An infectious disease model considering the impact of imported cases on internal spread of COVID-19

The coronavirus disease 2019(COVID-19) pandemic spreads across borders with the frequent global population movement. To explore the impact of the COVID-19 pandemic on China's domestic epidemic prevention and control, based on the classical infectious disease dynamics model this paper proposes an infectious disease model that considers oversea imported cases. The model can simulate three situations:national pandemic without imported cases, no domestic cases with only imported cases, and domestic cases with international travellers entering simultaneously. By calculating the peak case number and range of infection spread duration in these situations, as well as the amount of medical resources invested, the model has shown the different results of impact of entry type on the domestic pandemic and different pressures on medical resources. Finally, the paper suggests that testing measures should be taken according to the degree of pandemic risk and resource conditions, that strict prevention and control should be applied to the people not entering through customs, and closed-loop management to the people entering through customs, that entry quarantine measures and quarantine periods should be dynamically adjusted and international exchanges should be gradually resumed in the context of ensuring domestic and overseas epidemic prevention and control in advance, and that it is necessary to integrate medical resources, improve allocation efficiency, and relieve the pressure of resource occupation.

Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain

The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms underlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to secondary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope masking in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies. Graphical abstract Yang et al. investigate why three doses of mRNA COVID vaccines elicit improved antibody breadth against a mutated strain (e.g., the Omicron variant), compared to two doses. Their modeling results and clinical data show that antigen presentation dynamics and epitope masking play key roles in determining the humoral recall response.

Antigen presentation dynamics shape the antibody response to variants like SARS-CoV-2 Omicron after multiple vaccinations with the original strain.

The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms underlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to secondary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope masking in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.

Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination.

Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent work showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies, and subsequently two doses of an mRNA vaccine4-8. We found that monoclonal antibody recipients produced antigen binding and neutralizing titers that were only fractionally lower than controls. In contrast, their memory B cells differed from controls in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered RBD target specificity consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centers (GCs) formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias GC and memory B cell selection by two distinct mechanisms: (1) by lowering the activation threshold for B cells thereby permitting abundant lower-affinity clones to participate in the immune response, and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.

Immune Repertoire Sequencing Reveals an Abnormal Adaptive Immune System in COVID-19 Survivors.

Accumulating evidence suggests that SARS-CoV-2 impairs the adaptive immune system during acute infection. Still, it remains largely unclear whether the frequency and functions of T and B cells return to normal after the recovery of COVID-19. Here, we analyzed immune repertoires and SARS-CoV-2-specific neutralization antibodies in a prospective cohort of 40 COVID-19 survivors with a six-month follow-up after hospital discharge. Immune repertoire sequencing revealed abnormal T- and B-cell expression and function with large TCR/BCR clones, decreased diversity, abnormal class switch recombination and somatic hypermutation. A decreased number of B cells but an increased proportion of CD19+ CD138+ B cells were found in COVID-19 survivors. The proportion of CD4+ T cells, especially circulating follicular helper T (cTfh) cells, was increased, whereas the frequency of CD3+ CD4- T cells was decreased. SARS-CoV-2-specific neutralization IgG and IgM antibodies were identified in all survivors, especially those recorded with severe COVID-19 who showed a higher inhibition rate of neutralization antibodies. All severe cases complained of more than one COVID-19 sequelae after 6 months of recovery. Overall, our findings indicate that SARS-CoV-2-specific antibodies remain detectable even after 6 months of recovery. Because of their abnormal adaptive immune system with a low number of CD3+ CD4- T cells and high susceptibility to infections, COVID-19 patients might need more time and medical care to fully recover from immune abnormalities and tissue damage. This article is protected by copyright. All rights reserved.

Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape.

Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.

Analysis of COVID-19 Guideline Quality and Change of Recommendations: A Systematic Review

