Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus (RSV) Vaccine in Healthy RSV-Seropositive Children 12-23 Months of Age.

BACKGROUND: Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12-23-month-old RSV-seropositive children followed up for 2 years after vaccination. METHODS: Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti-RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. RESULTS: Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. CONCLUSIONS: Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. CLINICAL TRIALS REGISTRATION: NCT02927873.

Respiratory syncytial virus (RSV) is among the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing 3 important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted for 1 year.

Longitudinal survey of humoral and cellular response to SARS-CoV-2 infection in children.

BACKGROUND: Data regarding humoral and cellular response against SARS-CoV-2 in children are scarce. We analysed seroconversion rate, decrease of anti-RBD IgG antibodies over time and T-cell response in paediatric patients who suffered COVID-19. METHODS: Longitudinal study of paediatric patients COVID-19 diagnosed by positive molecular assay in nasopharyngeal swabs. Blood samples were drawn 1-2 months and 6-7 months after acute infection. Anti-RBD IgG were determined using the Alinity® SARS-CoV-2 IgG II Quant assay (Abbott). Cellular immune response was analysed by T-SPOT® SARS-CoV-2 assay kit (Oxford Immunotec Ltd.). RESULTS: 27/39 (69,2%) patients seroconverted. Despite a significant decrease in antibody levels over time (p < 0,01), no children seroreverted between first and second visits. Only 6/16 (37,2%) children under 6 years-old were seropositive compared to 21/23 (91,3%) over 6 years-old (p < 0,01). Highest antibody levels were found in seropositive younger children (p = 0,036). Thirteen (33,3%) children showed T-cell response. Among participants showing humoral response, no cellular response was detected in 14 (51,9%). CONCLUSIONS: Anti-RBD IgG antibodies persistence at 6-7-months after SARS-CoV-2 infection was observed. A different IgG response was found depending on age. As measured by T-SPOT, most patients did not display cellular response 6-7 months after infection.

A Prospective Study of the Serological, Clinical, and Epidemiological Features of a SARS-CoV-2 Positive Pediatric Cohort.

Background: SARS-CoV-2 was a global pandemic. Children develop a mild disease and may have a different rate of seroconversion compared to adults. The objective was to determine the number of seronegative patients in a pediatric cohort. We also reviewed the clinical−epidemiological features associated with seroconversion. Methods: A multicenter prospective observational study during September−November 2020, of COVID-19, confirmed by reverse transcription-polymerase chain reaction. Data were obtained 4−8 weeks after diagnosis. Blood samples were collected to investigate the humoral response, using three different serological methods. Results: A total of 111 patients were included (98 symptomatic), 8 were admitted to hospital, none required an Intensive Care Unit visit. Median age: 88 months (IQR: 24−149). Median time between diagnosis and serological test: 37 days (IQR: 34−44). A total of 19 patients were non-seroconverters when using three serological techniques (17.1%; 95% CI: 10.6−25.4); most were aged 2−10 years (35%, p < 0.05). Univariate analysis yielded a lower rate of seroconversion when COVID-19 confirmation was not present amongst household contacts (51.7%; p < 0.05). Conclusions: There was a high proportion of non-seroconverters. This is more commonly encountered in childhood than in adults. Most seronegative patients were in the group aged 2−10 years, and when COVID-19 was not documented in household contacts. Most developed a mild disease. Frequently, children were not the index case within the family.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/µL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016.

Characterization and circulation of seasonal influenza viruses in Madrid, 2010-2016.

Influenza virus infection is a major health care burden and is associated with significant morbidity and mortality. The 2009 influenza pandemic highlighted the importance of influenza surveillance. The objective of this study was to assess the epidemiology and activity of influenza A and B viruses in adults and children in the post-pandemic period with a special focus on the pediatric population. We performed a retrospective descriptive study involving adults and children with influenza-like illness at the Clinico San Carlos Hospital (Madrid, Spain) over six influenza seasons, between August 2010 and April 2016. Respiratory specimens were collected from 3131 patients and routinely processed for influenza diagnosis. Epidemiological analysis was performed in terms of gender, age, and seasonal distribution. Globally, Influenza A and B viruses were detected in the respiratory specimens of 696 (22.2%) of the 3131 studied population. Among all influenza positive specimens, 142 (20.4%) were influenza A(H1N1)pdm09, 61 (8.8%) were influenza A(H3N2), 321 (46.1%) were untypeable influenza A viruses and 166 (23.9%) were influenza B. Co-infection by both influenza A and B viruses was detected in six patients (0.9%). Meanwhile, co-infection with other non-influenza respiratory viruses was identified in 5 children and 20 adults. Influenza A(H1N1)pdm09 virus activity has been significantly high since the 2009 pandemic and has gradually replaced the previously circulating seasonal influenza A(H1N1) virus. Moreover, influenza A(H3N2) virus activity remained at low levels during the last winter season while influenza B virus isolates increased significantly over the past 2 years.

A Case of IL-7R Deficiency Caused by a Novel Synonymous Mutation and Implications for Mutation Screening in SCID Diagnosis.

