Pneumococcal Vaccine Breakthrough and Failure in Infants and Children: A Narrative Review.

Globally, Streptococcus pneumoniae is a leading cause of vaccine-preventable morbidity and mortality in infants and children. In recent decades, large-scale pediatric immunization programs have substantially reduced the incidence of invasive pneumococcal disease. Despite this, residual vaccine-type pneumococcal disease remains in the form of vaccine breakthrough and vaccine failure. This targeted literature review aims to discuss aspects of vaccine breakthrough and failure in infants and children, including disease epidemiology, clinical presentation, risk factors, vaccination schedules, vaccine serotypes, correlates of protection, comorbidities, disease surveillance, and potential implications for future vaccine development.

A multicenter study on the epidemiology of complicated parapneumonic effusion in the era of currently available pneumococcal conjugate vaccines.

BACKGROUND: Parapneumonic effusion (PPE) is a common complication of pneumonia. Streptococcus pneumoniae is the most common cause of bacterial pneumonia. A reduction in pneumonia hospitalizations has been observed since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). Despite this apparent benefit, an increase in the incidence of PPE was recorded in some countries following PCV7 implementation. As the 13-valent pneumococcal conjugate vaccine (PCV13) was expected to provide a wider protection against PPE, the aim of the present study was to evaluate the impact of PCV13 introduction on the epidemiology of complicated parapneumonic effusion (c-PPE) among children in the Athens greater area. METHODS: All cases of community-acquired pneumonia (CAP) with PPE requiring chest tube insertion (complicated PPE, c-PPE) hospitalized in the 3 public Children's hospitals in Athens between 01/01/2004 and 31/12/2019 were included in the study. RESULTS: A total of 426 cases of c-PPE associated with pneumonia were recorded of which 198 were admitted during 2004-2010 (period A, prePCV13/PCV -7 introduction period) and 228 during 2011-2018 (period B, post - PCV13 period). A definite bacterial etiology was established in 44.4 % of all cases and of those 25.4 % were caused by S. pneumoniae. An increasing trend in c-PPE incidence was observed during period A; although, a significant decrease on c-PPE annual rates was observed during the period B (p = 0.011), a remarkable increase in serotype 3 cases was recorded. CONCLUSION: A decreasing time trend in c-PPE cases among children was shown after the introduction of PCV13 in our area. However, serotype 3 is nowadays a common cause of PPE. Hence, continuous surveillance is imperative in order to follow c-PPE epidemiology over time.

Receptor-Binding-Domain-Specific B Cell Responses Induced by mRNA Immunization against SARS-CoV-2.

mRNA vaccines have been instrumental in controlling the SARS-CoV-2 pandemic, but the short-lived protection mediated by Receptor Binding Domain (RBD)-specific antibodies necessitates frequent revaccinations to enhance vaccine-induced immunity. The development of RBD-specific B cell memory is critical for improving the qualitative and quantitative characteristics of the immune response. However, the effect of additional doses of mRNA vaccines on the composition of the RBD-specific B cell memory pool remains unclear. In this study, we found that dual BNT162b2 vaccination significantly increased both total RBD-specific and memory RBD-specific B cells and neutralizing antibodies. Following the second BNT162b2 dose, we showed a trend for the enrichment of CD27+IgM- memory RBD-specific B cells, which are known to correlate with a strong humoral response upon re-challenge. Repeated Measures Correlation (rmcorr) analysis revealed a significant correlation between antibody titers and both total and memory RBD-specific B cells, demonstrating that B cell and antibody responses are generated in a coordinated manner following BNT162b2 mRNA immunization. Our findings indicate that additional doses of the BNT162b2 mRNA vaccine enhance the qualitative and quantitative enrichment of the memory B cell pool against the vaccine antigens and collectively demonstrate the induction of a coordinated immune response to mRNA vaccination.

Intrafamilial Transmission of Pneumococcal Acute Spontaneous Peritonitis.

Streptococcus pneumonia (S. pneumoniae, Pneumococcus) is a major cause of childhood morbidity and mortality worldwide. The most common presentations of invasive pneumococcal disease (IPD) in children include bacteremic pneumonia, meningitis, and septicemia. However, pneumococcal acute spontaneous peritonitis is a highly uncommon-and potentially life-threatening-presentation of invasive pneumococcal disease and should be considered in cases of abdominal sepsis. To our knowledge, we report the first case of intrafamilial transmission of pneumococcal peritonitis in two previously healthy children.

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.

