Background:Otitis media (OM) is the leading cause of childhood hearing loss but its burden in low-middle-income countries like Papua New Guinea (PNG) is poorly understood. We aimed to determine the proportion of children aged ≤15 years attending clinics in Goroka, Eastern Highlands Province, PNG with OM and associated risk factors. Methods:In 2021-2022 any child attending outpatient clinics because they were sick or for ear screening or immunisation and accompanying siblings were eligible for enrolment into this cross-sectional study. Clinical and risk factor data were collected, ears examined by trained research nurses using otoscopy and tympanometry and findings independently reviewed by Australia-based audiologists. A child-level diagnosis was made based on the worst affected ear. Findings:Of 498 enrolled children, 68.1% attended for treatment, 15.3% for immunisation, 1.2% for ear screening and 15.5% were siblings. The proportion of children with any OM was similar among those attending because they were sick and other reasons (75.5% vs 71.4%) but suppurative OM (acute OM with/without perforation and chronic suppurative OM) was more common in children attending because they were sick (47.4% vs 16.9%). A tympanic membrane perforation was present in 22.1% of children. OM affected 79.0% of children <6 months; 45.4% of 1-2-year-olds had suppurative OM. Maternal smoking was associated with increased risk of any OM (adjusted odds ratio [aOR] 1.80, 95% CI: 1.08-3.00). Suppurative OM was associated with antibiotic use in preceding 30 days (aOR 1.78, 95% CI: 1.04-3.06). Interpretation:Children in the PNG highlands have among the world's highest burden of OM. Urgent public health action is required, including health worker training, regular ear screening, and strategies to prevent this under-reported disease in PNG. Funding:This project was funded by a Wesfarmers Centre for Vaccines and Infectious Diseases Deborah Lehmann Research Award.

OBJECTIVE:To compare risks of adverse birth outcomes between maternally vaccinated and unvaccinated twin pregnancies. DESIGN:Multi-jurisdictional data linkage cohort study. SETTING:All registered births in Queensland (Qld) and Northern Territory (NT), Australia between 1 January 2012 and 31 December 2017. POPULATION:Twin pregnancies with infants born ≥ 20 weeks gestation and weighing ≥ 400 g. METHODS:We used Cox proportional-hazard models to calculate risk, with maternal vaccination status as the time-varying exposure, and national birthweight percentile charts specific for Australian-born twins to accurately reflect risk among small for gestational age (SGA) infants. MAIN OUTCOME MEASURES:Adverse birth outcomes including preterm birth, stillbirth and SGA infants. RESULTS:Among our cohort of n = 11 435 infants, there was no statistically significant increased risk of preterm births, stillbirths or SGA infants between women who received a maternal influenza or pertussis vaccination and unvaccinated women. We observed a non-significant lower risk of SGA infants among pertussis vaccinated Qld (aHR 0.85, 95% CI 0.70-1.03) and NT women (aHR 0.50, 95% CI 0.17-1.44), and a lower risk of preterm infants among influenza vaccinated Qld women (aHR 0.93, 95% CI 0.84-1.03) and pertussis vaccinated NT women (aHR 0.78, 95% CI 0.44-1.38). CONCLUSION:Maternal influenza and pertussis vaccinations did not increase the risk of preterm birth, stillbirth or SGA infants among twin pregnancies. These novel and important findings alleviate safety concerns for a cohort that carries a higher baseline risk of adverse birth outcomes compared to singleton pregnancies.

