Product of natural evolution (SARS, MERS, and SARS-CoV-2); deadly diseases, from SARS to SARS-CoV-2

Figures & data

Table 1. History of epidemics since 1900

Year	Outbreak
1918	Great flu pandemic
1976	Legionnaires disease
1993	Hanta virus pulmonary syndrome
1994	Hendra virus infection
1997	H5N1 influenza infection
1999	Nipah virus encephalitis/pneumonitis
2002	Severe acute respiratory syndrome (SARS)
2012	Middle east respiratory syndrome (MERS)
2019	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Table 2. Three main coronavirus outbreaks and their origin

Coronavirus outbreak	Origin
SARS	Civets (although, the virus originated in bats, and civets consider as intermediary)
MERS	Camels (The virus also came from bats)
SARS-CoV-2	Malayan pangolins (armadillo-like mammals) (the virus also came from bats)

Table 3. Important steps allow the virus entry.^20.

(a) Bind to a target host cell, typically via interactions with cellular receptors.

(b) Fuse its envelope with a cellular membrane, either at the plasma membrane or through the endocytic pathway.

(c) Deliver its genetic material inside the cell.

Table 4. Host information and distribution of SARSr-CoVs available in GenBank.^21.

Provinces	Bat species
Guangdong	Rhinolophus sinicus
Guangxi	Rhinolophus pearsonii, Rhinolophus sinicus
Guizhou	Rhinolophus rex, Rhinolophus sinicus
Hebei	Rhinolophus ferrumequinum
Henan	Rhinolophus ferrumequinum
Hong Kong	Rhinolophus sinicus
Hubei	Rhinolophus ferrumequinum, Rhinolophus macrotis, Rhinolophus sinicus
Jilin	Rhinolophus ferrumequinum
Shaanxi	Rhinolophus pusillus
Shanxi	Rhinolophus ferrumequinum
Taiwan	Rhinolophus monoceros
Yunnan	Aselliscus stoliczkanus, Rhinolophus affinis, Rhinolophus ferrumequinum, Rhinolophus sinicus
Zhejiang	Rhinolophus monoceros, Rhinolophus pearsonii, Rhinolophus sinicus, Rhinolophus thomasi

Figure 1. Taxonomy of the coronaviridae family

Table 5. The most important characteristic of SARS

1. The first international disease epidemic of the twenty-first century.

2. It is the first time this Coronavirus has been found in humans.

3. It was the first public health challenge for international communities.

4. The first disease that globalization visibly exacerbated its spread in a short time and contributed significantly to its end.

Table 6. Possible origins of SARS-CoV-2.^60.

The virus evolved to its current pathogenic state via natural selection in a non-human host and then jumped to humans. Bats are more likely reservoir of SARS-Cov-2 because it is similar to a bat coronavirus, and it may be an intermediate host was involved between bats and humans. A nonpathogenic version of the virus transferred from an animal host into humans and then evolved to its current pathogenic state within the human population. Armadillo-like mammals in Asia and Africa, have an RBD structure which is similar to that of SARS-CoV-2. A coronavirus from a pangolin may possibly have been transmitted to a human, directly or through an intermediary host like civets or ferrets.

Table 7. Homologous analysis of SARS-CoV-2 (NC_045512) and six other Coronavirus strains isolated from different hosts in China (%).^61.

Isolate	Host	Complete genome	ORF1ab	N	S
SARS coronavirus civet020 (AY572038)	Civet	73.58	79.23	87.79	71.41
Bat SARS-like coronavirus As6526 (KY417142)	Aselliscus stoliczkanus	74.58	79.23	87.55	68.17
Bat SARS-like coronavirus Rs4874 (KY417150)	Rhinolophus sinicus	71.98	79.18	87.94	71.29
Alphacoronavirus Mink/China/1/2016 (MF113046)	Mink	34.97	38.47	33.70	30.89
Bat coronavirus isolate RaTG13 (MN996532)	Rhinolophus affinis	93.7	96.5	96.9	92.86
Pangolin coronavirus (MT084071)	Manis javanica	?	?	95	90

Note: N, N protein. S, spike protein. ?, Sequence of Pangolin coronavirus (MT084071) is not completed in this part of genome.

Table 8. Most relevant clinical similarities and differences between SARS-CoV and SARS-CoV-2.^62.

