Coadministration of Anti-Viral Monoclonal Antibodies With Routine Pediatric Vaccines and Implications for Nirsevimab Use: A White Paper

Routine childhood vaccinations are key for the protection of children from a variety of serious and potentially fatal diseases. Current pediatric vaccine schedules mainly cover active vaccines. Active vaccination in infants is a highly effective approach against several infectious diseases; however, thus far, for some important viral pathogens, including respiratory syncytial virus (RSV), vaccine development and license by healthcare authorities have not been accomplished. Nirsevimab is a human-derived, highly potent monoclonal antibody (mAb) with an extended half-life for RSV prophylaxis in all infants. In this manuscript, we consider the potential implications for the introduction of an anti-viral mAb, such as nirsevimab, into the routine pediatric vaccine schedule, as well as considerations for coadministration. Specifically, we present evidence on the general mechanism of action of anti-viral mAbs and experience with palivizumab, the only approved mAb for the prevention of RSV infection in preterm infants, infants with chronic lung disease of prematurity and certain infants with hemodynamically significant heart disease. Palivizumab has been used for over two decades in infants who also receive routine vaccinations without any alerts concerning the safety and efficacy of coadministration. Immunization guidelines (Advisory Committee on Immunization Practices, Joint Committee on Vaccination and Immunization, National Advisory Committee on Immunization, Centers for Disease Control and Prevention, American Academy of Pediatrics, The Association of the Scientific Medical Societies in Germany) support coadministration of palivizumab with routine pediatric vaccines, noting that immunobiologics, such as palivizumab, do not interfere with the immune response to licensed live or inactivated active vaccines. Based on the mechanism of action of the new generation of anti-viral mAbs, such as nirsevimab, which is highly specific targeting viral antigenic sites, it is unlikely that it could interfere with the immune response to other vaccines. Taken together, we anticipate that nirsevimab could be concomitantly administered to infants with routine pediatric vaccines during the same clinic visit

Transcriptomic Profiling in Childhood H1N1/09 Influenza Reveals Reduced Expression of Protein Synthesis Genes

We compared the blood RNA transcriptome of children hospitalized with influenza A H1N1/09, respiratory syncytial virus (RSV) or bacterial infection, and healthy controls. Compared to controls, H1N1/09 patients showed increased expression of inflammatory pathway genes and reduced expression of adaptive immune pathway genes. This was validated on an independent cohort. The most significant function distinguishing H1N1/09 patients from controls was protein synthesis, with reduced gene expression. Reduced expression of protein synthesis genes also characterized the H1N1/09 expression profile compared to children with RSV and bacterial infection, suggesting that this is a key component of the pathophysiological response in children hospitalized with H1N1/09 infection

Early metallurgy in SE Iberia. The workshop of Las Pilas (Mojacar, Almeria, Spain)

Big narratives on the role of metallurgy in social change and technological innovations are common in archaeology. However, informed discussion of these issues requires a contextualised characterisation of metallurgical technology at the local level in its specific social and technological context. This paper approaches early metallurgy in Iberia from a technological perspective. We focus on the site of Las Pilas in the Vera Basin (Mojácar, Almería, Spain), where the whole metallurgical chaîne opératoire has been documented in situ through archaeological excavation of a 3rd Millennium BC context. The study includes microstructural, mineralogical and chemical analyses of ores, slag, technical ceramics and finished artefacts, as well as domestic pottery used for comparative purposes. These results are discussed with reference to the archaeological context and evidence for other domestic activities and crafts. Our aim is to contribute to better characterise the early metallurgical tradition of Southeast Iberia, paying particular attention to specific technological tools, knowledge and recipes that may allow future comparative approaches to knowledge transmission or independent innovation debates. For this particular case, we demonstrate the direct production of arsenical copper in a low-scale, low-specialisation, low-efficiency set up that involved the crucible smelting of complex oxidic ores in a context that suggests associations with cereal roasting and, indirectly, with basket and pottery making

What have we learnt about rotavirus in Spain in the last 10 years?

En España, las vacunas frente a rotavirus (RV) están disponibles desde 2006 pero no están ni recomendadas ni financiadas por el Sistema Nacional de Salud. Sin embargo, a través de las recomendaciones de la Asociación Española de Pediatría se han alcanzado coberturas de vacunación intermedias. Se ha realizado una revisión sistemática de la literatura sobre los estudios realizados en España en los últimos 12 a˜nos (2006-2018) en relación con la infección y las vacunas frente a RV. Se identifican 43 estudios que cumplían los criterios de selección. La carga de enfermedad en población <5 a˜nos en atención primaria oscila entre 15 y 19 casos por 1.000 ni˜nos y en hospitalaria entre 120 y 480 casos por 100.000, lo que supone una importante repercusión económica y social. Las vacunas frente a RV han mostrado en España una efectividad de entre el 83 y el 96% y un impacto de hasta un 70% de reducción de hospitalizaciones, que es dependiente de la cobertura de vacunación alcanzada. Se identifican además nuevas líneas de investigación relacionadas con el papel de la vacuna del RV y la protección frente a convulsiones, o el papel del microbiota, entre otros. La información actualmente disponible refrenda la importante carga de enfermedad por RV en España y la elevada efectividad de las vacunas disponibles. Estas evidencias permiten una reevaluación de las recomendaciones nacionales sobre vacunación frente a RV.Vaccines against rotavirus (RV) have been available in Spain since 2006, but they are neither recommended nor financed by the National Health System. Nevertheless, through recommendations of the Spanish Association of Paediatrics vaccination has achieved interme- diate coverage. A systematic literature review was performed on studies carried out in Spain in the last 12 years (2006-2018) on RV infection and vaccination. Results: A total of 43 studies were identified that met the inclusion criteria. The disease burden in children less than 5 years in the Primary Care setting ranged from 15 to 19 cases per 1,000 children, and between 120 and 480 cases per 100,000 in the hospital setting, which has a significant economic and social impact. Vaccines against RV have shown an effectiveness of between 83% and 96%, and an impact of up to 70% in reducing hospital admissions, which is dependent on the achieved vaccine coverage. New research lines are identified, such as the role of the rotavirus vaccine and protection against seizures or the impact on the gut microbiota. The current available information supports the significant burden of rotavirus disease in Spain and the high effectiveness of the available vaccines. This evidence should allow for an updated re-evaluation of the national recommendations on rotavirus vaccination.La redacción de este artículo ha sido apoyada en parte a través de una beca de MSD España.Medicin