The Northern Territory (NT) of Australia has high reported rates of both preterm birth and childhood respiratory syncytial virus (RSV) infections. The aim of this study was to investigate the association between preterm birth and risk of RSV-associated acute lower respiratory infection (RSV-ALRI) hospital admission among NT infants during their first year of life. A retrospective, population-based cohort study of NT mother-infant pairs from 2008 to 2017. Preterm birth was defined as gestation < 37 weeks. RSV-ALRI hospitalisations were identified using ICD-10-AM codes (J12.1, J20.5, J21.0, or J09-J22 plus B97.4). Risk of RSV-ALRI in preterm infants was assessed using generalised linear regression to calculate risk ratios (RR). A multivariable risk model adjusted for all available maternal, perinatal, and infant characteristics. Temporal trends in hospitalisation incidence were assessed using negative binomial regression. Overall, 10

OBJECTIVES:To evaluate the effectiveness of maternal pertussis vaccination for preventing pertussis infections in Aboriginal and Torres Strait Islander infants under seven months of age.STUDY DESIGN:Retrospective cohort study; analysis of linked administrative health data.SETTING, PARTICIPANTS:Mother-infant cohort (Links2HealthierBubs) including all pregnant women who gave birth to live infants (gestational age ≥ 20 weeks, birthweight ≥ 400 g) in the Northern Territory, Queensland, and Western Australia during 1 January 2012 - 31 December 2017.MAIN OUTCOME MEASURES:Proportions of women vaccinated against pertussis during pregnancy, rates of pertussis infections among infants under seven months of age, and estimated effectiveness of maternal vaccination for protecting infants against pertussis infection, each by Indigenous status.RESULTS:Of the 19 892 Aboriginal and Torres Strait Islander women who gave birth to live infants during 2012-2017, 7398 (37.2%) received pertussis vaccine doses during their pregnancy, as had 137 034 of 259 526 non-Indigenous women (52.8%; Indigenous v non-Indigenous: adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.62-0.70). The annual incidence of notified pertussis infections in non-Indigenous infants declined from 16.8 (95% CI, 9.9-29) in 2012 to 1.4 (95% CI, 0.3-8.0) cases per 10 000 births in 2017; among Aboriginal and Torres Strait Islander infants, it declined from 47.6 (95% CI, 16.2-139) to 38.6 (95% CI, 10.6-140) cases per 10 000 births. The effectiveness of maternal vaccination for protecting non-Indigenous infants under seven months of age against pertussis infection during 2014-17 was 68.2% (95% CI, 51.8-79.0%); protection of Aboriginal and Torres Strait Islander infants was not statistically significant (36.1%; 95% CI, -41.3% to 71.1%).CONCLUSIONS:During 2015-17, maternal pertussis vaccination did not protect Aboriginal and Torres Strait Islander infants in the NT, Queensland, and WA against infection. Increasing the pertussis vaccination rate among pregnant Aboriginal and Torres Strait Islander women requires culturally appropriate, innovative strategies co-designed in partnership with Indigenous organisations and communities.

Background Preterm birth (PTB) is the single most important cause of perinatal mortality and morbidity in high income countries. In Australia, 8.6% of babies are born preterm but substantial variability exists between States and Territories. Previous reports suggest PTB rates are highest in the Northern Territory (NT), but comprehensive analysis of trends and risk factors are lacking in this region. The objective of this study was to characterise temporal trends in PTB among First Nations and non-First Nations mothers in the Top End of the NT over a 10-year period and to identify perinatal factors associated with the risk of PTB. Methods This was a retrospective population-based cohort study of all births in the Top End of the NT over the 10-year period from January 1st, 2008, to December 31st, 2017. We described maternal characteristics, obstetric complications, birth characteristics and annual trends in PTB. The association between the characteristics and the risk of PTB was determined using univariate and multivariate generalised linear models producing crude risk ratios (cRR) and adjusted risk ratios (aRR). Data were analysed overall, in First Nations and non-First Nations women. Results During the decade ending in 2017, annual rates of PTB in the Top End of the NT remained consistently close to 10% of all live births. However, First Nations women experienced more than twice the risk of PTB (16%) compared to other women (7%). Leading risk factors for PTB among First Nations women as compared to other women included premature rupture of membranes (RR 12.33; 95% CI 11.78, 12.90), multiple pregnancy (RR 7.24; 95% CI 6.68, 7.83), antepartum haemorrhage (RR 4.36; 95% CI 3.93, 4.84) and pre-existing diabetes (RR 4.18; 95% CI 3.67, 4.76). Conclusions First Nations women experience some of the highest PTB rates globally. Addressing specific pregnancy complications provides avenues for intervention, but the story is complex and deeper exploration is warranted. A holistic approach that also acknowledges the influence of socio-demographic influences, such as remote dwelling and disadvantage on disease burden, will be required to improve perinatal outcomes.