Characteristic	SARS-CoV	SARS-CoV-2
Target receptor	ACE-2	ACE-2
N protein	IFN-γ inhibitor	Unknown
R0	0.4	1.4–2.5
Chest X-ray	Ground glass opacities	Bilateral, multilobar ground glass opacities
Chest CT-scan	Lobar consolidation Nodular opacities	No nodular opacities
Prevention	Hand hygiene, cough etiquette	Possibly hand hygiene, cough etiquette
Transmission	Droplets Contact with infected individuals	Droplets even asymptomatic ones
Case fatality rate (overall)	9.6%	2.3%

Abbreviations: SARS-CoV, Severe Acute Respiratory Syndrome Coronavirus; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; N protein, Nucleocapsid protein: IFN-γ, interferon-γ; R₀, R through; X-ray, radiography; CT-scan, computerized tomography.

Table 9. The most important symptoms of SARS and MERS from the highest to the lowest

SARS	MERS
Fever more than 30°C	Fever
Dry cough	Cough
Sore throat	Shortness of breath
Problems in breathing, such as shortness of breath, inability to maintain oxygenation (hypoxia)	Sore throat
Headache	Diarrhea
Body aches and muscles pain	Head and body aches
Loss of appetite	Vomiting
Malaise	Chest pain/tightness
Night sweats and chills	Running nose
Confusion	Altered conscious/confusion
Rash	Sweating
Nausea, vomiting and diarrhea	Abdominal pain
Weakness	Weakness/fatigue
Fever	Dizziness
Poor appetite	Loss of appetite
Respiratory distress syndrome (ARD or ARDS)	Shivering
Attacking the alveoli (air sacs) in the lungs
Kidney failure
Inflammation of the heart sac (pericarditis)
Sever systematic bleeding from disruption of clotting system (disseminated intravascular coagulation)
Reduced lymphocyte cell counts (lymphopenia)
Inflammation of the arteries (vasculitis)

Table 10. Criteria for disease control and prevention case definition of SARS.^94.

Clinical Criteria	Characteristics
Asymptomatic or mild respiratory illness
Moderate respiratory illness	Temperature of > 100.4°F(>38° C)
	One or more clinical findings of respiratory illness (e.g. cough, shortness of breath, difficulty breathing, or hypoxia)
Severe respiratory illness	Temperature of >100.4°F (>38°)
	One or more clinical findings of respiratory illness (e.g. cough, shortness of breath, difficulty breathing, or hypoxia)
	Radiographic evidence of pneumonia
	Respiratory distress syndrome
	Autopsy findings consistent with pneumonia or respiratory distress syndrome without an identifiable cause
Epidemiologic Criteria	Travel (including transit in an airport) within 10 days onset of symptoms to an area with current or previously documented or suspected community transmission of SARS
	Close contact within 10 days of onset of symptoms with a person known or suspected to have SARS
Laboratory Criteria
Confirmed	Detection of antibody to SARS-CoV in specimens obtained during acute illness or >21 days after illness onset
	Detection of SARS-CoV RNA by RT-PCR confirmed by a second PCR assay, by using a second aliquot of the specimen and a different set of PCR primers
	Isolation of SARS-CoV
Negative	Absence of antibody to SARS-CoV in convalescent serum obtained >21 days after symptom onset
Undetermined	Laboratory testing either not performed or incomplete

Table 11. Case classification of SARS

Under investigation	A person who has been referred to the public health service for possible SARS-CoV infection
Suspected case	A person with all of these following: (a) Sudden onset of high fever, > 38°C (b) One or more of the following respiratory symptoms: cough, sore throat, shortness of breath, and difficulty in breathing (c) Showing symptoms within 10 days of either traveling to one of the suspected areas of SARS or being in close contact with a person who has traveled to those areas
Probable case	(a) A suspected case with chest X-ray findings of pneumonia or adult respiratory distress syndrome (b) A person with an unexplained respiratory illness resulting in death, with a postmortem examination demonstrating the pathology or respiratory distress syndrome without an identifiable cause
Confirmed case	A clinically compatible illness which is confirmed by laboratories
Not a case	A case that has been investigated and subsequently found not to meet the case definition

Table 12. Lessons learned from the SARS outbreak and concerns identified by WHO because of SARS.^113–116.

