key: cord-0896306-y4cqgbm2
authors: Zimmermann, Petra; Curtis, Nigel
title: Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children
date: 2020-03-12
journal: Pediatr Infect Dis J
DOI: 10.1097/inf.0000000000002660
sha: 95e7b3d5aac1a54ace50bee0d0cad6efac8cdba8
doc_id: 896306
cord_uid: y4cqgbm2

Coronaviruses (CoVs) are a large family of enveloped, single-stranded, zoonotic RNA viruses. Four CoVs commonly circulate among humans: HCoV2-229E, -HKU1, -NL63 and -OC43. However, CoVs can rapidly mutate and recombine leading to novel CoVs that can spread from animals to humans. The novel CoVs severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. The 2019 novel coronavirus (SARS-CoV-2) is currently causing a severe outbreak of disease (termed COVID-19) in China and multiple other countries, threatening to cause a global pandemic. In humans, CoVs mostly cause respiratory and gastrointestinal symptoms. Clinical manifestations range from a common cold to more severe disease such as bronchitis, pneumonia, severe acute respiratory distress syndrome, multi-organ failure and even death. SARS-CoV, MERS-CoV and SARS-CoV-2 seem to less commonly affect children and to cause fewer symptoms and less severe disease in this age group compared with adults, and are associated with much lower case-fatality rates. Preliminary evidence suggests children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. However, the importance of children in transmitting the virus remains uncertain. Children more often have gastrointestinal symptoms compared with adults. Most children with SARS-CoV present with fever, but this is not the case for the other novel CoVs. Many children affected by MERS-CoV are asymptomatic. The majority of children infected by novel CoVs have a documented household contact, often showing symptoms before them. In contrast, adults more often have a nosocomial exposure. In this review, we summarize epidemiologic, clinical and diagnostic findings, as well as treatment and prevention options for common circulating and novel CoVs infections in humans with a focus on infections in children.

Betacoronavirus which initially emerged in Guangdong province, south China in 2002, [23] [24] [25] then spread to Hong Kong and from there rapidly to many other countries. 125 It caused severe lower respiratory tract infection with a severe morbidity and a high case-fatality rate (approaching 50% in individuals over 60 years of age, overall 10%). 63, 106, 107, 126 Person-toperson transmission of SARS-CoV is well established. 55 The virus has spread to 29 countries and has been estimated to have caused more than 8000 infections and 774 deaths worldwide (Table 1) . 52 MERS-CoV is a novel group 2c Betacoronavirus which first appeared in Saudi Arabia in 2012. 26, 27, 127 It can spread from personto-person 128 and can cause severe lower respiratory tract infections with a case-fatality rate of 20% to 40%. 67, 106, [108] [109] [110] [111] [112] Apart from being endemic in the Middle East, there was a nosocomial outbreak of MERS-CoV in South Korea in 2014, involving 16 hospitals and 186 patients, caused by a medical doctor returning from the Middle East. 49, 68 MERS-CoV spread to 27 countries causing an estimated 2494 infections and 858 deaths (Table 1) . 53 The overall reproductive number (R0) for SARS-CoV was estimated to be 0.3-2.9 37, 39, 40, 42, 43, 47 and for MERS-CoV to be 0.5-3.5 (Table 1) . 39, 46, 48 R0s largely depend on geographic location, stage of the outbreak and inclusion of only nosocomial versus general transmission. Both viruses have been associated with early super-spreading events with R0s of up to 22 for SARS-CoV 39, 40, 43 and up to 30 for MERS-CoV. 39, 49 These large numbers of secondary infections have been mostly associated with nosocomial outbreaks: 30% of all SARS-CoV cases (mostly health care workers) and 44%-100% of all MERS-CoV cases (mostly patients) occurred from nosocomial transmissions. 39, 55, 56 These super-spreading events were followed by reduced spread in the following generations of viruses with a decrease in the R0s to 0.8 for SARS-CoV 39 and to 0.7 for MERS-CoV (Table 1) . 128 Therefore, both SARS-CoV and MERS-CoV have low potential for long-term sustained community transmission. No human SARS-CoV infections have been detected since July 2003. However, SARS-CoV-like viruses can be found in bats, which are known to be able infect human cells without adaptation, making it possible for SARS-CoVs to reemerge 84 (as has now happened with SARS-CoV-2). The zoonotic transmission of MERS-CoV to humans has continued, attributed to the role of dromedary camels as a reservoir and their close contact with humans (in contrast to human-bat-interactions). 21 37 8 d (SD 4 d) 45 12 d (SD 3 d) 70 Shedding duration 6 d (3-10 d) in children in daycare 73 Mostly after onset of symptoms 74, 75 Mostly after onset of symptoms 70 Unknown Asymptomatic proportion of children 13% asymptomatic 16 2% asymptomatic [57] [58] [59] 42% asymptomatic 60, 76 9%-11% asymptomatic 61, 77 Clinical features in children Fever, 5, 11, 32 rhinitis, 5, 11 conjunctivitis, 78 otitis, 5 pharyngitis, 5, 11 laryngitis, 5 croup, 11, 79, 80 headache, 5, 16, 81 bronchitis, 5, 11 bronchiolitis, 5, 11 wheezing, 4,11,32 asthma exacerbations, 11, 12 pneumonia, 5 Normal or reduced WBC 61, 72 Decreased neutrophil count 85 Decreased neutrophil count 61 Decreased lymphocyte count [57] [58] [59] 86 Decreased lymphocyte count 61, 72 Thrombocytopenia [57] [58] [59] 86 Thrombocytopenia 76 CRP and PCT levels usually normal 61, 72 Increased alanine aminotransferase [57] [58] [59] 86 Normal liver function tests 76 Abnormal liver function tests 72 Increased lactate dehydrogenase 57 Increased lactate dehydrogenase 61 Normal urea and creatinine levels 76 Deranged coagulation and increased d-dimers in severe cases [57] [58] [59] 86 Increased Monoplex RT-PCR on stool (not routine) 98 RT-PCR on stool (not routine) 91 RT-PCR on stool (not routine) 99 Serology only when RT-PCR not available 97