Prevention of new respiratory episodes in children with recurrent respiratory infections: An expert consensus statement

In healthy infants and young children, the development of respiratory tract infections (RTIs) is extremely common. In this paper, we present an international consensus of the available approaches for the prevention of recurrent RTIs in children, including the atopic/allergic ones as well as those with asthma. Few convincing measures for reducing the frequency and clinical relevance of recurrent respiratory episodes in RTI-prone children have been developed until now. Among the most recently suggested measures, immunotherapy is attractive, but only for OM-85 is there a sufficient number of well-conducted clinical trials confirming efficacy in RTIs prevention with an adequate safety profile. In the case of probiotics, it is not clear which bacteria can offer the best results and which dosage and schedule of administration are the most effective. The problems of dosage and the schedule of administration are not solved also for vitamin D, despite some promising efficacy results. While we wait for new knowledge, the elimination or reduction as much as possible of the environmental factors that favor RTIs, vaccination when available and/or indicated, and the systematic application of the traditional methods for infection prevention, such as hand washing, remain the best measures to prevent recurrent infections in RTI-prone children

Analysis of blood and nasal epithelial transcriptomes to identify mechanisms associated with control of SARS-CoV-2 viral load in the upper respiratory tract

Objectives: The amount of SARS-CoV-2 detected in the upper respiratory tract (URT viral load) is a key driver of transmission of infection. Current evidence suggests that mechanisms constraining URT viral load are different from those controlling lower respiratory tract viral load and disease severity. Understanding such mechanisms may help to develop treatments and vaccine strategies to reduce transmission. Combining mathematical modelling of URT viral load dynamics with transcriptome analyses we aimed to identify mechanisms controlling URT viral load. Methods: COVID-19 patients were recruited in Spain during the first wave of the pandemic. RNA sequencing of peripheral blood and targeted NanoString nCounter transcriptome analysis of nasal epithelium were performed and gene expression analysed in relation to paired URT viral load samples collected within 15 days of symptom onset. Proportions of major immune cells in blood were estimated from transcriptional data using computational differential estimation. Weighted correlation network analysis (adjusted for cell proportions) and fixed transcriptional repertoire analysis were used to identify associations with URT viral load, quantified as standard deviations (z-scores) from an expected trajectory over time. Results Eighty-two subjects (50% female, median age 54 years (range 3–73)) with COVID-19 were recruited. Paired URT viral load samples were available for 16 blood transcriptome samples, and 17 respiratory epithelial transcriptome samples. Natural Killer (NK) cells were the only blood cell type significantly correlated with URT viral load z-scores (r = −0.62, P = 0.010). Twenty-four blood gene expression modules were significantly correlated with URT viral load z-score, the most significant being a module of genes connected around IFNA14 (Interferon Alpha-14) expression (r = −0.60, P = 1e-10). In fixed repertoire analysis, prostanoid-related gene expression was significantly associated with higher viral load. In nasal epithelium, only GNLY (granulysin) gene expression showed significant negative correlation with viral load. Conclusions: Correlations between the transcriptional host response and inter-individual variations in SARS-CoV-2 URT viral load, revealed many molecular mechanisms plausibly favouring or constraining viral replication. Existing evidence corroborates many of these mechanisms, including likely roles for NK cells, granulysin, prostanoids and interferon alpha-14. Inhibition of prostanoid production and administration of interferon alpha-14 may be attractive transmission-blocking interventions

Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0-2.3). Management per ED varied as follows: use of diagnostic tests 14-83%, antibiotic treatment 23-54%, admission 34-86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0-38%), partial adherence occurred in 56% (484/868, range 35-77%). CONCLUSION: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. WHAT IS KNOWN: • Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. • There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence. WHAT IS NEW: • Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe. • Guideline revision including new biomarkers is needed to improve management in young febrile children

Global Perspectives on Immunization During Pregnancy and Priorities for Future Research and Development: An International Consensus Statement

Immunization during pregnancy has been recommended in an increasing number of countries. The aim of this strategy is to protect pregnant women and infants from severe infectious disease, morbidity and mortality and is currently limited to tetanus, inactivated influenza, and pertussis-containing vaccines. There have been recent advancements in the development of vaccines designed primarily for use in pregnant women (respiratory syncytial virus and group B Streptococcus vaccines). Although there is increasing evidence to support vaccination in pregnancy, important gaps in knowledge still exist and need to be addressed by future studies. This collaborative consensus paper provides a review of the current literature on immunization during pregnancy and highlights the gaps in knowledge and a consensus of priorities for future research initiatives, in order to optimize protection for both the mother and the infant