Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease 2019 (COVID-19), has caused substantial morbidity and mortality. Operation Warp ...Speed aims to accelerate the development of a safe and effective vaccine by early 2021. Multiple vaccine candidates with reassuring safety and efficacy profiles have advanced to phase 3 clinical trials in adults. The purpose of this review is to describe the burden of COVID-19 in children, to update pediatricians about adult COVID-19 vaccine clinical trials, to discuss the importance of COVID-19 vaccine trials in children and to instill confidence in the established vaccine development and licensure processes.
Children of all ages are at risk for SARS-CoV-2 infection and severe disease manifestations. Children are also susceptible to downstream effects of COVID-19, including social isolation and interruption in education. Developing a pediatric COVID-19 vaccine could prevent disease, mitigate downstream effects and enable children to re-engage in their world.
Children could benefit both directly and indirectly from vaccination. In light of the safety and immunogenicity results from recent adult COVID-19 vaccine clinical trials, children should have the opportunity to be included in clinical trials in parallel to ongoing adult phase 3 clinical trials in a manner that is careful, methodical and transparent.
Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and ...death from coronavirus disease 2019 (Covid-19) have been associated with an older age.
We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart.
Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells.
In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).
Background The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives We sought to determine the ...effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.
Mathematical models indicate there will not be an adequate supply of vaccines available to cover the global population until 2023,5 further exacerbating health and other disparities in LMICs. ...the ...early safety and immunogenicity results from Raches Ella and colleagues published in The Lancet Infectious Diseases6 of BBV152, a SARS-CoV-2 vaccine manufactured and produced in India by Bharat Biotech, are a welcome addition to the COVID-19 vaccine landscape. Despite these favourable phase 1 results, concerns linger regarding the potential for an inactivated whole-virus vaccine to elicit antibody-dependent enhancement of infection or vaccine-associated enhanced respiratory disease upon SARS-CoV-2 infection.7 Both of these effects are thought to be attributable to the development of binding, poorly neutralising antibodies that can promote either enhanced infection of Fc-bearing immune cells or immune complex deposition with T-helper-2 cell-biased allergic inflammation. The inactivated platform raises concern, because inactivation might alter antigenic structures and thereby elicit binding, non-neutralising antibodies. ...achieving high titres of neutralising antibodies and T-helper-1 (Th1)-biased cellular responses are considered important safety metrics in the assessment of candidate vaccines.
We aimed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological responses in children hospitalized with multisystem inflammatory syndrome in children (MIS-C) compared ...with those with coronavirus disease 2019 (COVID-19), those with Kawasaki disease (KD), and hospitalized pediatric controls.
From March 17, 2020, to May 26, 2020, we prospectively identified hospitalized children with MIS-C (
= 10), symptomatic COVID-19 (
= 10), and KD (
= 5) and hospitalized controls (
= 4) at Children's Healthcare of Atlanta. With institutional review board approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike receptor-binding domain (RBD) immunoglobulin M and immunoglobulin G (IgG), full-length spike IgG, and nucleocapsid protein antibodies using quantitative enzyme-linked immunosorbent assays and SARS-CoV-2 neutralizing antibodies using live-virus focus-reduction neutralization assays. We statistically compared the log-transformed antibody titers among groups and performed linear regression analyses.
All children with MIS-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated with full-length spike IgG antibodies (
= 0.956;
< .001), nucleocapsid protein antibodies (
= 0.846;
< .001), and neutralizing antibodies (
= 0.667;
< .001). Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer 6800; 95% confidence interval 3495-13 231) than children with COVID-19 (geometric mean titer 626; 95% confidence interval 251-1563;
< .001), children with KD (geometric mean titer 124; 95% confidence interval 91-170;
< .001), and hospitalized controls (geometric mean titer 85;
< .001). All children with MIS-C also had detectable RBD immunoglobulin M antibodies, indicating recent SARS-CoV-2 infection. RBD IgG titers correlated with the erythrocyte sedimentation rate (
= 0.512;
< .046) and with hospital (
= 0.548;
= .014) and ICU lengths of stay (
= 0.590;
= .010).
Quantitative SARS-CoV-2 serology may have a role in establishing the diagnosis of MIS-C, distinguishing it from similar clinical entities, and stratifying risk for adverse outcomes.
Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if ...low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student's
test. Arginine-to-ornithine ratio, a biomarker of arginase activity, and global arginine bioavailability ratio (GABR, arginine/ornithine+citrulline) were assessed in all three groups. A total of 80 patients were included (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C). Mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls. There was no difference between arginine bioavailability in children with COVID-19 vs. MIS-C. Adults and children with COVID-19 and MIS-C in our cohort had low arginine bioavailability compared to healthy adult controls. This may contribute to immune dysregulation and endothelial dysfunction in COVID-19. Low arginine-to-ornithine ratio in patients with COVID-19 or MIS-C suggests an elevation of arginase activity. Further study is merited to explore the role of arginine dysregulation in COVID-19.
Background
Although the radiographic features of coronavirus disease 2019 (COVID-19) in children have been described, the distinguishing features of multisystem inflammatory syndrome in children ...(MIS-C) associated with COVID-19 are not well characterized.
Objective
We compared the chest radiographic findings of MIS-C with those of COVID-19 and described other distinguishing imaging features of MIS-C.
Materials and methods
We performed a retrospective case series review of children ages 0 to 18 years who were hospitalized at Children’s Healthcare of Atlanta from March to May 2020 and who either met the Centers for Disease Control and Prevention (CDC) case definition for MIS-C (
n
=11) or who had symptomatic, laboratory-confirmed COVID-19 (
n
=16). Two radiologists reviewed the most severe chest radiographs for each patient. The type and distribution of pulmonary opacities and presence or absence of pleural effusions were recorded. The chest radiographs were categorized based on potential COVID-19 imaging findings as typical, indeterminate, atypical or negative. An imaging severity score was also assigned using a simplified version of the Radiographic Assessment of Lung Edema Score. Findings were statistically compared between patients with MIS-C and those with COVID-19. Additional imaging findings of MIS-C were also described.
Results
Radiographic features of MIS-C included pleural effusions (82% 9/11), pulmonary consolidations (73% 8/11) and ground glass opacities (91% 10/11). All of the lung opacities (100% 10/10) were bilateral, and the majority of the pleural effusions (67% 6/9) were bilateral. Compared to children with COVID-19, children with MIS-C were significantly more likely to develop pleural effusions on chest radiograph (82% 9/11 vs. 0% 0/0,
P
-value <0.01) and a lower zone predominance of pulmonary opacifications (100% 10/10 vs. 38% 5/13,
P
-value <0.01). Children with MIS-C who also had abdominal imaging had intra-abdominal inflammatory changes.
Conclusion
Key chest radiographic features of MIS-C versus those of COVID-19 were pleural effusions and lower zone pulmonary opacifications as well as intra-abdominal inflammation. Elucidating the distinguishing radiographic features of MIS-C may help refine the case definition and expedite diagnosis and treatment.
Children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can experience neurological symptoms, but limited data are available on neurological symptoms associated with ...other respiratory infections. We compared proportions of neurological symptoms in children hospitalized with seizures and respiratory infections, including SARS-CoV-2, influenza, and endemic coronaviruses.
A retrospective cohort study was performed on children admitted for seizures who had positive respiratory polymerase chain reactions for SARS-CoV-2, coronavirus NL63, coronavirus OC34, influenza (A and B), adenovirus, Mycoplasma pneumoniae, or parainfluenza 3 or 4. Primary outcomes were rates of new neurological diagnoses and mortality.
A total of 883 children were included. Mortality rates ranged from 0% with M. pneumoniae to 4.9% with parainfluenza 4. Strokes were observed with all infections except for coronavirus OC43 and M. pneumoniae, with the highest rates in parainfluenza 4 (4.9%) and SARS-CoV-2 (5.9%). Compared with other infections, children with SARS-CoV-2 were older, had higher rates of stroke, and lower rates of intubation. The most common brain magnetic resonance imaging (MRI) abnormality was diffusion restriction. Abnormal MRI rates were lower in SARS-CoV-2, compared with patients with other coronavirus (OC). However, rates of stroke, encephalopathy, hypoxic-ischemic encephalopathy, and meningoencephalitis were similar between SARS-CoV-2 and influenza cohorts.
In children hospitalized with seizures, higher rates of stroke were observed in SARS-CoV-2 versus OC. Similar rates of neurological symptoms were observed in patients with SARS-CoV-2 and those with influenza. Strokes can occur in children with these viral infections, particularly SARS-CoV-2.
As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA
. Previous studies have found human adenoviruses (HAdVs) ...in the blood from patients in Europe and the USA
, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.
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