Serology (not in acute phase) [100] [101] [102] Serology (not in acute phase) 103 Case-fatality rate in adults Sporadic cases reported in immunosuppressed adults 104 SARS-CoV-2 is currently estimated at 2.7. 38 The incubation period is estimated at 5-6 days, which is similar to that for SARS-CoV and MERS-CoV. 38, [63] [64] [65] [67] [68] [69] [70] [71] [72] The serial interval is estimated to be 8 days, also similar to the other novel CoVs (Table 1) . 38, 45, 48, 70 By March 2020, the World Health Organization reported that SARS-CoV-2 had spread to over 100 countries and caused over 100,000 infections and over 3500 deaths. 54 At that time the case-fatality rate was uncertain but estimated at 0.9%-3%, 54, 113, 114 which is much lower than for SARS-CoV and MERS-CoV (6%-17% and 20%-40%, respectively). 63, 67, [106] [107] [108] [109] [110] [111] [112] 

In children, common circulating HCoVs can cause common cold symptoms such as fever, 5,11,32 rhinitis, 5,11 otitis, 5 pharyngitis, 5,11 laryngitis 5 and headache, 5,16,81 but also bronchitis, 5,11 bronchiolitis, 5,11 wheezing, 4,11,32 pneumonia, 5, 81, 82 and, in up to 57% of cases, gastrointestinal symptoms (which are more common in children than adults). [5] [6] [7] In a study including children and adults, fatigue, headache, myalgia and sore throat were more common in HCoVinfected patients compared with RSV-infected patients, while fever, cough and dyspnea were more frequent in the later. 36 Fewer patients infected with HCoVs had fever compared with those infected with RSV or influenza. 36 In children, HCoV-NL63 has been associated with conjunctivitis, 78 croup, 11,79,80 asthma exacerbations, 11,12 febrile seizures 11 and HCoV-HKU1 with febrile seizures. 7 Rare cases of neurologic diseases have also been described (eg, the detection of HCoV in cerebrospinal fluid in a child presenting with acute disseminated encephalomyelitis 83 or in cerebrospinal fluid of adults with multiple sclerosis.) 129, 130 A suspected association between HCoVs and Kawasaki disease could not be confirmed. 131, 132 Common HCoVs can be isolated from asymptomatic individuals. 16 During an infection, the viral load is high in the first 2 days and decreases thereafter. 29 A correlation between viral load and severity of disease has not been observed 29 This contrasts with SARS-CoV for which a higher initial viral load is independently associated with a worse prognosis, including a higher case-fatality rate. 133, 134 Virus particles can be isolated from nasopharyngeal secretions up to 14 days after the onset of infection. 135

There are 3 case series that report a total of 41 children who were affected by SARS-CoV. [57] [58] [59] The virus was associated with milder disease in children compared with adults, and no deaths have been reported in children. [57] [58] [59] 86 Symptomatic children with SARS-CoV infection were reported to have fever (91%-100%), 57-59 myalgia (10%-40%), 57,58 rhinitis (33%-60%), 57-59 sore throat (5%-30%), 57-59 cough (43%-80%), 57-59 dyspnea (10%-14%), 38, 84 headache (14%-40%) [57] [58] [59] and, less commonly, vomiting (20%), 57, 59 abdominal pain (10%), 57 diarrhea (10%) 58, 59 and febrile seizures (10%). 57 In total, 50%-80% of children had other family members who were infected 57-59 and 30% had a nosocomial contact with SARS-CoV. 57 Most children recover quickly from an infection with SARS-CoV. 86 However, abnormalities on chest computed tomography (CT) can persist for several months (eg, air trapping and ground-glass opacifications). 136 There is no evidence that SARS-CoV can be vertically transmitted to the fetus. 137 However, SARS-CoV infections during pregnancy have been associated with possible miscarriage, intrauterine growth retardation and preterm delivery. 137, 138 

Most case series of patients infected with MERS-CoV report a low proportion (0.1%-4%) of children. 34 (Table 1) . 34 There are 2 small case series of children infected with MERS-CoV: one including 31 children with a mean age of 10 years 60 and the other one only 7 children. 76 In both studies, 42% of children were asymptomatic. 60, 76 In the case series of 7 children, 57% suffered from fever, 28% from vomiting and diarrhea and 14% from cough and shortness of breath. 76 Two children required oxygen supplementation and one mechanical ventilation. 76 In the other case series, 2 died (6%). 60 The main sources of MERS-CoV infection in children were household (32%) and other contacts (23%), followed by nosocomial transmission (19%). 60 Eight cases of MERS-CoV maternal infections during pregnancy have been reported (occurring between 20 and 28 weeks of pregnancy), three of the affected infants died. [141] [142] [143] [144] 