BackgroundIn Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations.Methods and findingsIn 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size.ConclusionsIn this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation.Trial registrationClinicalTrials.gov NCT01735084 and NCT01174849.

Introduction Globally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life. Methods and analysis ‘D-Kids’ is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother–infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups. Ethics and dissemination This trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences. Trial registration number ACTRN12618001174279.

BackgroundReducing rates of preterm birth (PTB) remains a significant challenge. The Northern Territory (NT) records some of the highest rates of PTB in the country, especially in First Nations women. In 2014, a Western Australian (WA) preterm birth prevention initiative involved the implementation of seven key initiatives. One of these was routine mid-trimester cervical length measurement. The initiative successfully reduced PTB rates following its first year of implementation. This was the first successful reduction in PTB, including the earlier gestational ages, across a population. AimsTo assess the uptake of routine cervical length measurement in the Top End of the NT after the success of the WA PTB prevention initiative and assess if treatment of a short cervix improved PTB rates. MethodsA retrospective cohort study of all women who received antenatal care and delivered their baby at the NT's only tertiary hospital was performed. Mid-trimester ultrasound scan data were collected from two separate time windows, before and after the implementation of the WA intervention. Treatments and gestational age at birth were recorded. ResultsAdoption of routine screening of cervical length measurement at mid-trimester ultrasound in the NT was successful, increasing from 4 to 88%. Detection rates of short cervix doubled. However, there was no difference to PTB rates despite targeted management. ConclusionPTB remains a significant challenge in the NT, especially for First Nations women who are found to have a short cervix more commonly than non-Indigenous women in the Top End.

BACKGROUND AND OBJECTIVE:The importance of extracellular traps (ETs) in chronic respiratory conditions is increasingly recognized but their role in paediatric bronchiectasis is poorly understood. The specialized techniques currently required to study ETs preclude routine clinical use. A simple and cost-effective ETs detection method is needed to support diagnostic applications. We aimed to determine whether ETs could be detected using light microscopy-based assessment of Romanowsky-stained bronchoalveolar lavage (BAL) slides from children with bronchiectasis, and whether the ETs cellular origin could be determined.METHODS:Archived Romanowsky-stained BAL slides from a cross-sectional study of children with bronchiectasis were examined for ETs using light microscopy. The cellular origin of individual ETs was determined based on morphology and physical contact with surrounding cell(s).RESULTS:ETs were observed in 78.7% (70/89) of BAL slides with neutrophil (NETs), macrophage (METs), eosinophil (EETs) and lymphocyte (LETs) ETs observed in 32.6%, 51.7%, 4.5% and 9%, respectively. ETs of indeterminate cellular origin were present in 59.6% of slides. Identifiable and indeterminate ETs were co-detected in 43.8% of slides.CONCLUSION:BAL from children with bronchiectasis commonly contains multiple ET types that are detectable using Romanowsky-stained slides. While specialist techniques remain necessary to determining the cellular origin of all ETs, screening of Romanowsky-stained slides presents a cost-effective method that is well-suited to diagnostic settings. Our findings support further research to determine whether ETs can be used to define respiratory endotypes and to understand whether ETs-specific therapies may be required to resolve airway inflammation among children with bronchiectasis.

