Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

A high CMV-specific T cell response associates with SARS-CoV-2-specific IL-17 T cell production.

Human cytomegalovirus (CMV) is a widespread persistent herpes virus requiring lifelong immune surveillance to maintain latency. Such long-term interactions with the immune system may be associated with deleterious effects including immune exhaustion and senescence. Regarding the COVID-19 pandemic, we asked whether CMV-specific cellular and humoral activity could influence immune responses toward SARS-CoV-2 and/or disease severity. All adults with mild (n = 15) and severe (n = 14) COVID-19 were seropositive for anti-CMV IgG, but negative for IgM antibodies. Antibody titers did not correlate with COVID-19 severity. Six patients presented elevated frequencies of CMV-specific CD4 + and CD8 + T cells producing IFNγ, IL-17, and TNFα, designated as CMV high responders (hiT CMV). In comparison to low CMV responders, hiT CMV individuals exhibited higher frequencies of SARS-CoV-2-specific CD4 + IL-17 + and CD8 + IFNγ + , IL-17 + or TNFα + T cells. These results indicate that high frequencies of CMV-specific T cells may be associated with a SARS-CoV-2-reactive profile skewed toward Th17-dominated immunity.

Early Impact of Social Distancing in Response to Coronavirus Disease 2019 on Hospitalizations for Acute Bronchiolitis in Infants in Brazil.

BACKGROUND: Interventions to tackle the coronavirus disease 2019 (COVID-19) pandemic may affect the burden of other respiratory diseases. Considering the repercussions of these unique social experiences to infant health, this study aims to assess the early impact of social distancing due to the COVID-19 pandemic in hospital admissions for acute bronchiolitis. METHODS: Data from hospitalizations of acute bronchiolitis in infants <1 year of age were obtained from the Department of Informatics of the Brazilian Public Health database for the period between 2016 and 2020. These data were also analyzed by macroregions of Brazil (North, Northeast, Southeast, South, and Midwest). To evaluate the effect of social distancing strategy on the incidence of acute bronchiolitis, the absolute and relative reductions were calculated by analyzing the yearly subsets of 2016 vs 2020, 2017 vs 2020, 2018 vs 2020, and 2019 vs 2020. RESULTS: There was a significant reduction in all comparisons, ranging from -78% (incidence rate ratio [IRR], 0.22 [95% confidence interval {CI}, .20-.24]) in 2016 vs 2020 to -85% (IRR, 0.15 [95% CI, .13-.16]) in 2019 vs 2020, for the data from Brazil. For analyses by macroregions, the reduction varied from -58% (IRR, 0.41 [95% CI, .37-.45]) in the Midwest in 2016 vs 2020 to -93% (IRR, 0.07 [95% CI, .06-.08]) in the South in 2019 vs 2020. CONCLUSIONS: There was a significant reduction in hospitalization for acute bronchiolitis in children <1 year old in Brazil, on the order of >70% for most analysis. Our data suggest an important impact of social distancing on reducing the transmission of viruses related to acute bronchiolitis. Such knowledge may guide strategies for prevention of viral spread.

IL-21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21-treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.

Cholinergic anti-inflammatory pathway confers airway protection against oxidative damage and attenuates inflammation in an allergic asthma model.

Asthma is characterized by the influx of inflammatory cells, especially of eosinophils as well as reactive oxygen species (ROS) production, driven by the release of the T helper 2 (Th2)-cell-associated cytokines. The cholinergic anti-inflammatory pathway (CAP) inhibit cytokines production and controls inflammation. Thus, we investigated the effects of pharmacological activation of CAP by neostigmine on oxidative stress and airway inflammation in an allergic asthma model. After the OVA challenge, mice were treated with neostigmine. We showed that CAP activation by neostigmine reduced the levels of pro-inflammatory cytokines (IL-4, IL-5, IL-13, IL-1ß, and TNF-α), which resulted in a decrease of eosinophils influx. Furthermore, neostigmine also conferred airway protection against oxidative stress, attenuating ROS production through the increase of antioxidant defense, evidenced by the catalase (CAT) activity. We propose, for the first time, that pharmacological activation of the CAP can lead to new possibilities in the therapeutic management of allergic asthma.

