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Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children in 1966 and elicited non-protective, pathogenic antibody. Two immunized infants died and 80% were hospitalized after subsequent RSV exposure. No vaccine was licensed since. A widely accepted hypothesis attributed vaccine failure to formalin disruption of protective antigens. Instead, we show that lack of protection was not due to alterations caused by formalin, but to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor stimulation. This study explains why the inactivated RSV vaccine failed to protect and consequently led to severe disease, hampering vaccine development for forty-two years. Also, it suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR-agonists in their formulation. In addition, it identifies affinity maturation as a critical factor for the safe immunization of infants.

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

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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 ...

HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants.

We conducted a prospective, observational study to characterize the clinical manifestations of respiratory infections caused by human metapneumovirus (hMPV) and other viruses in 194 premature infants and young children with chronic lung disease or congenital heart disease in Buenos Aires. Children had 567 episodes of respiratory illness and were monitored until they were 2 years old or until the completion of the study. hMPV elicited 12 infections (2%) year-round; 30% were of moderate or greater severity. Human parainfluenza virus type 3 caused 24 infections (4%), and 5 (25%) of 20 lung infections led to hospitalization. Respiratory syncytial virus (RSV) caused 33 episodes--17% of infections and 32% of hospitalizations during the respiratory season. None of the 10 children infected with influenza virus had severe disease. The present study of at-risk children suggests that hMPV and influenza virus are infrequent agents of severe disease and highlights the need for preventive interventions against RSV in developing countries.

BackgroundTherapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression.MethodsA randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV2 in elderly subjects within 72 hours of mild COVID-19 symptoms. The primary endpoint was severe respiratory disease defined as a respiratory rate ≥30 and/or an O2 sat<93% in room air. The study was interrupted at 76% of its projected sample size, because cases in the region decreased considerably and steady enrollment of study subjects became virtually impossible.Results160 patients underwent randomization. In the intention-to-treat analysis (ITT), 13/80(16.2%) patients receiving plasma vs. 25/80(31.2%) receiving placebo experienced severe respiratory disease [RR(95%CI)= 0.52(0.29,0.94); p=0.026)] with an RRR=48%.A modified ITT analysis, excluding six subjects who experienced the primary endpoint before infusion, showed a larger effect size [RR(95%CI) = 0.40(0.20, 0.81), p=0.007]. High- and low-titer donor analyses, based on a median IgG titer=1:3,200, evidenced a dose-dependent response with an RRR=73.3% for recipients of high-titer plasma (p=0.016) and a number needed to treat (NNT)=4.4. All secondary endpoints exhibited trends towards protection. No solicited adverse events were observed.ConclusionsEarly administration of high-titer convalescent plasma against SARS-CoV2 to mildly ill infected seniors reduced COVID-19 progression. This safe, inexpensive, outpatient intervention facilitates access to treatment from industrialized to LMIC, can decompress demands on hospitals, and may contribute to save lives.Funded by The Bill & Melinda Gates Foundation and The Fundación INFANT Pandemic Fund. Registered in the Dirección de Sangre y Medicina Transfusional del Ministerio de Salud (PAEPCC19), Plataforma PRIISA (1421), and clinicaltrials.gov (NCT04479163).All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 trial from Pfizer; no other relationships or activities that could appear to have influenced the submitted work.