ABSTRACT Importance In remote communities of the Northern Territory, Australia, children experience high rates of otitis media (OM), commonly caused by non‐typeable Haemophilus influenzae (NTHi). Few data exist on antibiotic susceptibility of NTHi from OM. Objective To determine whether population‐level nasopharyngeal NTHi antibiotic susceptibility data could inform antibiotic treatment for OM. Methods NTHi isolates (n = 92) collected from ear discharge between 2003 and 2013 were selected to time‐ and age‐match NTHi isolates from the nasopharyngeal carriage (n = 95). Antimicrobial susceptibility were tested. Phylogenomic trees and a genome‐wide association study (GWAS) were performed to determine the similarity of nasopharyngeal and ear isolates at a population level. Results Among 174 NTHi isolates available for antimicrobial susceptibility testing, 10.3% (18/174) were resistant to ampicillin and 9.2% (16/174) were resistant to trimethoprim‐sulfamethoxazole. Small numbers of isolates (≤3) were resistant to tetracycline, chloramphenicol, or amoxicillin‐clavulanic acid. There was no statistical difference in the proportion of ampicillin‐resistant (P = 0.11) or trimethoprim‐sulfamethoxazole‐resistant isolates (P = 0.70) between ear discharge and nasopharynx‐derived NTHi isolates. Three multi‐drug resistant NTHi isolates were identified. Phylogenomic trees showed no clustering of 187 Haemophilus influenzae isolates based on anatomical niche (nasopharynx or ear discharge), and no genetic variations that distinguished NTHi derived from ear discharge and nasopharyngeal carriage were evident in the GWAS. Interpretation In this population‐level study, nasopharyngeal and ear discharge isolates did not represent distinct microbial populations. These results support tracking of population‐level nasopharyngeal NTHi antibiotic resistance patterns to inform clinical management of OM in this population.

BackgroundAntenatal inactivated influenza (IIV) and pertussis‐containing vaccines (dTpa) offer protection against severe respiratory infections for pregnant women and infants <6 months of age. Both vaccines are recommended in pregnancy; however, little is known about temporal or jurisdictional trends and predictors of uptake.AimsTo identify gaps and predictors of IIV and/or dTpa vaccinations in Australian pregnancies from 2012 to 2017.Materials and MethodsWe conducted a probabilistically linked, multi‐jurisdictional population‐based cohort study, drawing from perinatal data collections and immunisation databases. We used a generalised linear mixed model with a random effect term to account for clustering of multiple pregnancies within mothers, to calculate vaccination uptake, and identify predictors of uptake by maternal demographic, pregnancy, and health characteristics.ResultsOf 591 868 unique pregnancies, IIV uptake was 15%, dTpa 27% and 12% received both vaccines. Pertussis vaccinations in First Nations pregnancies were 20% lower than non‐Indigenous pregnancies; dTpa was strongly associated with IIV uptake (risk ratio (RR): 8.60, 95% CI 8.48–8.73). This trend was temporally and jurisdictionally consistent. First Nations women were more likely to have had IIV in pregnancy before the introduction of dTpa in the pregnancy program: (RR: 1.48, 95% CI 1.40–1.57), but less likely after dTpa implementation (RR: 0.78, 95% CI 0.76–0.80).ConclusionsInequity in vaccine uptake between First Nations and non‐Indigenous pregnancies, and dismal rates of vaccination in pregnancy overall need urgent review, particularly before the next influenza pandemic or pertussis outbreak. If antenatal dTpa is driving IIV uptake, changes in antenatal healthcare practices are needed to ensure vaccines are offered equitably and optimally to protect against infection.

Single and multiple ascending PF-07304814 (lufotrelvir) infusions were generally safe and well tolerated in participants hospitalized with COVID-19. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250 and 500 mg/d, respectively. Background An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies.