Autophagy induces eosinophil extracellular traps formation and allergic airway inflammation in a murine asthma model.

Studies have shown autophagy participation in the immunopathology of inflammatory diseases. However, autophagy role in asthma and in eosinophil extracellular traps (EETs) release is poorly understood. Here, we attempted to investigate the autophagy involvement in EETs release and in lung inflammation in an experimental asthma model. Mice were sensitized with ovalbumin (OVA), followed by OVA challenge. Before the challenge with OVA, mice were treated with an autophagy inhibitor, 3-methyladenine (3-MA). We showed that 3-MA treatment decreases the number of eosinophils, eosinophil peroxidase (EPO) activity, goblet cells hyperplasia, proinflammatory cytokines, and nuclear factor kappa B (NFκB) p65 immunocontent in the lung. Moreover, 3-MA was able to improve oxidative stress, mitochondrial energy metabolism, and Na+ , K+ -ATPase activity. We demonstrated that treatment with autophagy inhibitor 3-MA reduced EETs formation in the airway. On the basis of our results, 3-MA treatment can be an interesting alternative for reducing lung inflammation, oxidative stress, mitochondrial damage, and EETs formation in asthma.

Global molecular diversity of RSV - the "INFORM RSV" study.

BACKGROUND: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. METHODS: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. DISCUSSION: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.

Neostigmine treatment induces neuroprotection against oxidative stress in cerebral cortex of asthmatic mice.

During chronic inflammatory disease, such asthma, leukocytes can invade the central nervous system (CNS) and together with CNS-resident cells, generate excessive reactive oxygen species (ROS) production as well as disbalance in the antioxidant system, causing oxidative stress, which contributes a large part to neuroinflammation. In this sense, the aim of this study is to investigate the effects of treatment with neostigmine, known for the ability to control lung inflammation, on oxidative stress in the cerebral cortex of asthmatic mice. Female BALB/cJ mice were submitted to asthma model induced by ovalbumin (OVA). Control group received only Dulbecco's phosphate-buffered saline (DPBS). To evaluate neostigmine effects, mice received 80 µg/kg of neostigmine intraperitoneally 30 min after each OVA challenge. Our results revealed for the first time that treatment with neostigmine (an acetylcholinesterase inhibitor that no crosses the BBB) was able to revert ROS production and change anti-oxidant enzyme catalase in the cerebral cortex in asthmatic mice. These results support the communication between the peripheral immune system and the CNS and suggest that acetylcholinesterase inhibitors, such as neostigmine, should be further studied as possible therapeutic strategies for neuroprotection in asthma.

The Syndrome We Agreed to Call Bronchiolitis.

We are ignoring evidence suggesting that the diagnosis of bronchiolitis encompasses several diseases with distinct underlying mechanisms, considerable heterogeneity in treatment responses, and ultimately different therapeutic targets. Understanding this heterogeneity may be the only way to deliver appropriate, stratified treatments.

Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages.

OBJECTIVE AND DESIGN: Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. METHODS: We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. RESULTS: We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. CONCLUSIONS: In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.

Respiratory Syncytial Virus Seasonality: A Global Overview.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in children. By the age of 1 year, 60%-70% of children have been infected by RSV. In addition, early-life RSV infection is associated with the development of recurrent wheezing and asthma in infancy and childhood. The need for precise epidemiologic data regarding RSV as a worldwide pathogen has been growing steadily as novel RSV therapeutics are reaching the final stages of development. To optimize the prevention, diagnosis, and treatment of RSV infection in a timely manner, knowledge about the differences in the timing of the RSV epidemics worldwide is needed. Previous analyses, based on literature reviews of individual reports obtained from medical databases, have failed to provide global country seasonality patterns. Until recently, only certain countries have been recording RSV incidence through their own surveillance systems. This analysis was based on national RSV surveillance reports and medical databases from 27 countries worldwide. This is the first study to use original-source, high-quality surveillance data to establish a global, robust, and homogeneous report on global country-specific RSV seasonality.

Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives.