Lesson	Means	Concerns
The capacity of global alerts to improve awareness and vigilance	Wide support by responsible press and amplified by electronic communications	Inadequate surge capacity in hospitals and public health systems
The advantage of quick detection and reporting	Immediate reporting of initial cases by South Africa and India	Healthcare providers themselves being the victims of the disease
The successful containment that can be achieved by readying health services with preparedness plans and campaigns to guard against imported cases	Climate of high alert that was established after reports of the disease became known	Shortage of expert staff to coordinate national and global responses to a rapidly evolving public health emergency
The value of immediate political commitment at the highest level	The experience in Vietnam, where the government took immediate measures to protect its people	In some cases, the need for hasty construction of new facilities; in other cases, hospitals being closed
The ability of even developing countries to triumph over a disease when reporting is prompt and open and when rapid case detection, immediate isolation and infection control, and vigorous contact tracing are put in place	The appeal by Vietnam, where WHO assistance was requested quickly and fully supported	The power of poorly understood infectious diseases to incite widespread public anxiety and fear, social unease, economic losses, and unwarranted discrimination

Table 13. Duration of clinical phases of the mild and moderately severe variants of severe acute respiratory syndrome^112.

	Phase Respiratory
Time	Prodrome	Early	Late	Recovery
From onset, days	0	2–7	8–12	14–18
Duration, days	2–7	1–10	5–10	5–7

Table 14. The most important characteristics of MERS-CoV infections

MERS-CoV infects more males than females^Citation134–136 It is accompanied by a cluster of flu-like symptoms^Citation137–139 Life threatening severe illnesses consist of acute respiratory distress syndrome, pneumonia, myocarditis, and organ failure^Citation135,Citation136,Citation140–142 Death occurs in 30% to 60% of the cases^Citation135 Those who have preexisting medical conditions such as diabetes, cardiovascular diseases, renal failure, obesity, and immunodeficiency are more vulnerable to this disease^Citation135,Citation137

Table 15. Comparison between SARS and MERS-CoV in respect to their virology, epidemiology, and clinical outcomes.^224.

	MERS-CoV	SARS
Virology	Betacoronavirus lineage 2 C	Betacoronavirus lineage 2B
Receptor	hDPP4	ACE2
Genome size	29.9 kb	29.3kb
Source	Not yet confirmed, camel is the likely host	Civet Cat
Epidemiology	Limited human to human transmission, the disease is mostly localized in the Middle East	Human to human transmission is well-recognized, affected many countries but spared the Middle East
Ro	2–3 (for Jeddah 3.5–6.7, for Riyadh 2–2.8)	Variable, ranges from 2 to 6
Superspreading event	Not known	Reported
M:F	1.74:1	0.75:1
Median age (range) in years	48 (1–99)	Less than a third had
Mean incubation period in days (range)	5 (2–15)	Comorbidities
Comorbidities	Three quarter of the patients had comorbidities	Less than a third has Comorbidities
Clinical presentation	Unpredictable and erratic clinical course ranging from asymptomatic illness to severe pneumonia	A typical biphasic clinical course
Hemoptysis	More common	Less common
Respiratory failure	Presents relatively early	Presents relatively late
Travel association	Limited travel-associated exposure	Recognized travel-associated exposure
Time from symptom onset to hospitalization	0–16 days	2–8 days
Median time from symptom onset to death	12 days	21 days

Table 16. The difference between MERS-CoV and SARS-CoV in symptoms, signs, laboratory tests, and chest film.^225.

Symptoms	MERS-CoV	SARS-CoV
Headache	+	++
Fever and chills	+++	++
Prominent fatigue	+	-
Myalgias	++	+++
Dry cough	+++	++
Shortness of breath	+++	++
Sore throat	+	+
Nausea/vomiting	+	+
Diarrhea	±	±
Abdominal pain	±	-
Hemoptysis	±	-
Signs
Tachycardia	+	+
Conjunctival suffusion	+	-
Diminished breath sounds	+	+
Acute renal failure (ARF)	±	-
Laboratory tests
Normal WBC count	-
Leukopenia	+	-
Relative lymphopenia	+++	+++
Thrombocytopenia	++	+++
Elevated serum transaminases	+	±
Elevated ldh	+	++
Elevated cpk	++	-
Chest film
Normal/minimal basilar infiltrates (early)	-	+
Unilateral infiltrates (late)	+	-
Pleural effusion	+++	++
Cavitation	+	-
ARDS (severe cases)	-	-

Table 17. Enhanced infection control measures that were effective in controlling nosocomial outbreaks.^226–235.

Hand hygiene, and droplet and contact precautions for febrile patients with a fever before testing these patients for MERS-CoV. Putting surgical masks on all patients undergoing haemodialysis, and ensuring health-care workers wear N95 filtering facepiece respirators when managing any patient with a confirmed MERS-CoV infection who is undergoing an aerosol-generating procedure. Patients with suspected MERS-CoV infection admitted to dialysis or intensive care units should be placed in isolation rooms with a portable dialysis machine. Increasing environmental cleaning, and preventing non-essential staff and visitors from coming into contact with patients infected with MERS-CoV.