Abstract Background Pregnancy and early infancy are increased risk periods for severe adverse effects of respiratory infections. Aboriginal and/or Torres Strait Islander (respectfully referred to as First Nations) women and children in Australia bear a disproportionately higher burden of respiratory diseases compared to non-Indigenous women and infants. Influenza vaccines and whooping cough (pertussis) vaccines are recommended and free in every Australian pregnancy to combat these infections. We aimed to assess the equity of influenza and/or pertussis vaccination in pregnancy for three priority groups in Australia: First Nations women; women from culturally and linguistically diverse (CALD) backgrounds; and women living in remote areas or socio-economic disadvantage. Methods We conducted individual record linkage of Perinatal Data Collections with immunisation registers/databases between 2012 and 2017. Analysis included generalised linear mixed model, log-binomial regression with a random intercept for the unique maternal identifier to account for clustering, presented as prevalence ratios (PR) and 95% compatibility intervals (95%CI). Results There were 445,590 individual women in the final cohort. Compared with other Australian women (n = 322,848), First Nations women (n = 29,181) were less likely to have received both recommended antenatal vaccines (PR 0.69, 95% CI 0.67–0.71) whereas women from CALD backgrounds (n = 93,561) were more likely to have (PR 1.16, 95% CI 1.10–1.13). Women living in remote areas were less likely to have received both vaccines (PR 0.75, 95% CI 0.72–0.78), and women living in the highest areas of advantage were more likely to have received both vaccines (PR 1.44, 95% CI 1.40–1.48). Conclusions Compared to other groups, First Nations Australian families, those living in remote areas and/or families from lower socio-economic backgrounds did not receive recommended vaccinations during pregnancy that are the benchmark of equitable healthcare. Addressing these barriers must remain a core priority for Australian health care systems and vaccine providers. An extension of this cohort is necessary to reassess these study findings.

Chronic wet cough for longer than 4 weeks is a hallmark of chronic suppurative lung diseases (CSLD), including protracted bacterial bronchitis (PBB), and bronchiectasis in children. Severe lower respiratory infection early in life is a major risk factor of PBB and paediatric bronchiectasis. In these conditions, failure to clear an underlying endobronchial infection is hypothesised to drive ongoing inflammation and progressive tissue damage that culminates in irreversible bronchiectasis. Historically, the microbiology of paediatric chronic wet cough has been defined by culture-based studies focused on the detection and eradication of specific bacterial pathogens. Various ‘omics technologies now allow for a more nuanced investigation of respiratory pathobiology and are enabling development of endotype-based models of care. Recent years have seen substantial advances in defining respiratory endotypes among adults with CSLD; however, less is understood about diseases affecting children. In this review, we explore the current understanding of the airway microbiome among children with chronic wet cough related to the PBB–bronchiectasis diagnostic continuum. We explore concepts emerging from the gut–lung axis and multi-omic studies that are expected to influence PBB and bronchiectasis endotyping efforts. We also consider how our evolving understanding of the airway microbiome is translating to new approaches in chronic wet cough diagnostics and treatments.

Objectives: In remote communities of northern Australia, First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance compared to their peers with no hearing loss. The aim of this trial is to prevent early childhood persisting otitis media (OM), associated hearing loss and developmental delay. To achieve this, we designed a mixed pneumococcal conjugate vaccine (PCV) schedule that could maximise immunogenicity and thereby prevent bacterial otitis media (OM) and a trajectory of educational and social disadvantage. Methods: In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 to standard or mixed PCV primary schedules at age 28-38 days, then at age 12 months to a booster dose (1:1) of 13-valent PCV, PCV13 (Prevenar13 (R), +P), or 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine, PHiD-CV10 (Synflorix (R), +S). Here we report findings of standardised ear assessments conducted six-monthly from age 12-36 months, by booster dose. Results: From March 2013 to September 2018, 261 children were allocated to booster + P (n = 131) or + S (n = 130). There were no significant differences in prevalence of any OM diagnosis by booster dose or when stratified by primary schedule. We found high, almost identical prevalence of OM in both boost groups at each age (for example 88% of 129 and 91% of 128 children seen, respectively, at primary endpoint age 18 months, difference -3% [95% Confidence Interval-11, 5]). At each age prevalence of bilateral OM was 52%-78%, and tympanic membrane perforation was 10%-18%. Conclusion: Despite optimal pneumococcal immunisation, the high prevalence of OM persists throughout early childhood. Novel approaches to OM prevention are needed, along with improved early identification strategies and evaluation of expanded valency PCVs.

