Decreasing Incidence of the Multisystem Inflammatory Syndrome in Children Over 3 Pandemic Waves.

In this nationwide retrospective study, a substantial decline in the incidence of multisystem inflammatory syndrome in children over 3 successive pandemic waves characterized by different severe acute respiratory syndrome coronavirus 2 variants was documented-from 3.4 of 1000 to 1.1 of 1000 and finally to 0.25 of 1000 confirmed severe acute respiratory syndrome coronavirus 2 positive cases (P < 0.0001), respectively, whereas clinical findings and severity did not significantly vary.

SARS-CoV-2 mRNA Dual Immunization Induces Innate Transcriptional Signatures, Establishes T-Cell Memory and Coordinates the Recall Response.

BACKGROUND: mRNA vaccines have played a crucial role in controlling the SARS-CoV-2 global pandemic. However, the immunological mechanisms involved in the induction, magnitude and longevity of mRNA-vaccine-induced protective immunity are still unclear. METHODS: In our study, we used whole-RNA sequencing along with detailed immunophenotyping of antigen-specific T cells and humoral RBD-specific response to dual immunization with the Pfizer-BioNTech mRNA vaccine (BNT162b2) and correlated them with response to an additional dose, administered 10 months later, in order to comprehensively profile the immune response of healthy volunteers to BNT162b2. RESULTS: Primary dual immunization induced upregulation of the Type I interferon pathway and generated spike protein (S)-specific IFN-γ+ and TNF-α+ CD4 T cells, S-specific memory CD4 T cells, and RBD-specific antibodies against SARS-CoV-2. S-specific CD4 T cells induced by the primary series correlated with the RBD-specific antibody titers to a third dose. CONCLUSIONS: This study demonstrates the induction of both innate and adaptive immunity in response to the BNT162b2 mRNA vaccine in a coordinated manner and identifies the central role of primarily induced CD4+ T cells as a predictive biomarker of the magnitude of anamnestic immune response.

Protecting the Offspring, the Gift of Maternal Immunization: Current Status and Future Perspectives.

Pregnancy is characterized by immunological alterations in pregnant women that permit the growth of a semi-allogenic fetus, resulting in greater susceptibility of childbearing women to infections. Furthermore, due to the immaturity of the immune system of neonates, a protection gap is present in early life, leaving neonates and infants vulnerable to infectious diseases with increased morbidity and mortality. Maternal immunization against influenza, pertussis, and, in the context of the COVID-19 pandemic, SARS-CoV-2 has been implemented in several countries, with beneficial effects on both the mother and the offspring. The main protective mechanism of vaccination during pregnancy is transplacental transfer of maternal antibodies. However, recent evidence has implied that the fetal immune system may be influenced beyond passive immunity. This review sheds light on the current status of the routinely administered vaccinations during pregnancy, focusing on the impact of maternal immunization on the priming of the fetal immune system and suggesting future perspectives for the optimization of vaccination strategies.

Paving the Way Towards Precision Vaccinology: The Paradigm of Myocarditis After Coronavirus Disease 2019 (COVID-19) Vaccination.

Systems vaccinology approaches have introduced novel tools for the evaluation of the safety profile of novel vaccine antigens by developing biomarkers of vaccine reactogenicity associated with potential adverse events. The use of such approaches may prove extremely advantageous in the context of a global pandemic where accelerated approval of new vaccine formulations for all ages is essential for the containment of the epidemic. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had devastating effects on global health, but the emergency authorization of mRNA vaccines significantly reduced SARS-CoV-2-associated morbidity and mortality. Despite their favorable safety profile in adult populations, recent reports have raised concerns about an association of the mRNA-based vaccines with acute myocarditis, predominantly among male adolescents and young adults following the second vaccine dose. Here, we review data on myocarditis epidemiology following SARS-CoV-2 mRNA vaccination and describe potential mechanisms involved that may explain the sex- and age-related differences, focusing on mRNA immune reactivity. The case of vaccine-associated myocarditis highlights the need to incorporate precision vaccinology approaches for the development of safe and effective vaccines for everyone.

Comparative Characterization of Human Antibody Response Induced by BNT162b2 Vaccination vs. SARS-CoV-2 Wild-Type Infection.

Humoral immunity after SARS-CoV-2 immunization or natural infection is thought to be evanescent. In our study, we aimed to longitudinally characterize the kinetics of antibody titers after dual BNT162b2 immunization or wild-type infection. Vaccinated and recovered individuals displayed distinct antibody kinetics, as convalescents had detectable RBD-, S1-specific, and neutralizing IgG antibody titers two weeks post-infection that gradually increased longitudinally, while RBD-, S1-specific, and neutralizing IgG were detected in vaccinees after the first dose, increased significantly 3 weeks post the second dose and decreased significantly 4-5 months thereafter. Neutralizing IgG was significantly higher initially in convalescent individuals; however, vaccines displayed significantly higher neutralizing antibodies 4-5 months post the second dose. In both groups, there was a strong negative association between elapsed time and antibody levels. The avidity of anti-RBD antibody titers increased significantly in patients longitudinally, while in vaccinees initially increased, with subsequent decrease, remaining however higher than antibody avidity of recovered individuals at all time-points. Anti-RBD antibodies were strongly correlated with neutralizing and anti-S1 antibodies in both groups at all time-points. This study facilitates our further understanding of immune response to SARS-CoV-2 and vaccines.