Table 18 Middle East respiratory syndrome coronavirus vaccines^236.

Vaccine	Target	Use	Advantages	Problems
Anti-MERS-CoV monoclonal antibodies	Surface (S) glycoprotein	Passive immunization; prophylaxis or treatment at early times p.i.	High titer preparations; can be produced in large amounts	Short half-life; needs to be readministered for continued efficacy
Human polyclonal anti-MERS-CoV antibodies	Virus structural proteins	Passive immunization; treatment at early times p.i.	Polyclonal antibody so antibody escape unlikely; human antibody	Short half-life; needs to be readministered for continued efficacy; few MERS survivors available as donors
Inactivated virion vaccines	Virus structural proteins; anti-S neutralizing antibodies most important	Active immunization	High titer antibody to S protein	Response many not be long term; on challenge may induce immunopathological disease; may be ineffective in aged populations
Live attenuated vaccines (e.g. viruses deleted in envelope (E) protein; viruses with reduced fidelity (mutated in nsp14)	Mostly virus structural proteins	Active immunization	Generally safe; induce antibody and T-cell responses; long-term immunity	May not be safe is immunocompromised patients; may regain virulence by reversion or recombination with circulating CoV
Viral vector (attenuated) vaccines: poxvirus, AAV adenovirus, parainfluenza virus, rabies virus, measles virus, VSV	S protein	Active immunization	Safe: nonreplicating; induce antibody and T-cell responses	Long-term immunity, but not as long as live attenuated vaccines
Replicon particles (e.g. VEEV or VSV-based)	S protein or any viral protein	Active immunization	Safe; nonreplicating; induce antibody and T-cell responses; useful for mucosal immunity	Production is complex
Subunit vaccines (e.g. RBD of S protein)	Generally S protein	Active immunization	Safe; non-replicating; induce high antibody titers; may also induce T-cell responses	Duration of response not known
DNA vaccines	Generally S protein	Active immunization	Safe; induce high antibody titers and T-cell responses	Immunogenicity variable; may induce anti-DNA immune response

Abbreviations: MERS-CoV, Middle East respiratory syndrome coronavirus; p.i., post infection; AAV, adeno-associated virus; VSV, vesicular stomatitis virus; VEEV, Venezuelan equine encephalitis virus; RBD, receptor binding domain.

Table 19. Populations influenced by SARS-CoV-2 divided into 4 levels.^279.

Patients with severe symptoms of SARS-CoV-2, front-line medical staff, researchers or administrative staff. Patients with mild symptoms of SARS-CoV-2, close contacts, suspected patients or patients with fever who come to hospital for treatment. People related to the first and second-level population, such as family members, colleagues or friends; rescuers, such as commanders, administrative staff, or volunteers. People in affected areas, susceptible groups or general public.

Table 20. The most important Diagnostic Criteria for SARS-CoV-2.^305,306.

Supportive epidemiological history. Clinical manifestation: Fever; normal or low levels of white blood cells or decreased lymphocyte counts at onset. Chest radiology at early stage is characteristic of multiple small patchy shadows and interstitial changes, more prominent in the extra pulmonary bands. Multiple ground-glass opacities and infiltrations may develop bilaterally with disease progression, with possible consolidation in severe cases. Diagnosis: SARS-CoV-2 nucleic acid positive in samples of sputum, pharynx swabs, and secretions of lower respiratory tract tested by real-time reverse-transcriptase-polymerase-chain reaction (rRT-PCR) assay. For patients with acute fever (>37.5^oC within 72 hours) and normal chest imaging, if the absolute count of peripheral lymphocytes is less than 0.8×10^9/L, or the count of DC4^+ and CD8^+ T cells decrease significantly, isolation and close observation should be conducted at home even it the first SARS-CoV-2 nucleic acid test is negative. Repeat of rRT-PCR should be considered after 24 h, and a chest CT scan should be performed when necessary.

Table 21. Overview of vaccine production platforms and technologies for SARS-CoV-2^328.