Different case definitions for COVID-19 cases in adults and children from authoritive sources as of March 2020 are detailed in Table 2 . Children are less commonly affected by SARS-CoV-2, the Chinese Centers for Disease Control and Prevention reports that of the 72,314 cases reported as of February 11, 2020, only 2% were in individuals of less than 19 years of age. 114 There are 3 case series of children who have been infected with SARS-CoV-2. 61, 72, 77 The first included 20 children up to January 31, 2020, in the Province of Zhejiang, 72 the second 34 children between January 19, 2020, and February 7, 2020, in the Province of Shenzhen, 61 and the third 9 infants from different provinces in China. 77 The case series with 34 children provides the most clinical details: none of the children had an underlying disease, 65% had common respiratory symptoms, 26% had mild disease and 9% were asymptomatic. 61 The most common symptoms were fever (50%) and cough (38%). 61 In the case series of 20 children, presentation was with low to moderate or no fever, rhinitis, cough, fatigue, headache, diarrhea and, in more severe cases, with dyspnea, cyanosis and poor feeding, but the numbers were not specified. 72 In the series of 9 infants, only 4 were reported to have fever. One infant was asymptomatic. 77 Additional asymptomatic children infected with SARS-CoV-2 outside these case series have also been described (eg, a 10-year-old asymptomatic child with radiologic ground-glass lung opacities on chest CT). 28 Most infected children recover 1-2 weeks after the onset of symptoms and no deaths from SARS-CoV-2 had been reported by February 2020. 72 From these series, it appears that children have milder clinical symptoms than adults 61,72 (as has been reported for SARS-CoV and MERS-CoV infections), [57] [58] [59] [60] 76, 86 which could mean children might not be tested for SARS-CoV-2 as frequently as adults. It has therefore been suggested that asymptomatic or mildly symptomatic children might transmit the disease. 147 However, the majority of children infected with SARS-CoV-2 thus far have been part of a family cluster outbreak [100% in the infants series, in which other family member had symptoms before the infants in all cases; 82% in the case series of 34 children; 61 and the majority in the one with 20 children (exact number not specified)]. 72 This is similar to SARS-CoV, in which 50%-80% 57-59 of children were reported to have an affected household contact 60 and to MERS-CoV in which it was 32%. 60 A study prepublished in early March 2020 suggests that children are just as likely as adults to become infected with SARS-CoV-2 but are less likely to be symptomatic or develop severe symptoms. 246 However, the importance of children in transmitting the virus remains uncertain.

From a small case series of 9 mothers who were infected with SARS-CoV-2, there is, to date, no evidence that SARS-CoV-2 can be vertically transmitted to the infant. 148

Laboratory findings from children are similar with infections caused by different novel CoVs ( Table 1) . The white blood cell count is typically normal or reduced with decreased neutrophil 85 and/or lymphocyte counts. [57] [58] [59] 72, 86 Thrombocytopenia may occur. 57-59,76,86 C-reactive protein and procalcitonin levels are often normal. 72 In severe cases, elevated liver enzymes, [57] [58] [59] 72, 86 lactate dehydrogenase levels, 57 as well as a abnormal coagulation and elevated D-dimers have been reported. [57] [58] [59] 72, 86 

The same laboratory findings has above have been observed for children infected with SARS-CoV-2. 61 In the case series of 34 children, the white blood cell count was normal in 83%, neutropenia and lymphopenia were each found in 1 case (3%). The lactate dehydrogenase level was elevated in 30% of cases. 61 C-reactive protein and procalcitonin levels were each elevated in 1 case only (3%).

Similar to the laboratory findings, radiologic findings from children are also similar across infections with different novel CoVs (Table 1) . On chest radiography, children mostly show bilateral patchy airspace consolidations often at the periphery of the lungs, peribronchial thickening and ground-glass opacities. [57] [58] [59] 76, 86, 87 Chest CT mostly shows airspace consolidations and ground-glass opacities. 89

CT changes observed in children infected with SARS-CoV-2 include bilateral multiple patchy, nodular ground-glass opacities, A. Fever or signs/symptoms of lower respiratory illness (eg, cough or shortness of breath) AND close contact with a laboratory-confirmed SARS-CoV-2 patient within 14 d of symptom onset B. Fever and signs/symptoms of lower respiratory illness (eg, cough or shortness of breath) AND a history of travel from Hubei Province, China within 14 d of symptom onset C. Fever or signs/symptoms of lower respiratory illness (eg, cough or shortness of breath) requiring hospitalization AND a history from mainland China within 14 d of symptom onset

Suspected case A. Patient with acute respiratory infection [fever and at least one sign/symptom of respiratory disease (eg, cough, shortness of breath)] AND with no other etiology that fully explains the clinical presentation AND a history of travel to or residence in a country/area or territory reporting local transmission of COVID-19 during the 14 days prior to symptom onset; OR B. A patient with any acute respiratory illness AND having been in contact with a confirmed or probable COVID-19 case in the last 14 days prior to onset of symptoms; OR C. A patient with severe acute respiratory infection (as above) AND requiring hospitalization AND with no other etiology that fully explains the clinical presentation.

A suspected or probable case is defined as a case that meets: two clinical criteria and one epidemiologic criterion Clinical criteria: 1. Fever, fatigue, dry cough; some pediatric patients may have no fever 2. Patients with the following chest imaging findings: multiple small patchy shadows and interstitial changes, mostly in the lung periphery, bilateral multiple ground-galls opacity, infiltrating shadows, pulmonary consolidation on chest radiography or ground-glass opacities, bilateral segmental lung consolidation, especially in the periphery on chest CT 3. White blood cell counts are normal or decreased, or with decreased lymphocyte count Epidemiologic criteria:

1. Children with a travel or residence history in Wuhan City and neighboring areas, or other areas with persistent local transmission within 14 d prior to disease onset 2. Children with a history of contacting patients with fever or respiratory symptoms who have a travel or residence history in Wuhan City and neighboring areas, or in other areas with persistent local transmission within 14 d prior to disease onset 3. Children with a history of contacting confirmed or suspected cases infected with SARS-CoV-2 within 14 d prior to disease onset 4. Children who are related with a cluster outbreak: in addition to this patient, there are other patients with fever or respiratory symptoms, including suspected or confirmed cases infected with SARS-CoV-2 5. Newborns delivered by suspected or confirmed SARS-CoV-2-infected mothers A confirmed case is defined as a case that meets any of the following criteria: speckled ground-glass opacities and/or infiltrating shadows in the middle and outer zone of the lung or under the pleura. 61, 88 These findings are unspecific and milder compared with those in adults. 88 

