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Backgrounds:

Nirsevimab reduced medically attended (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) incidence in two double-blind, placebo-controlled studies (Phase IIb [NCT02878330]: healthy very and moderately preterm infants ≥29 to <35 weeks gestational age [wkGA], efficacy 70.1%; Phase III: MELODY [NCT03979313], healthy term and late preterm infants ≥35 wkGA, efficacy 74.5%). We report a pooled efficacy analysis of nirsevimab in term and preterm infants ≥29 wkGA through Day 151.

Methods

Infants were randomised 2:1 to receive either an intramuscular injection of nirsevimab (<5 kg, 50 mg; ≥5 kg, 100 mg) or placebo, before their first RSV season. Data were pooled from the Phase IIb and MELODY studies for those infants under the optimised dosing regimen (i.e., infants <5 kg at dosing and receiving the 50 mg dose from Phase IIb and all infants in MELODY) to evaluate efficacy (relative risk reduction versus placebo) against varying severities of MA RSV LRTI.

Results:

Overall, 860 infants from Phase IIb (median age at randomisation: 1.60 [range 0.1–6.4] months; female: 47.6%) and 1490 infants from MELODY (median age at randomisation: 2.60 [0.03–11.10] months; female: 48.4%) were included. Demographics were comparable across studies, except for GA and age at randomisation. Nirsevimab had an efficacy of 79.5% against MA RSV LRTI, 77.3% against RSV LRTI hospitalisation and 86.0% against very severe RSV LRTI through Day 151 (Figure). Consistent efficacy was observed across subgroups defined by age at randomisation, sex, ancestry, weight or geographical region and across endpoints of differing disease severity.

Conclusions/Learning Points:

In a pooled analysis of two randomised, placebo-controlled studies, prophylaxis with nirsevimab demonstrated consistent efficacy across severities of RSV LRTI through Day 151.

Backgrounds:

Most infants are exposed to respiratory syncytial virus (RSV) in the first year of life. Studies have observed an association between severe RSV infection and asthma, yet it is unclear if this relationship is causal or due to underlying factors that increase susceptibility to both conditions. One study partially mitigated the influence of these factors by examining the relationship between infant age at winter virus peak and subsequent asthma. We extended this approach by examining infant age at RSV, influenza, and rotavirus peaks, as well as proxies for the timing and severity of RSV, influenza, and rotavirus seasons, and their relationships with subsequent incidence of childhood asthma.

Methods

We analyzed province-wide administrative data for 1,437,731 infants born in Ontario, Canada from 2002-2013. We ascertained RSV, influenza, and rotavirus hospitalizations by 1 year and asthma by 5 years of age using inpatient/outpatient ICD-9/10 codes. We used regression models to investigate: (1) infant age in the calendar week with highest incidence of hospitalization for each virus and subsequent asthma (unit of analysis infant); (2) incidence of RSV-, influenza-, and rotavirus-related hospitalizations by 1 year and asthma by 5 years (unit of analysis calendar week of birth).

Results:

We observed highest likelihood of subsequent asthma at infant ages of approximately 13-, 11-, and 16-weeks during RSV, influenza, and rotavirus peaks, respectively. We observed apparent seasonal variation in childhood asthma by infant week of birth. The relationship between RSV seasonal variation and asthma appeared small in magnitude, while an unexpected relationship between rotavirus seasonal variation and asthma emerged (Figure).

Conclusions/Learning Points:

We find limited evidence in support of a causal relationship between RSV and asthma, and suggest further investigation of other mechanisms, including underlying seasonal characteristics.

Backgrounds:

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) and hospitalisation in infants. In two global, pivotal, placebo-controlled studies, nirsevimab, a monoclonal antibody to the RSV fusion protein with extended half-life, reduced medically attended RSV LRTI versus placebo throughout the RSV season (Phase III NCT03979313: MELODY, healthy term and late preterm infants, 74.5%; Phase IIb NCT02878330: healthy preterm infants, 70.1%). We measured RSV neutralising antibodies (Nab) from these studies through Day 361.

