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.

Background Pneumonia is the leading cause of death in young children globally and is prevalent in the Papua New Guinea highlands. We investigated clinical predictors of hypoxic pneumonia to inform local treatment guidelines in this resource -limited setting. Methods Between 2013 and 2020, two consecutive prospective observational studies were undertaken enrolling children 0 - 4 years presenting with pneumonia to health-care facilities in Goroka Town, Eastern Highlands Province. Logistic regression models were developed to identify clinical predictors of hypoxic pneumonia (oxygen saturation <90% on presentation). Model performance was compared against established criteria to identify severe pneumonia. Findings There were 2067 cases of pneumonia; hypoxaemia was detected in 36.1%. The strongest independent predictors of hypoxic pneumonia were central cyanosis on examination (adjusted odds ratio [aOR] 5.14; 95% CI 3.47 - 7.60), reduced breath sounds (aOR 2.92; 95% CI 2.30 - 3.71), and nasal fl aring or grunting (aOR 2.34; 95% CI 1.62 - 3.38). While the model developed to predict hypoxic pneumonia outperformed established pneumonia severity criteria, it was not sensitive enough to be clinically useful at this time. Interpretation Given signs and symptoms are unable to accurately detect hypoxia, all health care facilities should be equipped with pulse oximeters. However, for the health care worker without access to pulse oximetry, consideration of central cyanosis, reduced breath sounds, nasal fl aring or grunting, age -speci fi c tachycardia, wheezing, parentreported drowsiness, or bronchial breathing as suggestive of hypoxaemic pneumonia, and thus severe disease, may prove useful in guiding management, hospital referral and use of oxygen therapy.

OBJECTIVE Describe the ear and hearing outcomes in Aboriginal infants in an Australian urban area. DESIGN Aboriginal infants enrolled in the Djaalinj Waakinj prospective cohort study had ear health screenings at ages 2-4, 6-8 and 12-18 months and audiological assessment at ∼12 months of age. Sociodemographic, environmental characteristics, otoscopy, otoacoustic emissions, tympanometry and visual reinforcement audiometry data were collected. STUDY SAMPLE 125 infants were enrolled in the study; 67 completed audiological assessment, 62, 54, and 58 of whom attended ear screenings at 2-4, 6-8 and 12-18 months. RESULTS Of the children that attended the audiological assessment, 36.5%, 50% and 64.3% of infants had otitis media (OM) at 2-4, 6-8 and 12-18 months. Using a 10 dB correction factor, 44.8% of infants had hearing loss (HL) (≥ 25 dB HL) at ∼ 12 months of age. More males (X2=5.4 (1df, p = 0.02)) and infants with OM at audiological assessment (X2=5.8 (1df, p = 0.02)) had HL. More infants that used a pacifier at 12-18 months of age had HL (X2=4.7 (1df, p = 0.03)). CONCLUSION Aboriginal infants in an urban area have high rates of HL and OM, which requires early surveillance and timely treatment to reduce the medical and developmental impacts of OM and HL.

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.

AimAustralian Aboriginal and/or Torres Strait Islander children in rural/remote areas suffer high rates of persistent otitis media (OM) from early infancy. We aimed to determine the proportion of Aboriginal infants living in an urban area who have OM and investigate associated risk factors.MethodsBetween 2017 and 2020, the Djaalinj Waakinj cohort study enrolled 125 Aboriginal infants at 0–12 weeks of age in the Perth South Metropolitan region, Western Australia. Proportion of children with OM based on tympanometry at ages 2, 6 and 12 months was evaluated, type B tympanogram indicating middle ear effusion. Potential risk factors were investigated by logistic regression with generalised estimating equations.ResultsThe proportion of children with OM was 35% (29/83) at 2 months, 49% (34/70) at 6 months and 49% (33/68) at 12 months of age. About 70% (16/23) of those with OM at ages 2 and/or 6 months had OM at 12 months compared with 20% (3/15) if no prior OM (relative risk = 3.48, 95% confidence interval (CI): 1.22–40.1). On multivariate analysis, infants living in houses with ≥1 person/room were at increased risk of OM (odds ratio = 1.78, 95% CI: 0.96–3.32).ConclusionApproximately half of Aboriginal infants enrolled into the South Metropolitan Perth project have OM by the age of 6 months and early onset of disease strongly predicts subsequent OM. Early surveillance for OM in urban areas is needed for early detection and management to reduce the risk of long‐term hearing loss which can have serious developmental, social, behavioural, educational and economic consequences.

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.