Gene therapy protocols require robust and long-term gene expression. For two decades, retrovirus family vectors have offered several attractive properties as stable gene-delivery vehicles. These vectors represent a technology with widespread use in basic biology and translational studies that require persistent gene expression for treatment of several monogenic diseases. Immunogenicity and insertional mutagenesis represent the main obstacles to a wider clinical use of these vectors. Efficient and safe non-viral vectors are emerging as a promising alternative and facilitate clinical gene therapy studies. Here, we present an updated review for beginners and expert readers on retro and lentiviruses and the latest generation of transposon vectors (sleeping beauty and piggyBac) used in stable gene transfer and gene therapy clinical trials. We discuss the potential advantages and disadvantages of these systems such as cellular responses (immunogenicity or genome modification of the target cell) following exogenous DNA integration. Additionally, we discuss potential implications of these genome modification tools in gene therapy and other basic and applied science contexts.

Identifying a biomarker network for corticosteroid resistance in asthma from bronchoalveolar lavage samples.

Corticosteroid resistance (CR) is a major barrier to the effective treatment of severe asthma. Hence, a better understanding of the molecular mechanisms involved in this condition is a priority. Network analysis is an emerging strategy to explore this complex heterogeneous disorder at system level to identify a small own network for CR in asthma. Gene expression profile of GSE7368 from bronchoalveolar lavage (BAL) of CR in subjects with asthma was downloaded from the gene expression omnibus (GEO) database and compared to BAL of corticosteroid-sensitive (CS) patients. DEGs were identified by the Limma package in R language. In addition, DEGs were mapped to STRING to acquire protein-protein interaction (PPI) pairs. Topological properties of PPI network were calculated by Centiscape, ClusterOne and BINGO. Subsequently, text-mining tools were applied to design one own cell signalling for CR in asthma. Thirty-five PPI networks were obtained; including a major network consisted of 370 nodes, connected by 777 edges. After topological analysis, a minor PPI network composed by 48 nodes was indentified, which is composed by most relevant nodes of major PPI network. In this subnetwork, several receptors (EGFR, EGR1, ESR2, PGR), transcription factors (MYC, JAK), cytokines (IL8, IL6, IL1B), one chemokine (CXCL1), one kinase (SRC) and one cyclooxygenase (PTGS2) were described to be associated with inflammatory environment and steroid resistance in asthma. We suggest a biomarker network composed by 48 nodes that could be potentially explored with diagnostic or therapeutic use.

Burden of asthma among inner-city children from Southern Brazil.

OBJECTIVE: To assess the impact of asthma in a population of inner-city Brazilian children. METHODS: In a cross-sectional study, we selected children with asthma and healthy controls from public schools (8-16 years) from a capital city of Southern Brazil. Divided into three phases, questionnaires were administered, assessing lung function, body mass index and allergic sensitization. RESULTS: From 2500 children initially included in the study (48.4% males; mean age of 11.42 ± 2.32 years), asthma prevalence was detected in 28.6% (715/2500). The disease was not controlled in 42.7% (305/715) of the children, with 7.6% of hospitalization rate. School absenteeism (at least one day of missing school because of asthma) and sedentary behavior were high (57.1 and 67.2%, respectively), with 47.9% of subjects requiring oral steroids in the previous year, and physical well-being significantly lower than controls, directly interfering with quality of life, and therefore in the daily activities of these students. Moreover, 38% of the parents admitted to being non-adherent to treatment with their children and 31.1 and 53.6%, respectively, believed that rescue medication and exercise might be harmful. CONCLUSIONS: The burden of asthma in Brazilian children seems to be substantial. New international guidelines with a special focus in developing countries settings, with more pragmatic approaches, should be a priority for discussion and implementation actions.

Systematic Review on the Definition of Allergic Diseases in Children: The MeDALL Study.

BACKGROUND: During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis. METHODS: We conducted a search of MEDLINE up to December 2012, to identify relevant original studies published in the English language that examine at least one objective of this systematic review in subjects aged 0-18 years. The screening of titles and abstracts and the extraction of data were conducted independently by two reviewers. RESULTS: From a total of 13,767 citations, 197 studies met the criteria for inclusion, with 54% being cohort studies. Allergic diseases were studied as a single entity in 55% (109/197) of the studies or in the context of multimorbidity in 45%. Asthma accounted for 81.7% of the studies examining single diseases. Overall, up to 33 different phenotypes of allergic disease were reported. Transient early, late-onset and persistent wheeze were the most frequently reported phenotypes. Most studies (78%) used questionnaires. The skin-prick test was the preferred measurement of sensitization (64%). Spirometry and bronchial hyperresponsiveness were assessed in one third of the studies, peak flow rate in 8.6% and disease severity in 35%. CONCLUSIONS: Studies reporting phenotypes of allergic diseases in children are highly heterogeneous and often lack objective phenotypical measures. A concerted effort to standardize methods and terminology is necessary.