The main basis for diagnosis of infections with HCoVs is real-time polymerase chain reaction (RT-PCR) on upper or lower respiratory secretions. 5, 15, [90] [91] [92] [93] [94] [95] [96] For SARS-CoV, MERS-CoV and SARS-CoV-2, higher viral loads have been detected in samples from the lower respiratory tract compared with the upper respiratory tract. 28, 149 Therefore, in clinically suspected cases with an initially negative result on nasopharyngeal or throat swab, repeat testing of upper respiratory tract samples or (preferably) testing of lower respiratory tract samples should be done. RT-PCRs on stool samples can be positive for HCoVs but is not used for routine diagnosis. 91, 98, 99 For SARS-CoV and SARS-CoV-2, rare cases with positive PCRs in blood have been reported. 28, 150 Serology has been used to diagnose infections with SARS-CoV and MERS-CoV, but is not useful in the acute phase of the infection. [100] [101] [102] [103] Cross-reactivities between antibodies against SARS-CoV and common CoVs have been observed. 151

Whole genome sequencing allowed the rapid development of molecular diagnostic tests for SARS-CoV-2. 28 RT-PCR for genes encoding the internal RNA-dependent RNA polymerase and surface spike glycoprotein are commonly used. 28

Supportive treatment including sufficient fluid and calorie intake, and additional oxygen supplementation should be used in the treatment of children infected with HCoVs. The aim is to prevent ARDS, organ failure and secondary nosocomial infections. If bacterial infection is suspected broad-spectrum antibiotics such as second or third generation cephalosporins may be used.

In the absence of specific antiviral drugs for CoVs, broadspectrum antiviral drugs, such as interferon alpha and beta or ribavirin were used for the treatment of SARS-CoV, including in children. [57] [58] [59] Ribavirin was subsequently shown to be ineffective or even harmful because it can cause hemolytic anemia or liver dysfunction. 152 In adults, interferon-alpha alone or together with ribavirin also did not consistently improve outcomes. 152, 153 There is some evidence that intravenous corticosteroids led to clinical and radiologic improvement in SARS-CoV-infected individuals. 58 However, a systematic review showed that the evidence for this is inconclusive and corticosteroids might also be harmful (delayed viral clearance, avascular necrosis, osteoporosis, new onset of diabetes). 152 There is some evidence from adult studies that lopinavir/ritonavir (Kaletra) started early during infection is associated with improved clinical outcomes (decreased intubation, ARDS and death rates). 154, 155 However, a systematic review found inconclusive results for the use of lopinavir/ritonavir because of a possible selection bias in many of the studies. 152 Inconclusive results were also found for intravenous immunoglobulins because studies did not account for comorbidities, stage of illness and effect of other treatments. 152 There is no evidence for the use of monoclonal antibodies against tumor necrosis factor alpha. 156 

There are no studies on treatment outcomes for MERS-CoV in children. In adults, as for SARS-CoV, interferon or ribavirin alone or in combination have not been shown to have a clear benefit. [157] [158] [159] Mycophenolate mofetil, which inhibits guanine (and therefore RNA) synthesis, was identified as a potential anti-MERS-CoV drug in vitro. 160 However, animal studies showed that the drug leads to worse outcomes with higher viral loads in lung and extrapulmonary tissues. 161 Consistent with this, renal transplant patients on mycophenolate mofetil have been reported to develop severe and sometimes fatal MERS-CoV infections. 162

Until the results of on-going clinical trials become available, there is no definitive evidence on which to base treatment of patients infected with SARS-CoV-2. The only treatment recommendation for children, published by the Zhejiang University School of Medicine, suggests the use of nebulized interferon alpha-2b and oral lopinavir/ritonavir together with corticosteroids for complications (ARDS, encephalitis, hemophagocytic syndrome or septic shock) and intravenous immunoglobulin for severe cases. 72 However, as none of these therapies have shown a clear benefit in the treatment of other novel CoVs, it is questionable whether they will be beneficial in the treatment of SARS-CoV-2. Neither the World Health Organization nor the US Centers for Disease Control and Prevention recommends any specific treatment in children or adults. 97, 163 Despite this, in the previously mentioned case series of the 34 children infected with SARS-CoV-2, 59% were treated with lopinavir/ritonavir. 61 None of the children received glucocorticoids or immunoglobulins. 61

Despite their diversity, CoVs share many proteins among different species, which is helpful for the design of new drugs. One of them is the surface structural spike glycoprotein S, which is responsible for virus-cell interaction. 164 Monoclonal antibodies (from convalescent human plasma, animal plasma or manufactured) against the spike glycoprotein S have been shown to inhibit fusion of CoVs with human cells and to decrease mortality rate in SARS-CoV-infected patients. [165] [166] [167] [168] [169] [170] [171] A protein, which also inhibits the spike glycoprotein S, although it is not a monoclonal antibody, has been isolated from a red alga called Griffithsia. 172 However, to date, it has only been tested in animal studies. 172 Angiotensin-converting enzyme 2, dipeptidyl peptidase 4, aminopeptidase N, O-acetylated sialic acid are further host receptors for HCoVs and monoclonal antibodies against these proteins might be useful in treatment of infections. [173] [174] [175] [176] However, rapid mutation of CoVs poses a potential problem, which might be diminished by using several monoclonal antibodies targeting different epitopes. 166