Methods

Infants were randomised 2:1 to receive one intramuscular injection of nirsevimab or placebo, before their first RSV season. Serum samples collected pre- and post-dose were tested in a validated RSV neutralisation assay; RSV Nab levels are reported in international units (IU)/mL.

Results:

Overall, 1402 infants from MELODY and 741 infants from Phase IIb had available data. Baseline geometric mean RSV Nab levels were similar in both studies (MELODY, 134 IU/mL; Phase IIb, 87 IU/mL). At Day 151, nirsevimab recipients exhibited RSV Nab levels approximately 50-fold higher (MELODY, 6901 IU/mL; Phase IIb, 4799 IU/mL) versus baseline, with highest levels sampled at Day 31 in MELODY (19,711 IU/mL; Figure) and at Day 91 in Phase IIb (8479 IU/mL); levels remained >7-fold higher through Day 361 (MELODY, 978 IU/mL; Phase IIb, 739 IU/mL). At Day 361, placebo recipients with no confirmed RSV infection during the studies had RSV Nab levels of 38–48 IU/mL; nirsevimab recipients had RSV Nab levels of 757–982 IU/mL, >19-fold higher than placebo recipients without confirmed RSV infection.

Conclusions/Learning Points:

Following immunisation with nirsevimab, RSV Nab levels at Day 151 were approximately 50-fold higher than baseline. RSV Nab levels remained high through Day 361, suggesting protection beyond Day 151.

Backgrounds:

The polymerase chain reaction (PCR) cycle threshold (Ct) value represents the number of amplification cycles required to yield a positive test result and inversely correlates with pathogen load. Here, we evaluated whether Ct values of respiratory pathogens were associated with the clinical severity of infections in acutely ill children.

Methods

In this cross-sectional study at a pediatric emergency department, we obtained nasopharyngeal swabs from 800 children with fever or respiratory symptoms. Samples were analyzed for 21 respiratory pathogens using point-of-care multiplex-PCR device (Qiastat). We compared Ct values in children who needed hospitalization and those who were discharged from ED using a multivariate logistic regression model adjusted for age and sex. In addition, the association of Ct values with CRP values was analyzed with linear regression.

Results:

Of the 800 participants, 356 (45 %) were girls. The median age was 3.0 years. At least one pathogen was detected in 594 (74 %) participants. The most common pathogen was picornavirus, i.e. rhinovirus or enterovirus (328, 41 %) followed by RSV (133, 17 %). In total, 334 (42 %) patients were hospitalized, ranging from 11 % (3/27) for those with influenza A to 61 % (81/133) for those with RSV infection (Figure). When adjusted for age and sex, no statistically significant associations between Ct-value and need for hospitalization were found for any pathogen. In participants with detection of rhino/enterovirus, high Ct-value, i.e. low viral load, associated with high CRP value (β coefficient 2.51 [95 % CI 0.79 to 4.22]).

Conclusions/Learning Points:

Viral or pathogen load, estimated by PCR cycle threshold values, was not associated with the need for hospitalization due to respiratory viral infection in children. Thus, the clinical utility of Ct-values appears to be limited.

Backgrounds:

Respiratory infections (RI) are characterized by significant morbidity and represent a very common health problem in the first years of life, requiring multiple physician visits and often hospitalization, with significant implications for the patient’s family. The risk of RI and gastrointestinal infections is 2 to 3 times higher in children attending childcare (preschool) compared to children cared for at home. Probiotics have demonstrated in various studies efficacy in reducing RI symptoms.

Methods

In this double blind, placebo-controlled study, healthy preschool children aged 1 to 5 years received a probiotic supplement daily for 6 months to assess the effect on presence or absence at school and on the incidence of upper respiratory tract infection symptoms. The intervention comprised of Streptococcus oralis 89a, Lactobacillus rhamnosus LB21, Lactococcus lactis W19, Lactococcus lactis L1A and Bifidobacterium lactis W51 at 2x10⁹ CFUs daily or placebo.