Background Hundreds of coronavirus disease 2019 (COVID-19) clinical practice guidelines (CPGs) and expert consensus statements have been developed and published since the outbreak of the epidemic. However, these CPGs are of widely variable quality. So, this review is aimed at systematically evaluating the methodological and reporting qualities of COVID-19 CPGs, exploring factors that may influence their quality, and analyzing the change of recommendations in CPGs with evidence published. Methods We searched five electronic databases and five websites from 1 January to 31 December 2020 to retrieve all COVID-19 CPGs. The assessment of the methodological and reporting qualities of CPGs was performed using the AGREE II instrument and RIGHT checklist. Recommendations and evidence used to make recommendations in the CPGs regarding some treatments for COVID-19 (remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir) were also systematically assessed. And the statistical inference was performed to identify factors associated with the quality of CPGs. Results We included a total of 92 COVID-19 CPGs developed by 19 countries. Overall, the RIGHT checklist reporting rate of COVID-19 CPGs was 33.0%, and the AGREE II domain score was 30.4%. The overall methodological and reporting qualities of COVID-19 CPGs gradually improved during the year 2020. Factors associated with high methodological and reporting qualities included the evidence-based development process, management of conflicts of interest, and use of established rating systems to assess the quality of evidence and strength of recommendations. The recommendations of only seven (7.6%) CPGs were informed by a systematic review of evidence, and these seven CPGs have relatively high methodological and reporting qualities, in which six of them fully meet the Institute of Medicine (IOM) criteria of guidelines. Besides, a rapid advice CPG developed by the World Health Organization (WHO) of the seven CPGs got the highest overall scores in methodological (72.8%) and reporting qualities (83.8%). Many CPGs covered the same clinical questions (it refers to the clinical questions on the effectiveness of treatments of remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir in COVID-19 patients) and were published by different countries or organizations. Although randomized controlled trials and systematic reviews on the effectiveness of treatments of remdesivir, glucocorticoids, hydroxychloroquine/chloroquine, interferon, and lopinavir-ritonavir for patients with COVID-19 have been published, the recommendations on those treatments still varied greatly across COVID-19 CPGs published in different countries or regions, which may suggest that the CPGs do not make sufficient use of the latest evidence. Conclusions Both the methodological and reporting qualities of COVID-19 CPGs increased over time, but there is still room for further improvement. The lack of effective use of available evidence and management of conflicts of interest were the main reasons for the low quality of the CPGs. The use of formal rating systems for the quality of evidence and strength of recommendations may help to improve the quality of CPGs in the context of the COVID-19 pandemic. During the pandemic, we suggest developing a living guideline of which recommendations are supported by a systematic review for it can facilitate the timely translation of the latest research findings to clinical practice. We also suggest that CPG developers should register the guidelines in a registration platform at the beginning for it can reduce duplication development of guidelines on the same clinical question, increase the transparency of the development process, and promote cooperation among guideline developers all over the world. Since the International Practice Guideline Registry Platform has been created, developers could register guidelines prospectively and internationally on this platform.

Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans.

Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.

Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens.

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID-19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations, and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV.2S, and two-dose ChAdOx1, or combination ChAdOx1/mRNA vaccination. Plasma-neutralizing activity, as well as the magnitude, clonal composition, and antibody maturation of the RBD-specific memory B cell compartments, showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV.2S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

Severe Acute Respiratory Syndrome Coronavirus 2 Neutralization After Messenger RNA Vaccination and Variant Breakthrough Infection.

The emergence of severe acute respiratory syndrome coronavirus 2 variants that have greater transmissibility and resistance to neutralizing antibodies has increased the incidence of breakthrough infections. We show that breakthrough infection increases neutralizing antibody titers to varying degrees depending on the nature of the breakthrough variant and the number of vaccine doses previously administered. Omicron breakthrough infection resulted in neutralizing antibody titers that were the highest across all groups, particularly against Omicron.

Antibody evolution to SARS-CoV-2 after single-dose Ad26.COV2.S vaccine in humans.

The single-dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the two available mRNA vaccines. In addition, Ad.26.COV.2 has been less effective in protection against severe disease during the Omicron surge. Here, we examined the memory B cell response to single-dose Ad.26.COV.2 vaccination. Compared with mRNA vaccines, Ad.26.COV.2 recipients had significantly lower numbers of RBD-specific memory B cells 1.5 or 6 mo after vaccination. Despite the lower numbers, the overall quality of the memory B cell responses appears to be similar, such that memory antibodies elicited by both vaccine types show comparable neutralizing potency against SARS-CoV-2 Wuhan-Hu-1, Delta, and Omicron BA.1 variants. The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective and why the Ad26.COV2.S vaccine can maintain some protective efficacy against severe disease during the Omicron surge.

Asymptomatic and pre-symptomatic infection in Coronavirus Disease 2019 pandemic.