Endosomal and nonendosomal virus entry into cells can be reduced by inhibiting responsible proteases. [177] [178] [179] Papain-like proteases (PLpro) are involved in viral replication in CoVs and are further potential targets for treatment. Numerous PLpro inhibitors have been identified. However, none of them has been validated in in vivo studies. 180, 181 Moreover, PLpro enzymes differ between CoVs species, making PLpro inhibitors narrow-spectrum antiviral drugs against CoVs. 182 A further protein involved in viral replication is CoV main proteinase, which is inhibited by lopinavir. However, as previously mentioned, lopinavir (plus ritonavir) has been shown to be effective against CoVs in animal and nonrandomized studies of SARS-CoVinfected humans. 154, 161 However, as previously mentioned, these results are considered inconclusive because of potential selection bias. 152

Chloroquine, which is commonly used against malaria and autoimmune diseases, increases the endosomal pH thereby inhibiting virus-cell fusion, and is therefore a potential broad-spectrum antiviral drug. 183 It also interferes with glycosylation of cellular receptors of SARS-CoV. 184 In addition, in vitro studies show that chloroquine inhibits entry and postentry stages of SARS-CoV-2 into cells. 185 Moreover, chloroquine possesses immune-modulating activity, which might enhance its antiviral effect in vivo. 185 

As previously mentioned, ribavirin, a guanosine analog has been shown to be ineffective or even harmful against SARS-CoV 152 and MERS-CoV. [157] [158] [159] Immucillin-A, a new adenosine analog that has recently been developed, inhibits the viral RNA polymerase of a wide range of RNA viruses, including SARS-CoV and MERS-CoV, 186 and might be useful in the treatment of other HCoVs. Furthermore, inhibitors of helicase (which are proteins unwinding double-stranded RNA into single strands during replication) might be useful in treatment of CoVs. 187 RNA synthesis inhibitors, which reduce the formation of double-membrane vesicles, a hallmark of CoV2 replication, have been identified as potential antiviral drugs. 188, 189 A double-stranded RNA activated caspase oligomerizer (DRACO) that targets long viral double-stranded RNA and induces apoptosis of infected cells, but spares healthy cells, might also be useful in the treatment of CoVs. 190

Several vaccines against HCoVs are in development with the aim of preventing infection, reducing disease severity and viral shedding. The main antigens for vaccine development are the structural spike glycoprotein S or its receptor-binding domain (RBD). 191 However, the propensity of CoVs to rapidly mutate and recombine poses a potential problem for vaccine development. [192] [193] [194] Furthermore, the enhanced disease after viral challenges postvaccination has been observed in animal models after several different vaccines. [195] [196] [197] 

The advantage of live-attenuated vaccines is that they usually induce a robust and long-lasting immune response, including cellular and humoral immunity to many different antigens. In SARS-CoV animal studies, attenuated mutants with deletion of the structural E gene have been shown to induce neutralizing antibodies, reduce viral loads and protect from clinical symptoms of SARS-CoV infection. [198] [199] [200] In contrast, deletion of open reading frames had little or no effect on viral loads in vitro and in vivo. 201 Other strategies under development for live-attenuated vaccines against CoVs are genome rearrangement or gene knockouts. [202] [203] [204] These have the advantage that the vaccine virus cannot recombine with wild viruses.

In mouse models, inactivated vaccines successfully induce cellular and humoral immunity (with many different neutralization antibodies) against SARS- CoV 191, [205] [206] [207] and humoral immunity against MERS-CoV. 208, 209 In a human phase 1 trial, inactivated vaccines against SARS-CoV were well tolerated and elicited neutralizing antibodies. 210 However, no challenge studies have been done in humans, and in monkey challenge studies, no clear evidence of protection was shown despite the induction of strong cellular and humoral responses. 211 Moreover, concerns have been raised that inactivated vaccines against SARS-CoV and MERS-CoV may lead to harmful immune and/or inflammatory responses postchallenge. 195, 209 

Subunit vaccines are purified antigens, usually combined with adjuvants and are the most popular method in the development of vaccines against novel CoVs. For SARS-CoV and MERS-CoV, these are mostly developed from spike glycoprotein S, RBD or nucleocapsid protein. [212] [213] [214] [215] [216] Some studies show that subunit vaccines given intranasally might induce stronger immune responses and mucosal immunity. 217 Several subunit vaccines have shown to be successful in animal challenging studies. [218] [219] [220] In a study in monkeys, recombinant RBD protein was used to successfully reduce viral loads in lungs and oropharynx and to prevent MERS-CoV pneumonia. 218 In mice, similar results were achieved using recombinant RBD protein vaccines from SARS-CoV. 221

Adenovirus-based vectors encoding SARS proteins (eg, nucleocapsid protein, spike glycoprotein S and other membrane proteins) have been shown to be immunogenic in mice and rhesus macaques in whom they induced humoral and cellular vaccine responses. 222, 223 Adenovirus-based vaccines carrying parts MERS-CoV have been shown to reduce morbidity and mortality (undetectable or reduced pulmonary viral loads) in mouse models. 196, 224 Initially, pulmonary hemorrhages were observed postviral challenge. 196 However, adding a CD40 ligand to the vaccine enhanced immunogenicity and efficacy, and also prevented inadvertent pulmonary pathology, which makes this vaccine a promising strategy. 196 Nonetheless, preexisting immunity against adenovirus might reduce efficacy. This might be addressed by giving a viral-based vaccine followed by a recombinant vaccine as a booster. 225 A adenovirusbased MERS-CoV vaccine has moved into a phase I clinical trial. 226 One study, comparing an inactivated SARS-CoV vaccine with an adenovirus-based vaccine against SARS-CoV, found that the first led to higher humoral responses. 227 Adenovirus-based vaccines administered intranasally led to immunoglobulin A antibody production which has been associated with superior protection from virus replication in lungs. 227 This indicates that measuring serum neutralizing antibodies might not be a sufficient way of assessing vaccine efficacy for HCoV as mucosal immunity might be more important.