OBJECTIVESFollowing the introduction of jurisdictional maternal pertussis vaccination programs in Australia, we estimated maternal vaccine effectiveness (VE) and whether maternal pertussis vaccination modified the effectiveness of the first 3 primary doses of pertussis-containing vaccines.METHODSWe conducted a population-based cohort study of 279 418 mother-infant pairs using probabilistic linkage of administrative health records in 3 Australian jurisdictions. Infants were maternally vaccinated if their mother had a documented pertussis vaccination ≥14 days before birth. Jurisdictional immunization records were used to identify receipt of the first 3 infant doses of pertussis-containing vaccines. Infant pertussis infections were identified using notifiable disease records. VE was estimated using Cox proportional hazard models.RESULTSPertussis was administered during 51.7% (n = 144 429/279 418) of pregnancies, predominantly at 28-31 weeks' gestation. VE of maternal pertussis vaccination declined from 70.4% (95% confidence interval [CI], 50.5-82.3) among infants <2 months old to 43.3% (95% CI, 6.8-65.6) among infants 7-8 months old and was not significant after 8 months of age. Although we observed slightly lower VE point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% CI, 0.61-3.39).CONCLUSIONSPertussis vaccination near 28 weeks' gestation was associated with lower risk of infection among infants through 8 months of age. Although there was some evidence of lower effectiveness of infant vaccination among maternally vaccinated infants, this did not appear to translate to greater risk of disease.

