 10.1086/587658; https://dx. dx.doi.org/10.1186/s40249-020-00646-x doi.org/10.1086/587658 54. Singhal T. A review of coronavirus disease-2019 65. Wu JT, Leung K, Bushman M, et al. Estimating (COVID-19). Indian J Pediatr. 2020;87(4): 281– clinical severity of COVID-19 from the 286. Available: 10.1007/s12098-020-03263-6; transmission dynamics in Wuhan, China. Nat Med. https://doi.org/10.1007/s12098-020-03263-6 2020;26(4):506–510. Available: 10.1038/s41591 55. Borsanahan SB, Jonkman AH, Kugler MC, -020-0822-7; https://doi.org/10.1038/s41591-0 Munger JS, Kaufman DA. COVID-19 and 20-0822-7 respiratory system disorders. Arterioscler Thromb 66. Zarchi MK, Neamatzadeh H, Dastgheib SA, et al. Vasc Biol. 2020;40(11):2586–2597. Available: Vertical transmission of coronavirus disease 19 10.1161/ATVBAHA.120.314515; https://dx.doi. (COVID-19) from infected pregnant mothers to org/10.1161/ATVBAHA.120.314515 neonates: a review. Fetal Pediatr Pathol. 56. Ali SZU, Muhammad A. Transmission routes and 2020;39(3):246–250. Available: 10.1080/15513 infection control of novel coronavirus-2019 in 815.2020.1747120; https://doi.org/10.1080/155 dental clinics – a review. J Islamabad Med Dental 13815.2020.1747120 Coll. 2020;1(9):65–72. Available: 10.1177/03000 67. Elahi S, Buchanan RM, Babiuk LA, Gerdts V. 60520943802; https://doi.org/10.1177/03000 Maternal immunity provides protection against 60520943802 pertussis in newborn piglets. Infect Immun. 57. Jain N, Choudhury A, Sharma J, Kumar V, De D, 2006;74(5):2619–2627. Available: 10.1128/IAI. Tiwari R. A review of novel coronavirus infection 74.5.2619-2627.2006; https://doi.org/10.1128/ (coronavirus disease-19). GlobJ Transfus Med. IAI.74.5.2619-2627.2006 2020;5(1):22. Available: 10.4103/GJTM.GJTM 68. Helmy Y. No scientific clinical evidence for long _24_20; https://doi.org/10.4103/GJTM.GJTM term safety of newly evolved COVID-19 vaccines: _24_20 review and meta-analysis. Al-Azhar Int Med J. 58. Wolfel R, Corman VM, Guggemos W, et al. 2020;1(4):106–110. Available: 10.21608/aimj. Virological assessment of hospitalized patients 2020.55247.1382; https://doi.org/10.21608/ with COVID-2019. Nature. 2020;581(7809): aimj.2020.55247.1382 465–469. Available: 10.1038/s41586-020-2196-x; https://doi.org/10.1038/s41586-020-2196-x Reviewer information Life Research thanks Anil Batta, 59. Kumar D, Malviya R, Sharma PK. Coronavirus: a Kanu Megha, Chinyere Mma Okoh, Yang Liu for the review of COVID-19. Eurasian J MedvOncol. contribution to the peer review of this paper. 2020;4(1):8–25. Available: 10.14744/ejmo.2020. 90853; https://doi.org/10.14744/ejmo.2020. 90853 60. Carbone M, Lednicky J, Xiao SY, et al. Coronavirus 2019 infectious disease epidemic: where we are, what can be done and hope for. J Thorac Oncol. 2021;16(4):546–571. Available: 10.1016/j.jtho.2020.12.014; https://doi.org/10. 1016/j.jtho.2020.12.014 61. Cheng VCC, Wong SC, Chuang VWM, et al. The role of community-wide wearing of face mask for control of coronavirus disease 2019 (COVID-19) epidemic due to SARS-CoV-2. J Infect. 2020;81(1):107–114. Available: 10.1016/j.jinf. 2020.04.024; https://doi.org/10.1016/j.jinf. 2020.04.024 62. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr. 2020;14(3):247–250. Available: 10.1016/j.dsx.2020.03.013; https://dx. doi.org/10.1016/j.dsx.2020.03.013 63. Gombart AF, Pierre A, Maggini S. A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients. 2020;12(1):236. Available: 10.3390/

Submit a manuscript: https://www.tmrjournals.com/lr 11