Platform	Target	Existing, Licensed Human Vaccines Using the Same Platform	Advantages	Disadvantages
RNA vaccines	S protein	No	No infectious virus needs to be handled, vaccines are typically immunogenic, rapid production possible.	Safety issues with reactogenicity have been reported.
DNA vaccines	S protein	No	No infectious virus needs to be handled, easy scale up, low production costs, high heat stability, tested in humans for SARS-CoV-1, rapid production	Vaccine needs specific delivery devices to reach good immunogenicity.
Recombinant protein vaccines	S protein	Yes for baculovirus (influenza, HPV) and yeast expression (HBV, HPV)	No infectious virus needs to be handled, adjuvants can be used to increase immunogenicity	Global production capacity might be limited. Antigen and/or epitope integrity needs to be confirmed. Yields need to be high enough.
Viral vector-based vaccines	S protein	Yes for VSV (Ervebo), but not for other viral vectored vaccines	No infectious virus needs to be handled, excellent preclinical and clinical data for many emerging viruses, including MERS-CoV	Vector immunity might negatively affect vaccine effectiveness (depending on the vector chosen)
Live attenuated vaccines	Whole virion	Yes	Straightforward process used for several licensed human vaccines, existing infrastructure can be used	Creating infectious clones for attenuated coronavirus vaccine seeds takes time because of large genome size. Safety testing will need to be extensive
Inactivated vaccines	Whole virion	Yes	Straightforward process used for several licensed human vaccines, existing infrastructure can be used, has been rested in humans for SARS-CoV-1, adjuvants can be used to increase immunogenicity	Large amounts of infectious virus need to be handled (Could be mitigated by using an attenuated seed virus). Antigen and/or epitope integrity needs to be confirmed

Table 22. Translational considerations for SARS-CoV-2 vaccine development.^350.

Stage	Translational category	Activity
T0	Basic Research	Characterize antibody-dependent enhancement (ADE) mechanisms
		Identify SARS-CoV-2 ADE-associated epitopes
		Bioinformatics of SARS-CoV-2 mutations
		Generating recombinant vaccine proteins
		Animal models for SARS-CoV-2 vaccines
T1	Preclinical Research	Phase 1 clinical trials
		Assay development for human anti-SARS-CoV-2 IgG
		Assay development for neutralizing versus ADE-inducing human IgG
		Assess effects of vaccine on ADE induction in animal models
		Modify vaccines to minimize ADE risk
T2	Clinical Research	Phase 2/3 clinical trials
		Consider limiting initial vaccine studies to subjects ≥20 years old
		Multiplex measurement of anti-COVID IgG
		Outcomes research
T3	Clinical Implementation	Phase 4 clinical trials
		Long-term follow-up of post-vaccinated and infected subjects for ADE
		Reexamine age indications for SARS-CoV-2 vaccination
T4	Public Health	Population-level studies of vaccine efficacy
		Assessment of ADE-associated antibody prevalence

Table 23. Vaccine platforms for Human coronaviruses

	Target	MERS-CoV	Target	SARS-CoV-2	Target
Inactivated SARS virus (β-propiolactone, formalin, UV, irradiation)	All virus structural proteins	Live attenuated MERS-CoV (E envelope-deleted)	All virus genome component s (except E)	Inactivated virus/alum	All structural proteins of the virus
Live attenuated/host adapted SARS virus (E-deleted)	All genome (except the envelope protein)	Chemically for physically-Inactivated virus (MERS-CoV, rabies virus)	S glycoprotein and S1 subunit	Virus-like particle (VLP)	Unknown
Live attenuated recombinant virus (parainfluenza virus, Vesicular Stomatitis Virus, Venezuela equine encephalitis virus, Newcastle disease virus)	S glycoprotein Nucleocapsid (N) protein	Replication-deficient viral-vectored vaccines (Poxvirus, adenocirus, measles, rabies)	S glycoprotein or S1 subdomain (containing the receptor-binding protein)	Protein nanoparticles/Matrix-M	S glycoprotein
Recombinant modified vaccinia Ankara (MVA) virus	Spike (S) glycoprotein or nucleocapsid (N) protein	Soluble protein vaccines/adjuvant	S glycoprotein and fragments	Non-replicating viral sector (adenovirus, chimeric chimpanaeeadenocirus)	S glycoprotein/unknown
Recombinant non-replicating adenovirus (E-deleted)	S glycoprotein/nucleocapsid (N) protein	Nanoparticles	S glycoprotein		S glycoprotein/unknown
DNA-based vaccines	Full spike (S) glycoprotein of fragments	DNA-based vaccines	S glycoprotein and subunits	DNA-based vaccine	S glycoprotein/unknown
Soluble proteins/adjuvant	Full spike (S) glycoprotein of fragments	Combination vaccines (protein and DNA)	S glycoprotein and subunits	Protein subunit	S glycoprotein and peptides/unknown
Virus-like particles (VLPs)/adjuvant	Spike (S) glycoprotein			Live attenuated virus	All proteins of the virus
Combination of vaccine approaches (DNA/peptide, DNA/recombinant viral vector, viral vector/peptides)	S glycoprotein or fragments			Replicating viral sector (measles, horsepox)	Unknown

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