Background: Children in Papua New Guinea (PNG) are at high risk of pneumococcal infections. We investigated pneumococcal carriage rates, serotype distribution, and antimicrobial susceptibility in PNG children after vaccination with 10-valent or 13-valent pneumococcal conjugate vaccines (PCV10; PCV13). Methods: Infants (N = 262) were randomized to receive 3 doses of PCV10 or PCV13 at 1-2-3 months of age, followed by pneumococcal polysaccharide vaccination (PPV) or no PPV at 9 months of age. Nasopharyngeal swabs (NPS) collected at ages 1, 4, 9, 10, 23 and 24 months were cultured using standard bacteriological procedures. Morphologically distinct Streptococcus pneumoniae colonies were serotyped by the Quellung reaction. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion and minimum inhibitory concentration (MIC). Results: S. pneumoniae was isolated from 883/1063 NPS collected at 1-23 months of age, including 820 serotypeable (64 different serotypes) and 144 non-serotypeable isolates. At age 23 months, 93.6% (95%CI 86.6-97.6%) of PCV10 recipients and 88.6% (95%CI 80.1-94.4%) of PCV13 recipients were pneumococcal carriers, with higher carriage of PCV10 serotypes by PCV10 recipients (19.8%, 95%CI 12.2-29.5) than PCV13 recipients (9.3%, 95%CI 4.1-17.3) (p = 0.049). There were no other statistically significant differences between PCV10 and PCV13 recipients and children receiving PPV or no PPV. Nearly half (45.6%) of carried pneumococci were non-susceptible to penicillin based on the meningitis breakpoint (MIC >= 0.12 mu g/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC >= 8 mu g/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19-2/38 mu g/mL) and 16.9% full resistance (MIC >= 4/76 mu g/mL). PCV serotypes 14 and 19A were commonly non-susceptible to both penicillin (14, 97%; 19A, 70%) and SXT (14, 97%; 19A, 87%). Conclusion: Even after PCV10 or PCV13 vaccination, children living in a high-risk setting such as PNG continue to experience high levels of pneumococcal colonization, including carriage of highly antimicrobial-resistant PCV serotypes.

Background:Pneumonia is a leading cause of childhood mortality with Streptococcus pneumoniae a major contributor. Pneumococcal conjugate vaccines (PCVs) have been introduced into immunisation programs in many low- to middle-income countries (LMICs) yet there is a paucity of data evaluating the effectiveness in these settings. We assess the effectiveness of 13-valent PCV (13vPCV) against hypoxic pneumonia, hospitalisation and other clinical endpoints in children <5 years living in Eastern Highlands Province, Papua New Guinea (PNG). Methods:Data from two consecutive prospective observational studies (2013-2019) enrolling children <60 months presenting with pneumonia were included. Hypoxic pneumonia was defined as oxygen saturations <90%. Outcomes included hospitalisation, severe clinical pneumonia and death. 13vPCV status was determined using written records. Logistic regression models were used to estimate the odds ratios of key outcomes by 13vPCV vaccination status adjusted for confounders using inverse probability of treatment weighting. Findings:Data from 2067 children (median age; 9 months [IQR: 5-11]) were included. 739 children (36.1%) were hypoxic and 623 (30.4%) hospitalised. Twelve children (0.6% of total cohort) died in hospital. 670 children (32.7%) were fully 13vPCV-vaccinated. 13vPCV vaccination was associated with a 28.7% reduction (95% confidence interval [CI]: 9.9; 43.6%) in hypoxic pneumonia and a 57.4% reduction (38.0; 70.7%) in pneumonia hospitalisation. Interpretation:13vPCV vaccination is effective against hypoxic pneumonia and pneumonia hospitalisation in PNG children. Strategies to improve access to and coverage of 13vPCV in PNG and other similar LMICs are urgently required. Funding:Funded by Pfizer Global and the Bill & Melinda Gates Foundation.