With the presence of Coronavirus Disease 2019 (COVID-19) asymptomatic infections detected, their proportion, transmission potential, and other aspects such as immunity and related emerging challenges have attracted people's attention. We have found that based on high-quality research, asymptomatic infections account for at least one-third of the total cases, whereas based on systematic review and meta-analysis, the proportion is about one-fifth. Evaluating the true transmission potential of asymptomatic cases is difficult but critical, since it may affect national policies in response to COVID-19. We have summarized the current evidence and found, compared with symptomatic cases, the transmission capacity of asymptomatic individuals is weaker, even though they have similar viral load and relatively short virus shedding duration. As the outbreak progresses, asymptomatic infections have also been found to develop long COVID-19. In addition, the role of asymptomatic infection in COVID-19 remains to be further revealed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge. Nevertheless, as asymptomatic infections transmit the SARS-CoV-2 virus silently, they still pose a substantial threat to public health. Therefore, it is essential to conduct screening to obtain more knowledge about the asymptomatic infections and to detect them as soon as possible; meanwhile, management of them is also a key point in the fight against COVID-19 community transmission. The different management of asymptomatic infections in various countries are compared and the experience in China is displayed in detail.

SARS-CoV-2 neutralization after mRNA vaccination and variant breakthrough infection

The emergence of SARS-CoV-2 variants that have greater transmissibility and resistance to neutralizing antibodies has increased the incidence of breakthrough infections. We show that breakthrough infection increases neutralizing antibody titers to varying degrees depending on the nature of the breakthrough variant and the number of vaccine doses previously administered. Omicron breakthrough infection resulted in neutralizing antibody titers that were the highest across, particularly against omicron.

Use of non-steroidal anti-inflammatory drugs and adverse outcomes during the COVID-19 pandemic: A systematic review and meta-analysis.

Background: There are concerns that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of adverse outcomes among patients with coronavirus COVID-19. This study aimed to synthesize the evidence on associations between the use of NSAIDs and adverse outcomes. Methods: A systematic search of WHO COVID-19 Database, Medline, the Cochrane Library, Web of Science, Embase, China Biology Medicine disc, China National Knowledge Infrastructure, and Wanfang Database for all articles published from January 1, 2020, to November 7, 2021, as well as a supplementary search of Google Scholar. We included all comparative studies that enrolled patients who took NSAIDs during the COVID-19 pandemic. Data extraction and quality assessment of methodology of included studies were completed by two reviewers independently. We conducted a meta-analysis on the main adverse outcomes, as well as selected subgroup analyses stratified by the type of NSAID and population (both positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or not). Findings: Forty comparative studies evaluating 4,867,795 adult cases were identified. Twenty-eight (70%) of the included studies enrolled patients positive to SARS-CoV-2 tests. The use of NSAIDs did not reduce mortality outcomes among people with COVID-19 (number of studies [N] = 29, odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.75 to 1.14, I2  = 89%). Results suggested that the use of NSAIDs was not significantly associated with higher risk of SARS-CoV-2 infection in patients with or without COVID-19 (N = 10, OR = 0.96, 95% CI: 0.86 to 1.07, I2  = 78%; N = 8, aOR = 1.01, 95% CI: 0.94 to 1.09, I2  = 26%), or an increased probability of intensive care unit (ICU) admission (N = 12, OR = 1.28, 95% CI: 0.94 to 1.75, I2  = 82% ; N = 4, aOR = 0.89, 95% CI: 0.65 to 1.22, I2  = 60%), requiring mechanical ventilation (N = 11, OR = 1.11, 95% CI: 0.79 to 1.54, I2  = 63%; N = 5, aOR = 0.80, 95% CI: 0.52 to 1.24, I2  = 66%), or administration of supplemental oxygen (N = 5, OR = 0.80, 95% CI: 0.52 to 1.24, I2  = 63%; N = 2, aOR = 1.00, 95% CI: 0.89 to 1.12, I2  = 0%). The subgroup analysis revealed that, compared with patients not using any NSAIDs, the use of ibuprofen (N = 5, OR = 1.09, 95% CI: 0.50 to 2.39; N = 4, aOR = 0.95, 95% CI: 0.78 to 1.16) and COX-2 inhibitor (N = 4, OR = 0.62, 95% CI: 0.35 to 1.11; N = 2, aOR = 0.73, 95% CI: 0.45 to 1.18) were not associated with an increased risk of death. Interpretation: Data suggests that NSAIDs such as ibuprofen, aspirin and COX-2 inhibitor, can be used safely among patients positive to SARS-CoV-2. However, for some of the analyses the number of studies were limited and the quality of evidence was overall low, therefore more research is needed to corroborate these findings. Funding: There was no funding source for this study.

Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost.

The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals1-3. Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection4. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses5,6. We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

Analysis of memory B cells identifies conserved neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins.

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor-binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for antibodies. Here, we use NTD-specific probes to capture anti-NTD memory B cells in a longitudinal cohort of infected individuals, some of whom were vaccinated. We found 6 complementation groups of neutralizing antibodies. 58% targeted epitopes outside the NTD supersite, 58% neutralized either Gamma or Omicron, and 14% were broad neutralizers that also neutralized Omicron. Structural characterization revealed that broadly active antibodies targeted three epitopes outside the NTD supersite including a class that recognized both the NTD and SD2 domain. Rapid recruitment of memory B cells producing these antibodies into the plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants, including Omicron.

Potentially effective drugs for the treatment of COVID-19 or MIS-C in children: a systematic review.

The purpose of this systematic review is to evaluate the efficacy and safety of using potential drugs: remdesivir and glucocorticoid in treating children and adolescents with COVID-19 and intravenous immunoglobulin (IVIG) in treating MIS-C. We searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to August 5, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19 or MIS-C. A total of nine cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that after the treatment, 54.7% (95%CI, 10.3 to 99.1%) experienced adverse events, 5.6% (95%CI, 1.2 to 10.1%) died, and 27.0% (95%CI, 0 to 73.0%) needed extracorporeal membrane oxygenation or invasive mechanical ventilation. As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, most of the included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone. CONCLUSIONS: Overall, the current evidence in the included studies is insignificant and of low quality. It is recommended to conduct high-quality randomized controlled trials of remdesivir, glucocorticoids, and IVIG in children and adolescents with COVID-19 or MIS-C to provide substantial evidence for the development of guidelines. WHAT IS KNOWN: • The efficacy and safety of using potential drugs such as remdesivir, glucocorticoid, and intravenous immunoglobulin (IVIG) in treating children and adolescents with COVID-19/MIS-C are unclear. WHAT IS NEW: • Overall, the current evidence cannot adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. • We are calling for the publication of high-quality clinical trials and provide substantial evidence for the development of guidelines.

Risk factors for poor prognosis in children and adolescents with COVID-19: A systematic review and meta-analysis.

BACKGROUND: This study provides the first systematic review and meta-analysis to identify the predictors of unfavorable prognosis of COVID-19 in children and adolescents. METHODS: We searched literature databases until July 2021 for studies that investigated risk factors for unfavorable prognosis of children and adolescents with COVID-19. We used random-effects models to estimate the effect size with 95% confidence interval (CI). FINDINGS: We identified 56 studies comprising 79,104 individuals. Mortality was higher in patients with multisystem inflammatory syndrome (MIS-C) (odds ratio [OR]=58.00, 95% CI 6.39-526.79) and who were admitted to intensive care (OR=12.64, 95% CI 3.42-46.68). Acute respiratry distress syndrme (ARDS) (OR=29.54, 95% CI 12.69-68.78) and acute kidney injury (AKI) (OR=55.02, 95% CI 6.26-483.35) increased the odds to be admitted to intensive care; shortness of breath (OR=16.96, 95% CI 7.66-37.51) increased the need of respiratory support; and neurological diseases (OR=5.16, 95% CI 2.30-11.60), C-reactive protein (CRP) level ≥80 mg/L (OR=11.70, 95% CI 4.37-31.37) and D-dimer level ≥0.5ug/mL (OR=20.40, 95% CI 1.76-236.44) increased the odds of progression to severe or critical disease. INTERPRETATION: Congenital heart disease, chronic pulmonary disease, neurological diseases, obesity, MIS-C, shortness of breath, ARDS, AKI, gastrointestinal symptoms, elevated CRP and D-dimer are associated with unfavourable prognosis in children and adolescents with COVID-19.

Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces B cell responses that continue to evolve for at least a year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern1. As a result, vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals with currently available mRNA vaccines produces high levels of plasma neutralizing activity against all variants tested1,2. Here we examine memory B cell evolution five months after vaccination with either Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) mRNA vaccine in a cohort of SARS-CoV-2-naive individuals. Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge five months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response. While individual memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination, the overall neutralizing potency of plasma is greater following vaccination. These results suggest that boosting vaccinated individuals with currently available mRNA vaccines will increase plasma neutralizing activity but may not produce antibodies with equivalent breadth to those obtained by vaccinating convalescent individuals.