Results:

In total 61 children finished the study and were included in the analysis. The total number of healthy days at preschool child care in the probiotic group was significantly higher than that in the placebo group. Incidence of fever and runny nose were significantly lower in the probiotic group compared to placebo. No statistical difference was found between the groups when acute otitis media and upper respiratory infection were studied.

Conclusions/Learning Points:

Our findings indicate that 6 months daily supplementation with probiotics reduces the incidence of fever, runny nose, and absence at preschool in children of age 1 to 5 years.

Backgrounds:

MK-1654 is an investigational RSV-neutralizing monoclonal antibody in development for the prevention of medically-attended lower respiratory tract infection (MALRI) in infants. This work summarizes interim pharmacokinetic (PK) and serum neutralizing antibody (SNA) results in infants. The efficacy of MK-1654 is also predicted using a published model.

Methods

This phase 1b/2a double-blind, randomized, placebo-controlled, study evaluated the safety, tolerability, PK, and SNA of MK-1654 in pre-term (born 29-35 weeks gestational age) and full-term infants. Participants (n=180) 2 weeks to 8 months of age were randomized in a 4:1 ratio within five separate panels (pre-term: 20, 50, 75 or 100-mg, full-term: 100mg) to receive a single intramuscular dose of MK-1654 or placebo. Blood samples were collected to quantify MK-1654 serum concentrations and SNA titers. A preliminary population PK (popPK) model was developed to describe PK of MK-1654 in infants. The efficacy of MK-1654 was predicted using clinical trial simulations which were based on the popPK model and a published model-based meta-analysis.

Results:

Concentration data from 111 pre-term infants and 32 full-term infants through at least 150 days post-administration were available. The pharmacokinetics of MK-1654 were best characterized by a linear two-compartment popPK model with first-order absorption and elimination. Clearance and volume of distribution (Vd) were scaled allometrically using time-varying body weight. Age was also a covariate on Vd. The half-life of MK-1654 was approximately 42 days. A linear relationship was observed between increasing concentrations of MK-1654 and increasing SNA. Clinical trial simulations predict that a single dose of ≥75 mg of MK-1654 will provide >75% efficacy for the prevention of RSV MALRI for a duration of 5 months in infants.

Conclusions/Learning Points:

These findings support the continued evaluation of MK-1654 in ongoing Phase 3 studies.

Backgrounds:

Determining the key genomic characteristics of childhood pneumonia may inform the development of new clinical interventions for the disease. We used a genome-wide association study (GWAS) to identify variants associated with all-cause pneumonia and subsequently used these data to identify eQTL.

Methods

DNA and peripheral blood RNA were collected from healthy Nepalese children and Nepalese children admitted to Patan Hospital, Kathmandu with clinician diagnosed pneumonia. Samples were genotyped using Illumina Global Screening Arrays. Array data underwent QC and filtering before imputation using the HRC R1.1 2016 reference panel. Association analysis, by conducting a logistic regression using multidimensional scaling values, was performed using PLINK 2. RNA underwent whole-transcriptome sequencing using Illumina HiSeq4000, 75bp paired-end reads. Count data underwent filtering, normalisation, and batch correction, before eQTL were identified using MatrixeQTL.

Results:

A GWAS of 773 children with pneumonia (cases) and 2121 healthy community-based children (controls) identified rs79755386, proximal to B3GLT (involved in glycosylating o-linked mucins) to be associated with all-cause pneumonia (p=1.1x10^-10, MAF cases = 0.09 vs MAF controls = 0.04, OR 2.3, 95% CI 1.8-2.9). Children with pneumonia who possessed the alternate allele, compared with those who had the reference, were more likely to have end-point consolidation on their chest x-ray (p=0.0492).

220 RNA samples from children with pneumonia were analysed. No cis eQTL were identified however, 230 significant trans eQTL to rs79755386 were identified with expression of HIC1 (p=8.9x10^-5) which regulates T-cell differentiation, and SSH3 (p=0.0001) which plays a role in actin filament dynamics, having the most significant associations.

Conclusions/Learning Points:

rs79755386 is associated with childhood pneumonia and the expression of genes which likely affect both immune and respiratory epithelial function. Further examination of the role rs79755386 plays in respiratory epithelium function is required.