Otitis media and associated hearing loss are highly prevalent in Indigenous Australian children.1 Most relevant prevalence studies have been undertaken in rural and remote regions, although most Indigenous children live in urban areas.2 One prospective cohort study found that hearing loss was frequent in young Aboriginal children in a semi-arid zone of Western Australia,3 but its prevalence in Aboriginal infants in urban areas has not been investigated.4 We therefore estimated the prevalence of hearing loss in Aboriginal infants in Perth, Western Australia, enrolled in the Djaalinj Waakinj cohort study (2017–2021),5 and examined the association between otitis media and hearing responses. The Djaalinj Waakinj methodology has been described in detail elsewhere.5 Infants underwent routine ear health screenings in their homes at 2–4, 6–8, and 12–18 months of age. A formal hearing assessment was conducted at 9–12 months of age, using free-field visual reinforcement audiometry in a sound-treated room to determine hearing responses at 500, 1000, 2000, and 4000 Hz.6 The mean hearing response for the more sensitive ear was classified as normal (25 dB), mild (26–40 dB), moderate (41–60 dB) and severe hearing loss (61 dB or more).7 The presence of middle ear effusion was assessed using tympanometry. Findings were classified by an audiologist: type A tympanograms were deemed to indicate normal middle ear function (no otitis media), type B tympanograms probable otitis media, and type C tympanograms probable Eustachian tube dysfunction. The Djaalinj Waakinj study was approved by the Western Australian Aboriginal Human Ethics Committee (WAAHEC #759) and the Child and Adolescent Health Services Human Ethics Research Committee (CAHS HREC #12). Sixty-seven of the 125 enrolled infants completed formal hearing assessments (mean age, 12.1 months; standard deviation, 2.3 months; range, 9–21 months); 41 were boys (61%). Twenty-one of the 67 infants (31%) had normal hearing, 46 (69%) had some degree of hearing loss (mean response, 36.0 dB; 95% confidence interval [CI], 33.3–38.7 dB), including 22 with mild (33%) and 24 with moderate hearing loss (36%). Mean hearing responses were poorer for the 35 infants with abnormal tympanograms at the time of hearing assessment (40.7 dB; 95% CI, 37.0–44.9 dB) than for the 30 infants with normal tympanograms (30.9 dB; 95% CI, 27.8–33.6 dB) (Box). * Normal: type A tympanogram (30 infants); abnormal: type B (30 infants) or type C (five infants). Tympanograms were not available for two infants. Visual reinforcement audiometry was performed with GSI 61 (Grason–Stadler), Equinox (Interacoustics), and Avant (MedRx) audiometers, using pure tone, warble, or filtered narrowband noise stimuli through loudspeakers one metre from the child’s ear at an angle of 90°. Tympanometry was conducted using either Titan Middle Ear Analyser (Interacoustics) or GSI 39 or MI 44 tympanometers (Maico). Our finding that 69% of urban Aboriginal infants in our study had hearing loss at about twelve months of age is comparable with that of a similar study in Kalgoorlie (65%).3 Hearing assessments in infants are based on minimum response levels rather than hearing thresholds,6 which probably explains the apparent mild hearing loss in infants with normal tympanograms. The mean hearing response in these children was nevertheless about 10 dB better than in infants with abnormal tympanograms. The mean hearing response in infants with abnormal tympanograms was 40.7 dB, a level at which they would not hear normal voices clearly, with implications for later speech, language, and behavioural development.8 Our findings support early monitoring of otitis media and hearing loss in Indigenous children, with prompt referral for audiological assessment as recommended by Australian otitis media guidelines.1 This investigation was supported by a research grant from the Western Australia Department of Health Telethon–Perth Children’s Hospital Research Fund and by the Wesfarmers Centre for Vaccines and Infectious Diseases at the Telethon Kids Institute. Chris Brennan-Jones was supported by a National Health and Medical Research Council Fellowship (GNT 1142897) and a Western Australian Department of Health Emerging Leader Fellowship. We acknowledge that this research was undertaken on Noongar Whadjuk Boodja, and acknowledge their Elders past, present and emerging. We acknowledge all members of the Djaalinj Waakinj team and the Aboriginal Community Advisory Group (listed in reference 5). Open access publishing facilitated by The University of Western Australia, as part of the Wiley - The University of Western Australia agreement via the Council of Australian University Librarians. No relevant disclosures.

Background Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules. Methods PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0.35 mu g/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849). Findings Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related. Interpretation Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children. Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved.

Background Serotype 24F is one of the emerging pneumococcal serotypes after the introduction of pneumococcal conjugate vaccine (PCV). We aimed to identify lineages driving the increase of serotype 24F in France and place these findings into a global context. Methods Whole-genome sequencing was performed on a collection of serotype 24F pneumococci from asymptomatic colonisation (n=229) and invasive disease (n=190) isolates among individuals younger than 18 years in France, from 2003 to 2018. To provide a global context, we included an additional collection of 24F isolates in the Global Pneumococcal Sequencing (GPS) project database for analysis. A Global Pneumococcal Sequence Cluster (GPSC) and a clonal complex (CC) were assigned to each genome. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted using the same 24F collection and supplemented with a global collection of genomes belonging to the lineage of interest from the GPS project database (n=25 590). Findings Serotype 24F was identified in numerous countries mainly due to the clonal spread of three lineages: GPSC10 (CC230), GPSC16 (CC156), and GPSC206 (CC7701). GPSC10 was the only multidrug-resistant lineage. GPSC10 drove the increase in 24F in France and had high invasive disease potential. The international dataset of GPSC10 (n=888) revealed that this lineage expressed 16 other serotypes, with only six included in 13-valent PCV (PCV13). All serotype 24F isolates were clustered in a single clade within the GPSC10 phylogeny and long-range transmissions were detected from Europe to other continents. Spatiotemporal analysis showed GPSC10-24F took 3-5 years to spread across France and a rapid change of serotype composition from PCV13 serotype 19A to 24F during the introduction of PCV13 was observed in neighbouring country Spain. Interpretation Our work reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.