Early-life respiratory syncytial virus disease and long-term respiratory health.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI), hospital admission, and mortality in children worldwide. Early-life RSV LRTI has also been associated with subsequent long-term respiratory sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment, and these effects can persist into adulthood as chronic respiratory disease. New preventive measures (maternal vaccine or long-acting monoclonal antibodies) have been licensed to reduce the burden of acute RSV LRTI in infants and children at high risk through passive immunisation. Studies of these RSV prevention products show high efficacy and effectiveness, particularly for preventing severe RSV LRTI, with implementation in many high-income countries, but limited access in low-income and middle-income countries (LMICs). These interventions might also reduce the risk of additional health outcomes and long-term morbidity. This Series paper provides the evidence for the long-term effects of early-life RSV disease, discusses mechanisms of disease development, and addresses the potential full public health value of prevention of RSV illness. Further research is needed to determine whether prevention of RSV LRTI or delay of RSV illness in early life might prevent or ameliorate the development of associated long-term respiratory disease. This potential further underscores the urgency for access and availability of new interventions to prevent early-life RSV LRTI in LMICs.

Seasonality of the incidence of bronchiolitis in infants - Brazil, 2016-2022: An interrupted time-series analysis.

OBJECTIVE: To evaluate the seasonality of acute bronchiolitis in Brazil during the 2020-2022 season and compare it with the previous seasons. METHODS: Data from the incidence of hospitalizations due to acute bronchiolitis in infants <1 year of age were obtained from the Department of Informatics of the Brazilian Public Health database for the period between 2016 and 2022. These data were also analyzed by macro-regions of Brazil (North, Northeast, Southeast, South, and Midwest). To describe seasonal and trend characteristics over time, we used the Seasonal Autoregressive Integrated Moving Averages Model. RESULTS: Compared to the pre-COVID-19 period, the incidence of hospitalizations related to acute bronchiolitis decreased by 97% during non-pharmacological interventions (March 2020 - August 2021) but increased by 95% after non-pharmacological interventions relaxation (September 2021 - December 2022), resulting in a 16% overall increase. During the pre-COVID-19 period, hospitalizations for acute bronchiolitis followed a seasonal pattern, which was disrupted in 2020-2021 but recovered in 2022, with a peak occurring in May, approximately 4% higher than the pre-COVID-19 peak. CONCLUSIONS: This study underscores the significant influence of COVID-19 interventions on acute bronchiolitis hospitalizations in Brazil. The restoration of a seasonal pattern in 2022 highlights the interplay between public health measures and respiratory illness dynamics in young children.

The respiratory syncytial virus vaccine and monoclonal antibody landscape: the road to global access.

Respiratory syncytial virus (RSV) is the second most common pathogen causing infant mortality. Additionally, RSV is a major cause of morbidity and mortality in older adults (age ≥60 years) similar to influenza. A protein-based maternal vaccine and monoclonal antibody (mAb) are now market-approved to protect infants, while an mRNA and two protein-based vaccines are approved for older adults. First-year experience protecting infants with nirsevimab in high-income countries shows a major public health benefit. It is expected that the RSV vaccine landscape will continue to develop in the coming years to protect all people globally. The vaccine and mAb landscape remain active with 30 candidates in clinical development using four approaches: protein-based, live-attenuated and chimeric vector, mRNA, and mAbs. Candidates in late-phase trials aim to protect young infants using mAbs, older infants and toddlers with live-attenuated vaccines, and children and adults using protein-based and mRNA vaccines. This Review provides an overview of RSV vaccines highlighting different target populations, antigens, and trial results. As RSV vaccines have not yet reached low-income and middle-income countries, we outline urgent next steps to minimise the vaccine delay.

The genomic evolutionary dynamics and global circulation patterns of respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.