Frequencies of pathogenic CFTR variants in Greek cystic fibrosis patients with allergic bronchopulmonary aspergillosis and Aspergillus fumigatus chronic colonization: A retrospective cohort study.

INTRODUCTION: The clinical spectrum of Aspergillus fumigatus diseases in cystic fibrosis (CF) patients, including allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus chronic colonization, has recently gained attention due to its association with the progression of lung disease. Our aim was to examine whether there is a difference on pathogenic variant frequencies of the CFTR gene between CF patients with ABPA and those with A. fumigatus chronic colonization. MATERIAL AND METHODS: Greek CF patients diagnosed with ABPA and/or A. fumigatus chronic colonization were grouped according to their CFTR genotype. Patients with "minimal" CFTR function were defined as carrying a combination of class I or II pathogenic variants, while patients with "residual" function as carrying at least one class III, IV, V or VI pathogenic variant. RESULTS: Fifty-four CF patients were included and all except one were defined as having "minimal" CFTR function. Among the 108 CFTR alleles, 69 (63.9%) of pathogenic variants belonged to class II, and 32 (29.6%) to class I. Five patients had a history of both ABPA and A. fumigatus chronic colonization. No significant difference was detected among patients diagnosed only with ABPA (n = 29) and those who had only a positive history of A. fumigatus chronic colonization (n = 20). The median age of ABPA diagnosis was significantly lower than the median age of A. fumigatus chronic colonization (P = 0.011), while no significant difference was detected on median FEV1% predicted. DISCUSSION: No significant differences were detected in the type of CFTR pathogenic variants among patients with ABPA and those with A. fumigatus colonization. Similar studies should be performed in larger CF populations of different ethnic origin to further confirm our results.

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.

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.

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.

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.

The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature.

Idiopathic nephrotic syndrome (INS) is a common glomerular disease in childhood, and the immunological involvement in the pathogenesis of non-genetic INS, although not fully elucidated, is evident. This narrative review aims to offer a concise and in-depth view of the current knowledge on the immunological mechanisms of the development of INS as well as the role of the immunological components of the disease in the responsiveness to treatment. T cell immunity appears to play a major role in the INS immunopathogenesis and has been the first to be linked to the disease. Various T cell immunophenotypes are implicated in INS, including T-helper-1, T-helper-2, T-helper-17, and T regulatory cells, and various cytokines have been proposed as surrogate biomarkers of the disease; however, no distinct T helper or cytokine profile has been conclusively linked to the disease. More recently, the recognition of the role of B cell mediated immunity and the various B cell subsets that are dysregulated in patients with INS have led to new hypotheses on the underlying immunological causes of INS. Finally, the disambiguation of the exact mechanisms of the INS development in the future may be the key to the development of more targeted personalized approaches in managing INS. CONCLUSIONS: INS demonstrates particularly interesting immunopathogenetic pathways, in which multiple interactions between T cell and B cell immunity and the podocyte are involved. The disambiguation of these pathways will provide promising novel therapeutic targets in INS. WHAT IS KNOWN: • INS is the most common glomerular disease in the paediatric population, and its onset and relapses have been linked to various immunological triggers. • Multiple immunological mechanisms have been implicated in the pathogenesis of INS; however, no single distinct immunological profile has been recognized. WHAT IS NEW: • Th17 cells and Treg cells play an important role in the immune dysregulation in INS. • Transitional B cell levels as well as the transitional/memory B cell ratio have been correlated to nephrotic relapses and have been proposed as biomarkers of INS relapses in SSNS patients.

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.

Pneumococcal Immunization Strategies for High-Risk Pediatric Populations Worldwide: One Size Does Not Fit All.

Despite the significant reduction in pneumococcal disease due to pneumococcal vaccines, protection of vulnerable high-risk individuals, especially pediatric populations, remains a great challenge. In an effort to maximize the protection of high-risk children against pneumococcal disease, a combined schedule that includes both conjugate and polysaccharide vaccines is recommended by several countries in the developed world. On the other hand, middle- and low-income countries do not have in place established policies for pneumococcal immunization of children at risk. Pneumococcal conjugate vaccines, despite their benefits, have several limitations, mainly associated with serotype replacement and the wide range of serotype coverage worldwide. In addition, PPV23-impaired immunogenicity and the hyporesponsiveness effect among populations at risk have been well-documented. Therefore, the added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among high-risk children in both developed and developing countries, assessing the optimization of current recommendations for their vaccination against pneumococcal 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.

Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review.

Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the "brute-force" recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.

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.

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.

BACKGROUND: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. METHODS: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RESULTS: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. CONCLUSION: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.