Reported synonymous substitutions are generally non-pathogenic, and rare pathogenic synonymous variants may be disregarded unless there is a high index of suspicion. In a case of IL7 receptor deficiency severe combined immunodeficiency (SCID), the relevance of a non-reported synonymous variant was only suspected through the use of additional in silico computational tools, which focused on the impact of mutations on gene splicing. The pathogenic nature of the variant was confirmed using experimental validation of the effect on mRNA splicing and IL7 pathway function. This case reinforces the need to use additional experimental methods to establish the functional impact of specific mutations, in particular for cases such as SCID where prompt diagnosis can greatly impact on diagnosis, treatment, and survival.

Once-daily antiretroviral therapy in a cohort of HIV-infected children and adolescents.

We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden.

Comparison of Mycobacterium lentiflavum and Mycobacterium avium-intracellulare complex lymphadenitis.

BACKGROUND: Mycobacterium lentiflavum is considered a rare pathogen causing nontuberculous mycobacterial (NTM) lymphadenitis. METHODS: A multicenter, retrospective study was performed in immunocompetent children <14 years of age with microbiologically confirmed NTM lymphadenitis treated at 6 hospitals in Madrid, Spain, during 2000-2010. We compared children with M. lentiflavum and Mycobacterium avium-intracellulare complex infection. RESULTS: Forty-five microbiologically confirmed NTM lymphadenitis patients were identified: 19 (45.2%) caused by M. avium-intracellulare complex, 17 (40.5%) by M. lentiflavum, 1 by both and 5 by other mycobacteria. Out of 17 M. lentiflavum cases, 14 were diagnosed in the past 5 years. Regarding M. lentiflavum cases, median age was 23 months. Submandibular nodes were the most frequently involved (76.5%), with multiple locations seen in 41% of the children and spontaneous drainage in 41% of them. Drug susceptibility tests were performed in 14 isolates and showed a complete susceptibility to clarithromycin and cycloserine, whereas 93% were resistant to rifampin, 33% to quinolones and full resistance to other tested antimycobacterial drugs was detected. All but 1 child required surgery and 11 were treated additionally with various drug combinations. Total resolution was achieved in 50% of children within 6 months.Compared with M. avium-intracellulare complex cases, children were younger and laterocervical nodes were significantly less frequently involved. No statistically significant differences were found related to clinical characteristics, treatment and outcome. CONCLUSIONS: M. lentiflavum is an emerging pathogen producing NTM lymphadenitis in Madrid.

"Induced sputum versus gastric lavage for the diagnosis of pulmonary tuberculosis in children".

BACKGROUND: Diagnosis of pulmonary tuberculosis (PTB) is difficult in infants and young children. For microbiological confirmation of PTB children, sequential gastric lavage (GL) is recommended. Induced sputum (IS) may be an alternative or complementary tool, but the information is limited in children in developed countries. The aim of this study is to assess the safety and diagnostic yield from IS combined with GL for PTB diagnosis in non-HIV infected children. METHODS: The study involved 22 children with suspected PTB admitted to the Getafe Hospital from January 2007 to May 2011. IS and GL were performed on three consecutive days, according to a standardized protocol. In all samples, BK staining, culture and PCR were carried out, including Genotype MTBDR plus for resistance to INH-RIF (Isoniazid-Rifampin) since 2008. A preliminary analysis of an ongoing prospective study is presented. RESULTS: Median age was 72 months (range 1 month to 14 years of age). Seven (33%) were ≤ 5 years of age. Seventeen were clinically diagnosed of PTB based on positive PPD and radiological criteria. Microbiological confirmation was achieved in 10 (58.8%) by either GL or IS. M. tuberculosis was identified by GL in 8 children (47.1%) and by IS in 7 (41.2%). One infant (2 IS samples) had transient oxygen desaturation recovered spontaneously. CONCLUSIONS: IS appears to be safe and well tolerated by children for diagnosis of PTB and is more convenient. Increasing the diagnostic yield of PTB in children with PTB may be a complementary technique. Largest studies are necessary to define the role of IS in paediatric PTB.

HIV-infected children vaccination coverage and safety in a Western European cohort: a retrospective study.

Since the implementation of highly active antiretroviral therapy in HIV-infected children, response to scheduled vaccines may determinate future morbidity and mortality. The aims of this study have been to describe the current vaccine coverage, vaccine safety and concordance with vaccine recommendations of the 68 HIV-infected children and adolescents followed up in our Unit. Forty-four percent of the children received at least one dose of the oral polio vaccine (OPV). Only 9.1% needed and received a second set of hepatitis B virus immunization because of low vaccine response. Only 14.7% were vaccinated against varicella. Coverages of 82.3% and 100% have been reached with the 23-valent and the 7-valent pneumococcal vaccines, respectively. Meningococcal conjugated vaccine uptake was moderate (80.8%). Influenza annual vaccination coverage was poor: only 22.7% had well-documented yearly vaccines. In our experience, vaccine coverage is lower in those vaccines administered in primary care centres compared with the immunizations given at the hospital. OPV administration did not cause any adverse effect in the children or in their families. Vaccine coverage in HIV-infected children was suboptimal.