Pandemic 2009 H1N1 influenza was associated with pediatric death rates that were 10 times the rates for seasonal influenza in previous years.

No abstract

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence has prompted booster immunizations. However, repeated antigen exposure effects on SARS-CoV-2 memory T cells are poorly understood. Here, we utilize MHC-multimers with scRNAseq to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two, or three antigen exposures, including vaccination, primary, and breakthrough infection. Exposure order determined the distribution between spike- and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P ¼ 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-l 1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P , 0.001) and increased with worsening symptoms (P , 0.001). Moreover, after adjusting for IFN-l 1 , children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P ¼ 0.66). Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-l 1 responses mediate exacerbations caused by HRV. Modulation of IFN-l 1 should be studied as a therapeutic target for exacerbations caused by HRV.Keywords: asthma; interferon-l; rhinovirus; children; asthma exacerbation Asthma exacerbations are the main cause of hospitalization in children, and occur in association with respiratory viral infections (1, 2). Human rhinoviruses (HRV) are frequently isolated in the upper airways of children during respiratory infections and during asthma attacks, and have been postulated to trigger these crises (3, 4). However, whether HRV are detected during asthma crises because they are the most frequent cause of upper respiratory infections (URI; which accompany asthma attacks), or because they can specifically elicit asthma exacerbations is unclear. To our knowledge, no pediatric study has compared the viral etiology of URI in patients with asthma with and without wheezing to investigate the specific association between HRV URI and asthma attacks.Several hypotheses have been advanced to explain the mechanisms that trigger asthma crises during respiratory infections (4-7). Focused mainly on HRV-associated episodes, two nonexclusive theories attribute asthma attacks to direct viral injury and immune-mediated exacerbations ...