For SARS-CoV, a poxvirus has also been used as a vector for an intranasally and intramuscularly administered vaccine. This vaccineinduced neutralizing antibodies and reduced viral loads in the respiratory tract of challenged mice. 228 However, a similar vaccine used in ferrets led to increased liver damage after SARS-CoV challenge. 197 Further vector vaccines for SARS-CoV that have been tested in animals are based on recombinant parainfluenza virus, 229 

Vaccines containing DNA encoding the spike glycoprotein seem to induce a more robust response of neutralizing antibodies against MERS-CoV than vaccines only containing the RBD protein. They have been shown to protect rhesus macaques from MERS-CoV pneumonia. 234, 235 Three DNA vaccines against MERS-CoV have advanced into clinical trials. [236] [237] [238] due to aerosol-generating procedures such as intubation and bronchoscopy. Appropriate hospital hygiene practices are therefore crucial to limit nosocomial outbreaks. The main aims are to effectively triage patients with fever, respiratory symptoms and a contact history 240 and to apply stringent infection control measures such as isolating patients and quarantine contacts as early as possible. Ideally, each patient is placed in a single negative pressure room. If this is not possible, patients and health care workers should be cohorted. 241 Protective gear should include waterresistant gowns, disposable gloves, N95 masks and goggles or face shields. 240 Only suction catheters and mechanical respirators with a closed-circuit system and viral filters should be used. 240 In contrasts, nebulizers, oxygen masks or nasal continuous positive airway pressure systems should not be used on an open ward. 240, 241 Needless to say, strict hand hygiene needs to be applied and visitors should be avoided or limited to an absolute minimum. HCoVs have been shown to persist on dry surfaces for up to 9 days. [242] [243] [244] The persistence depends on temperature (shorter duration at 30-40°C) and humidity (longer at higher humidity). 245 HCoVs, including novel CoVs, can be inactivated by heating to 56°C for 30 minutes or by using lipid solvents such as ethanol (>75%), isopropanol (>70%), formaldehyde (>0.7%), povidone-iodine (>0.23%), sodium hypochlorite (>0.21%), hydrogen peroxide (>0.5%), but not chlorhexidine. 72, 244 SUMMARY SARS-CoV, MERS-CoV and SARS-CoV-2 infections seem to affect children less commonly and less severely as compared with adults. This might be because children are less frequently exposed to the main sources of transmission (which until now has been disproportionally nosocomial) or because they are less exposed to animals. However, it could also be that children are less frequently symptomatic or have less severe symptoms and are therefore less often tested, leading to an underestimate of the true numbers infected. In relation to SARS-CoV-2, a study prepublished in early March 2020 suggests that children are just as likely as adults to become infected with this virus but are less likely to be symptomatic or develop severe symptoms. 246 However, the importance of children in transmitting the virus remains uncertain. The majority of children infected by a novel CoVs reported thus far have a documented household contact, often showing symptoms before them, suggesting the possibility that children are not an important reservoir for novel CoVs. The clinical, laboratory and radiologic features in children are similar for all novel CoVs, except more children infected with SARS-CoV presented with fever compared with SARS-CoV-2 or MERS-CoV. To date, no deaths in children have been reported for SARS-CoV or SARS-CoV-2, except (in the case of the former) for infants of mothers who were infected during pregnancy.

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Distant relatives of severe acute respiratory syndrome coronavirus and close relatives of human coronavirus 229E in bats

Link of a ubiquitous human coronavirus to dromedary camels

Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event

SARS and MERS: recent insights into emerging coronaviruses

A review of studies on animal reservoirs of the SARS coronavirus

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

SARS-CoV infection in a restaurant from palm civet

Molecular epidemiology, evolution and phylogeny of SARS coronavirus

Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group

Genetic evidence of Middle East respiratory syndrome coronavirus (MERS-Cov) and widespread seroprevalence among camels in Kenya

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

A novel coronavirus from patients with pneumonia in China

Coronavirus disease 2019 (COVID-19) Situation Report -32

Clinical disease in children associated with newly described coronavirus subtypes

Burden and risk factors for coronavirus infections in infants in rural Nepal

Respiratory viruses and influenza-like illness: epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample

Acute viral respiratory infections among children in MERS-endemic Riyadh, Saudi Arabia, 2012-2013

Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010-2015 in Guangzhou

Human coronavirus infections in Israel: epidemiology, clinical symptoms and summer seasonality of HCoV-HKU1

Comparing nonpharmaceutical interventions for containing emerging epidemics

Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study

Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study

Superspreading and the effect of individual variation on disease emergence

Estimation of MERScoronavirus reproductive number and case fatality rate for the spring 2014 Saudi Arabia outbreak: insights from publicly available data

Different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures

Model parameters and outbreak control for SARS

Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions

Transmission dynamics and control of severe acute respiratory syndrome

The role of superspreading in Middle East respiratory syndrome coronavirus (MERS-CoV) transmission

Predictive models of control strategies involved in containing indoor airborne infections

Unraveling the drivers of MERS-CoV transmission

MERS transmission and risk factors: a systematic review

Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak

Mystery deepens over animal source of coronavirus

Summary of probable SARS cases with onset of illness from 1

MERS Monthly Summary

World Health Organization

Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China

Transmission of Middle East respiratory syndrome coronavirus infections in healthcare settings

Clinical presentations and outcome of severe acute respiratory syndrome in children

Severe acute respiratory syndrome in children: experience in a regional hospital in Hong Kong

Other Members of the Hospital for Sick Children SARS Investigation Team. Children hospitalized with severe acute respiratory syndrome-related illness in Toronto

Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia

Clinical and epidemiological characteristics of 34 children with

Incubation periods of acute respiratory viral infections: a systematic review

The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients

Does SARS-CoV-2 has a longer incubation period than SARS and MERS?