Coagulation Abnormalities and Management in Hospitalized Pediatric Patients With COVID-19.

BACKGROUND: The incidence and severity of coagulation abnormalities have not been extensively studied in pediatric populations with coronavirus disease 2019 (COVID-19). Moreover, their association with an increased risk for thromboembolic events remains unclear, and there is a lack of evidence for optimal prophylactic antithrombotic management. The aim of our study was to present our experience in evaluation, management, and long-term outcomes of coagulation abnormalities in pediatric hospitalized patients with COVID-19. METHODS: A prospective study was performed in all children hospitalized for COVID-19 during a 6-month period focusing on patients' coagulation abnormalities, the normalization of the coagulation profile with or without anticoagulation prophylaxis and the clinical outcome of the disease. RESULTS: Two hundred twenty-three patients (median age: 11.4 months) were enrolled in the study. Coagulation abnormalities were detected in 92.4% of patients with increased D-dimer levels to be the most common abnormality detected in 84.3% of patients. Prophylactic anticoagulation was initiated only in 7 (3.1%) selected patients with severe COVID-19 and at least 2 risk factors for venous thromboembolism (VTE) and in all patients with previous history of VTE. Follow-up coagulation profile in 85 patients showed that changes over time had a tendency towards normalization irrespectively of the initiation of anticoagulant thromboprophylaxis. No thrombotic complications were observed 3 months upon discharge. CONCLUSIONS: Although abnormal findings in coagulation profile were very common, they were not associated with risk for VTE even in severe cases. A trend of normalization early in the course of the disease was observed regardless of the use of anticoagulant thromboprophylaxis.

Systematic review with meta-analysis: COVID-19 outcomes in patients receiving anti-TNF treatments.

BACKGROUND: Accumulating evidence suggests a beneficial effective of tumour necrosis factor-alpha (TNF-α) inhibitors on the outcomes of COVID-19 disease, which, however is not validated by all studies. AIMS: To perform a systematic review and meta-analysis of existing reports to investigate the impact of anti-TNF treatments on the clinical outcomes of COVID-19 patients. METHODS: A systematic search at PubMed and SCOPUS databases using specific keywords was performed. All reports of COVID-19 outcomes for patients receiving anti-TNF therapy by September 2021 were included. Pooled effect measures were calculated using a random-effects model. The Newcastle Ottawa Scale for observational studies was used to assess bias. Studies that were not eligible for meta-analysis were described qualitatively. RESULTS: In total, 84 studies were included in the systematic review, and 35 were included in the meta-analysis. Patients receiving anti-TNF treatment, compared to non-anti-TNF, among COVID-19 cases had a lower probability of hospitalisation (eight studies, 2555 patients, pooled OR = 0.53, 95% CI: 0.42-0.67, I2  = 0) and severe disease defined as intensive care unit admission or death (two studies, 1823 patients, pooled OR = 0.63, 95% CI: 0.41-0.96, I2  = 0), after adjustment for validated predictors of adverse disease outcomes. No difference was found for the risk for hospitalisation due to COVID-19 in populations without COVID-19 for patients receiving anti-TNF treatment compared to non-anti-TNF (three studies, 5 994 958 participants, pooled risk ratio = 0.97, 95% CI: 0.68-1.39, I2  = 20) adjusted for age, sex and comorbidities. CONCLUSIONS: TNF-α inhibitors are associated with a lower probability of hospitalisation and severe COVID-19 when compared to any other treatment for an underlying inflammatory disease.

Development of an Enzyme-Linked Immunosorbent Assay (ELISA) for Accurate and Prompt Coronavirus Disease 2019 (COVID-19) Diagnosis Using the Rational Selection of Serological Biomarkers.

Prompt COVID-19 diagnosis is urgently required to support infection control measures. Currently available serological tests for measuring SARS-CoV-2 antibodies use different target antigens, although their sensitivity and specificity presents a challenge. We aimed to develop an "in-house" serological ELISA to measure antibodies against SARS-CoV-2 by combining different protein antigens. Sera (n = 44) from COVID-19-confirmed patients were evaluated against different SARS-CoV-2 protein antigens and all potential combinations using ELISA. Patients' sera were also evaluated against commercially available ELISA diagnostic kits. The mixture containing RBD 2.5 µg/mL, S2 1 µg/mL and N 1.5 µg/mL was found to be the most potent. Plates were incubated with patients' sera (1:100), and goat anti-human alkaline phosphatase-conjugated IgG, ΙgM and IgA antibody was added. The cut-off value for each assay was determined using the mean optical density plus two standard deviations of pre-pandemic controls. The "in-house" ELISA displayed 91% sensitivity and 97% specificity for IgG antibodies, whereas its sensitivity and specificity for IgM and IgA were 75% and 95% and 73% and 91%, respectively. The "in-house" ELISA developed here combined three SARS-CoV-2 antigens (RBD, S2 and N) as capture antigens and displayed comparable and even higher sensitivity and specificity than otherwise quite reliable commercially available ELISA diagnostic kits.