Fordadistrogene movaparvovec (PF 06939926) is an adeno-associated virus serotype-9 (AAV9) gene-replacement construct containing a mini-dystrophin being developed for DMD, which aims to restore functional protein to muscle. Magnetic resonance imaging (MRI) is an important non-invasive tool that can be used for monitoring disease progression and can inform future functional changes. Here we present 2-yr quantitative MRI measurements from 16 ambulatory participants with a genetic diagnosis of DMD from a phase 1b, multicenter, single-arm, open-label trial (NCT03362502). Fordadistrogene movaparvovec was administered as a single iv dose (2E14 vg/kg). An external reference (ER) cohort was derived from DMD participants (n=48) with ≥1 yr of randomized domagrozumab treatment (active→placebo, placebo→active, or active→active) from trial NCT02310763 and met the eligibility criteria for this trial. Whole thigh MRI scans were acquired at baseline, 6 months, 1-yr, and 2-yrs to evaluate changes in muscle volume (MV) and fat fraction (FF). At baseline, (mean±SD) thigh MV was 1,115±145cm3 and FF was 18.5±4.5% for fordadistrogene movaparvovec vs 1,150±282cm3 and 19.4±5.1% for ER participants. Fordadistrogene movaparvovec participants had a mean %change from baseline (CFB) in MV of 9.0±13.5% at 1-yr and 7.4±16.1% at 2-yrs. ER participants had a mean %CFB in MV of 2.7±8.3% after 1-yr and 2.4±12.1% after 2-yrs. Fordadistrogene movaparvovec participants had a mean CFB in FF of 0.6±2.8% at 1-yr and 3.3±3.2% at 2-yrs. ER participants had a mean CFB in FF of 1.6±2.6% after 1-yr and 3.3±4.1% after 2-yrs.Younger participants 6-7 yrs of age had the larger changes in %CFB in MV: fordadistrogene movaparvovec (n=6): 20.7±13.4% at 1-yr and 22.8±10.9% at 2-yrs vs ER (n=23): 4.5±8.4% at 1-yr and 6.0±13.6% at 2-yrs. After dosing with fordadistrogene movaparvovec, MRI scans of the thigh muscle and upper limb of study participants showed increases in MV and no clear difference in FF vs ER over 2 yrs. Fordadistrogene movaparvovec (PF 06939926) is an adeno-associated virus serotype-9 (AAV9) gene-replacement construct containing a mini-dystrophin being developed for DMD, which aims to restore functional protein to muscle. Magnetic resonance imaging (MRI) is an important non-invasive tool that can be used for monitoring disease progression and can inform future functional changes. Here we present 2-yr quantitative MRI measurements from 16 ambulatory participants with a genetic diagnosis of DMD from a phase 1b, multicenter, single-arm, open-label trial (NCT03362502). Fordadistrogene movaparvovec was administered as a single iv dose (2E14 vg/kg). An external reference (ER) cohort was derived from DMD participants (n=48) with ≥1 yr of randomized domagrozumab treatment (active→placebo, placebo→active, or active→active) from trial NCT02310763 and met the eligibility criteria for this trial. Whole thigh MRI scans were acquired at baseline, 6 months, 1-yr, and 2-yrs to evaluate changes in muscle volume (MV) and fat fraction (FF). At baseline, (mean±SD) thigh MV was 1,115±145cm3 and FF was 18.5±4.5% for fordadistrogene movaparvovec vs 1,150±282cm3 and 19.4±5.1% for ER participants. Fordadistrogene movaparvovec participants had a mean %change from baseline (CFB) in MV of 9.0±13.5% at 1-yr and 7.4±16.1% at 2-yrs. ER participants had a mean %CFB in MV of 2.7±8.3% after 1-yr and 2.4±12.1% after 2-yrs. Fordadistrogene movaparvovec participants had a mean CFB in FF of 0.6±2.8% at 1-yr and 3.3±3.2% at 2-yrs. ER participants had a mean CFB in FF of 1.6±2.6% after 1-yr and 3.3±4.1% after 2-yrs.Younger participants 6-7 yrs of age had the larger changes in %CFB in MV: fordadistrogene movaparvovec (n=6): 20.7±13.4% at 1-yr and 22.8±10.9% at 2-yrs vs ER (n=23): 4.5±8.4% at 1-yr and 6.0±13.6% at 2-yrs. After dosing with fordadistrogene movaparvovec, MRI scans of the thigh muscle and upper limb of study participants showed increases in MV and no clear difference in FF vs ER over 2 yrs.

Invasive meningococcal disease (IMD) causes significant morbidity and mortality worldwide with serogroup B being the predominant serogroup in Australia and other countries for the past few decades. The licensed 4CMenB vaccine is effective in preventing meningococcal B disease. Emerging evidence suggests that although 4CMenB impact on carriage is limited, it may be effective against gonorrhoea due to genetic similarities between Neisseria meningitidis and Neisseria gonorrhoeae. This study protocol describes an observational study that will assess the effect of the 4CMenB vaccine against meningococcal carriage, IMD and gonorrhoea among adolescents in the Northern Territory (NT). All 14–19-year-olds residing in the NT with no contraindication for 4CMenB vaccine will be eligible to participate in this cohort study. Following consent, two doses of 4CMenB vaccine will be administered two months apart. An oropharyngeal swab will be collected at baseline and 12 months to detect pharyngeal carriage of Neisseria meningitidis by PCR. The main methodological approaches to assess the effect of 4CMenB involve a nested case control analysis and screening method to assess vaccine effectiveness and an Interrupted Time Series regression analysis to assess vaccine impact. Research ethics approvals have been obtained from Menzies and Central Australian Human Research Ethics Committees and the Western Australian Aboriginal Health Ethics Committee. Results will be provided in culturally appropriate formats for NT remote and regional communities and published in international peer reviewed journals. ClinicalTrials.gov Identifier: NCT04398849.