A comparative epidemiologic analysis of SARS in Hong Kong, Beijing and Taiwan

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

Middle East respiratory syndrome coronavirus outbreak in the republic of Korea

Middle East respiratory syndrome

Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea

Comparison of incubation period distribution of human infections with MERS-CoV in South Korea and Saudi Arabia

Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus

Epidemiology of multiple respiratory viruses in childcare attendees

Epidemiology, transmission dynamics and control of SARS: the 2002-2003 epidemic

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia

Novel coronavirus infection in hospitalized infants under 1 year of age in China

Identification of a new human coronavirus

Croup is associated with the novel coronavirus NL63

The novel human coronaviruses NL63 and HKU1

Update on human rhinovirus and coronavirus infections

Seroepidemiologic studies of coronavirus infection in adults and children

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

A case-control study of SARS versus community acquired pneumonia

Severe acute respiratory syndrome among children

Severe acute respiratory syndrome (SARS): chest radiographic features in children

Analysis of CT features of 15 children with

Severe acute respiratory syndrome (SARS) in neonates and children

Direct diagnosis of human respiratory coronaviruses 229E and OC43 by the polymerase chain reaction

Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome

Genomic sequencing of the severe acute respiratory syndrome-coronavirus

Genomic sequencing of a SARS coronavirus isolate that predated the Metropole Hotel case cluster in Hong Kong

Evaluation of a Real-Time Reverse Transcription-PCR (RT-PCR) assay for detection of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in clinical samples from an outbreak in South Korea in 2015

Analytical and clinical validation of six commercial Middle East respiratory syndrome coronavirus RNA detection kits based on real-time reverse-transcription PCR

MERS-CoV diagnosis: an update

World Health Organization. WHO interim guidance on clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected

Detection of human coronaviruses in simultaneously collected stool samples and nasopharyngeal swabs from hospitalized children with acute gastroenteritis

Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus

Serology of severe acute respiratory syndrome: implications for surveillance and outcome

Laboratory diagnosis of SARS

Serological analysis of SARS coronavirus in children diagnosed clinically as severe acute respiratory syndrome cases during SARS

Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, crosssectional, serological study

Fatal lower respiratory tract disease with human corona virus NL63 in an adult haematopoietic cell transplant recipient

Human coronavirus NL-63 infection in a Brazilian patient suspected of H1N1 2009 influenza infection: description of a fatal case

A novel coronavirus emerging in China -key questions for impact assessment

Case fatality of SARS in mainland China and associated risk factors

Middle East respiratory syndrome coronavirus (MERS-CoV) infection: epidemiology, pathogenesis and clinical characteristics

Outbreak of Middle East respiratory syndrome coronavirus in Saudi Arabia: a retrospective study

Case characteristics among Middle East respiratory syndrome coronavirus outbreak and non-outbreak cases in Saudi Arabia from

Middle East respiratory syndrome coronavirus (MERS-CoV) -The Kingdom of Saudi Arabia

Middle East respiratory syndrome: what we learned from the 2015 outbreak in the Republic of Korea

National Health Commission of the People's Republic of China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention

Epidemiology of coronavirus respiratory infections

The Tecumseh study of respiratory illness. VI. Frequency of and relationship between outbreaks of coronavirus infection

Human coronavirus NL63 and 229E seroconversion in children

Prevalence of human coronavirus antibody in the population of southern Iraq

Seroepidemiologic survey of coronavirus (strain OC 43) related infections in a children's population

Epidemiology and clinical presentations of human coronavirus NL63 infections in hong kong children

Newly identified respiratory viruses associated with acute lower respiratory tract infections in children in Lanzou

Clinical manifestations of human coronavirus NL63 infection in children in Taiwan

Surveillance of community-acquired viral infections due to respiratory viruses in Rhone-Alpes (France) during winter 1994 to 1995

Coronavirus HKU1 and other coronavirus infections in Hong Kong

Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome

A cluster of cases of severe acute respiratory syndrome in Hong Kong

MERS coronavirus: diagnostics, epidemiology and transmission

Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk

Human coronavirus polyadenylated RNA sequences in cerebrospinal fluid from multiple sclerosis patients

Coronaviruses in spinal fluid of patients with acute monosymptomatic optic neuritis

Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease

Kawasaki Disease Research Group. Lack of association between infection with a novel human coronavirus (HCoV), HCoV-NH, and Kawasaki disease in Taiwan

Initial viral load and the outcomes of SARS

Nasopharyngeal shedding of severe acute respiratory syndrome-associated coronavirus is associated with genetic polymorphisms

Frequent detection of human coronaviruses in clinical specimens from patients with respiratory tract infection by use of a novel real-time reverse-transcriptase polymerase chain reaction

Radiological and pulmonary function outcomes of children with SARS

Infants born to mothers with severe acute respiratory syndrome

Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome

Surveillance and testing for Middle East respiratory syndrome coronavirus

Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study

Jordan MERS-CoV Investigation Team. Stillbirth during infection with Middle East respiratory syndrome coronavirus

Impact of Middle East respiratory syndrome coronavirus (MERS-CoV) on pregnancy and perinatal outcome

Middle East respiratory syndrome coronavirus during pregnancy

Middle East respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from Saudi Arabia

Evaluating and reporting persons under investigation (PUI)

Global Surveillance for human infection with novel coronavirus (2019-nCoV). 2020. Available at

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Respiratory tract samples, viral load, and genome fraction yield in patients with Middle East respiratory syndrome

Viral loads in clinical specimens and SARS manifestations

Antigenic cross-reactivity between severe acute respiratory syndrome-associated coronavirus and human coronaviruses 229E and OC43