Upregulation of Human Endogenous Retroviruses in Bronchoalveolar Lavage Fluid of COVID-19 Patients.

Severe COVID-19 pneumonia has been associated with the development of intense inflammatory responses during the course of infections with SARS-CoV-2. Given that human endogenous retroviruses (HERVs) are known to be activated during and participate in inflammatory processes, we examined whether HERV dysregulation signatures are present in COVID-19 patients. By comparing transcriptomes of bronchoalveolar lavage fluid (BALF) of COVID-19 patients and healthy controls, and peripheral blood monocytes (PBMCs) from patients and controls, we have shown that HERVs are intensely dysregulated in BALF of COVID-19 patients compared to those in BALF of healthy control patients but not in PBMCs. In particular, upregulation in the expression of specific HERV families was detected in BALF samples of COVID-19 patients, with HERV-FRD being the most highly upregulated family among the families analyzed. In addition, we compared the expression of HERVs in human bronchial epithelial cells (HBECs) without and after senescence induction in an oncogene-induced senescence model in order to quantitatively measure changes in the expression of HERVs in bronchial cells during the process of cellular senescence. This apparent difference of HERV dysregulation between PBMCs and BALF warrants further studies in the involvement of HERVs in inflammatory pathogenetic mechanisms as well as exploration of HERVs as potential biomarkers for disease progression. Furthermore, the increase in the expression of HERVs in senescent HBECs in comparison to that in noninduced HBECs provides a potential link for increased COVID-19 severity and mortality in aged populations. IMPORTANCE SARS-CoV-2 emerged in late 2019 in China, causing a global pandemic. Severe COVID-19 is characterized by intensive inflammatory responses, and older age is an important risk factor for unfavorable outcomes. HERVs are remnants of ancient infections whose expression is upregulated in multiple conditions, including cancer and inflammation, and their expression is increased with increasing age. The significance of this work is that we were able to recognize dysregulated expression of endogenous retroviral elements in BALF samples but not in PBMCs of COVID-19 patients. At the same time, we were able to identify upregulated expression of multiple HERV families in senescence-induced HBECs in comparison to that in noninduced HBECs, a fact that could possibly explain the differences in disease severity among age groups. These results indicate that HERV expression might play a pathophysiological role in local inflammatory pathways in lungs afflicted by SARS-CoV-2 and their expression could be a potential therapeutic target.

Clinical characteristics of COVID-19 in neonates and young infants.

We report the clinical characteristics and management of fourteen neonates and very young infants with COVID-19. Although all presented with mild symptoms and did not require specific treatment, most of them had abnormal laboratory and radiological findings. Ten infants presented with neutropenia and/or monocytosis but none with lymphopenia. Transient hypertriglyceridemia and/or prolonged viral shedding were detected in 9 patients.Conclusion: Based to our experience, COVID-19 is mild in very young infants and might have distinct laboratory findings. What is Known: • SARS-CoV-2 in infants is a mild disease. • The period of transmission is approximately 2 weeks. What is New: • Very young age is not a risk factor for severe COVID-19 but could be associated with prolonged viral shedding. • Neutropenia and monocytosis are distinct characteristics of COVID-19 in very young infants.

SARS-CoV-2 molecular testing in Greek hospital paediatric departments: a nationwide study.

As most children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present with mild symptoms or they are asymptomatic, the optimal strategy for molecular testing it is not well defined. The aim of the study was to determine the extent and aetiology of molecular testing for SARS-CoV-2 in Greek paediatric departments during the first phase of the pandemic and identify possible differences in incidence, depending on the age group and geographical area. We conducted a nationwide study of molecular testing for SARS-CoV-2 of children in paediatric departments between March and June 2020. A total of 65 paediatric departments participated in the study, representing 4901 children who were tested for SARS-CoV-2 and 90 (1.8%) were positive. Most paediatric cases were associated with topical outbreaks. Adolescents 11-16 years had the highest positivity rate (3.6%) followed by children 6-10 years (1.9%). However, since the testing rate significantly differed between age groups, the modified incidence of SARS-CoV-2 infection per age group was highest in infants <1 year (19.25/105 population). Most children tested presented with fever (70.9%), respiratory (50.1%) or gastrointestinal symptoms (28.1%). Significant differences were detected between public and private hospitals regarding the positivity rate (2.34% vs. 0.39%, P-value <0.001). Significant variation in SARS-CoV-2 molecular testing positivity rate and incidence between age groups indicate discrepancies in risk factors among different age groups that shall be considered when ordering molecular testing.