SARS: systematic review of treatment effects

Clinical management and infection control of SARS: lessons learned

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Inflammatory cytokine profile in children with severe acute respiratory syndrome

Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study

IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study

Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study

Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset

MERS CoV infection in two renal transplant recipients: case report

Interim clinical guidance for management of patients with confirmed 2019 novel coronavirus (2019-nCoV) infection

Coronaviruses -drug discovery and therapeutic options

Use of convalescent plasma therapy in SARS patients in Hong Kong

Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein

Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies

Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution

Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection

Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients

Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine

Activity of and effect of subcutaneous treatment with the broad-spectrum antiviral lectin griffithsin in two laboratory rodent models

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

Human coronavirus HKU1 spike protein uses O-acetylated sialic acid as an attachment receptor determinant and employs hemagglutinin-esterase protein as a receptor-destroying enzyme

Identification of six new polymorphisms in the human coronavirus 229E receptor gene (aminopeptidase N/ CD13)

Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2

Protease inhibitors targeting coronavirus and filovirus entry

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

The SARS-coronavirus papainlike protease: structure, function and inhibition by designed antiviral compounds

A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication

Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV

New insights into the antiviral effects of chloroquine

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses

Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the Middle East respiratory syndrome virus

Antiviral activity of K22 against members of the order Nidovirales

Broad-spectrum antiviral therapeutics

Identification and characterization of novel neutralizing epitopes in the receptor-binding domain of SARS-CoV spike protein: revealing the critical antigenic determinants in inactivated SARS-CoV vaccine

Epidemiology, genetic recombination, and pathogenesis of coronaviruses

Variations in spike glycoprotein gene of MERS-CoV

Genetic diversity of MERS-CoV spike protein gene in Saudi Arabia

Inactivated SARS-CoV vaccine elicits high titers of spike protein-specific antibodies that block receptor binding and virus entry

A highly immunogenic, protective, and safe adenovirus-based vaccine expressing Middle East respiratory syndrome coronavirus S1-CD40L fusion protein in a transgenic human dipeptidyl peptidase 4 mouse model

Evaluation of modified vaccinia virus Ankara based recombinant SARS vaccine in ferrets

A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo

A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters

Pathogenicity of severe acute respiratory coronavirus deletion mutants in hACE-2 transgenic mice

Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice

The group-specific murine coronavirus genes are not essential, but their deletion, by reverse genetics, is attenuating in the natural host

Engineering a replication-competent, propagation-defective Middle East respiratory syndrome coronavirus as a vaccine candidate

Middle East respiratory syndrome coronavirus nonstructural protein 16 is necessary for interferon resistance and viral pathogenesis

Immunogenicity of SARS inactivated vaccine in BALB/c mice

A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice

A double-inactivated whole virus candidate SARS coronavirus vaccine stimulates neutralising and protective antibody responses

Enhanced protection in mice induced by immunization with inactivated whole viruses compare to spike protein of Middle East respiratory syndrome coronavirus

Immunization with inactivated Middle East respiratory syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus

Safety and immunogenicity from a phase I trial of inactivated severe acute respiratory syndrome coronavirus vaccine

Immunogenicity, safety, and protective efficacy of an inactivated SARS-associated coronavirus vaccine in rhesus monkeys

SARS CoV subunit vaccine: antibody-mediated neutralisation and enhancement

The spike protein of SARS-CoV-a target for vaccine and therapeutic development

Efficacy of an adjuvanted Middle East respiratory syndrome coronavirus spike protein vaccine in dromedary camels and alpacas

Receptor-binding domain of MERS-CoV with optimal immunogen dosage and immunization interval protects human transgenic mice from MERS-CoV infection

A recombinant receptor-binding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection

Intranasal vaccination with recombinant receptor-binding domain of MERS-CoV spike protein induces much stronger local mucosal immune responses than subcutaneous immunization: implication for designing novel mucosal MERS vaccines

Recombinant receptor binding domain protein induces partial protective immunity in rhesus macaques against Middle East respiratory syndrome coronavirus challenge

The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection

Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus

Yeast-expressed recombinant protein of the receptor-binding domain in SARS-CoV spike protein with deglycosylated forms as a SARS vaccine candidate

Severe acute respiratory syndrome coronavirus nucleocapsid protein expressed by an adenovirus vector is phosphorylated and immunogenic in mice

Effects of a SARS-associated coronavirus vaccine in monkeys

Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model

Recombinant viruses as tools to induce protective cellular immunity against infectious diseases

Safety and immunogenicity of a candidate MERS-CoV vaccine (MERS001)

Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus

Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice

Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity

Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS

Induction of neutralising antibodies and cellular immune responses against SARS coronavirus by recombinant measles viruses

A single immunization with a rhabdovirus-based vector expressing severe acute respiratory syndrome coronavirus (SARS-CoV) S protein results in the production of high levels of SARS-CoV-neutralizing antibodies

Type IVB pilus operon promoter controlling expression of the severe acute respiratory syndrome-associated coronavirus nucleocapsid gene in Salmonella enterica Serovar Typhi elicits full immune response by intranasal vaccination

Evaluation of candidate vaccine approaches for MERS-CoV

A synthetic consensus antispike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

Phase I, open label dose ranging safety study of GLS-5300 in healthy volunteers

Evaluate the safety, tolerability and immunogenicity study of GLS-5300 in healthy volunteers

Environmental contamination and viral shedding in MERS patients during MERS-CoV outbreak in South Korea

Infection control for SARS in a tertiary neonatal centre

Infection control for SARS in a tertiary paediatric centre in Hong Kong

Severe acute respiratory syndrome coronavirus on hospital surfaces

Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination

Persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents

Survival characteristics of airborne human coronavirus 229E

Epidemiology and transmission of COVID-19 in Shenzhen China: analysis of 391 cases and 1,286 of their close contacts