Streptococcus pneumoniae is a key contributor to childhood morbidity and mortality in Papua New Guinea (PNG). For the first time, whole genome sequencing of 174 isolates has enabled detailed characterisation of diverse S. pneumoniae causing invasive disease in young children in PNG, 1989-2014. This study captures the baseline S. pneumoniae population prior to the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into the national childhood immunisation programme in 2014. Relationships amongst lineages, serotypes and antimicrobial resistance traits were characterised, and the population was viewed in the context of a global collection of isolates. The analyses highlighted adiverse S. pneumoniae population associated with invasive disease in PNG, with 45 unique Global Pneumococcal Sequence Clusters (GPSCs) observed amongst the 174 isolates reflecting multiple lineages observed in PNG that have not been identified in other geographic locations. The majority of isolates were from children with meningitis, of which 52% (n=72) expressed non-PCV13 serotypes. Over a third of isolates were predicted to be resistant to at least one antimicrobial. PCV13 serotype isolates had 10.1 times the odds of being multidrug-resistant (MDR) compared to non-vaccine serotype isolates, and no isolates with GPSCs unique to PNG were MDR. Serotype 2 was the most commonly identified serotype; we identified a highly clonal cluster of serotype 2 isolates unique to PNG, and a distinct second cluster indicative of long-distance transmission. Ongoing surveillance, including whole-genome sequencing, is needed to ascertain the impact of the national PCV13 programme upon the S. pneumoniae population, including serotype replacement and antimicrobial resistance traits.

Background: Papua New Guinea (PNG) introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in 2014, with administration at 1, 2, and 3 months of age. PCV13 has reduced or eliminated carriage of vaccine types in populations with low pneumococcal carriage prevalence, carriage density and serotype diversity. This study investigated PCV13 impact on serotype-specific pneumococcal carriage prevalence, density, and serotype diversity in PNG infants, who have some of the highest reported rates of pneumococcal carriage and disease in the world. Methods: Nasopharyngeal swabs were collected at 1, 4 and 9 months of age from PCV13-vaccinated infants (n = 57) and age-/season-matched, unvaccinated infants (at approximately 1 month, n = 53; 4 months, n = 57; 9 months, n = 52). Serotype-specific pneumococcal carriage density and antimicrobial resistance genes were identified by qPCR and microarray. Results: Pneumococci were present in 89% of swabs, with 60 different serotypes and four non-encapsulated variants detected. Multiple serotype carriage was common (47% of swabs). Vaccine type carriage prevalence was similar between PCV13-vaccinated and unvaccinated infants at 4 and 9 months of age. The prevalence of non-vaccine type carriage was also similar between cohorts, with non-vaccine types present in three-quarters of samples (from both vaccinated and unvaccinated infants) by 4 months of age. The median pneumococcal carriage density was high and similar at each age group (similar to 7.0 log(10)-in genome equivalents/mL). PCV13 had no effect on overall pneumococcal carriage density, vaccine type density, non-vaccine type density, or the prevalence of antimicrobial resistance genes. Conclusion: PNG infants experience dense and diverse pneumococcal colonisation with concurrent serotypes from 1 month of age. PCV13 had no impact on pneumococcal carriage density, even for vaccine serotypes. The low prevalence of vaccine serotypes, high pneumococcal carriage density and abundance of non-vaccine serotypes likely contribute to the lack of PCV13 impact on carriage in PNG infants. Indirect effects of the infant PCV programs are likely to be limited in PNG. Alternative vaccines with broader coverage should be considered. (C) 2021 The Authors. Published by Elsevier Ltd.

We examined the association between otitis media (OM) and educational attainment in a retrospective population cohort of Western Australian children who participated in the grade 3 National Assessment Program—Literacy and Numeracy in 2012 (N = 19,262). Literacy and numeracy scores were linked to administrative hospital and emergency department data to identify secondary care episodes for OM. Results of multivariate multilevel models showed that children with OM episodes had increased odds of poor performance on literacy and numeracy tests, compared to children without OM episodes (46–79% increase in odds for Aboriginal children; 20–31% increase in odds for non-Aboriginal children). There were no significant effects found for age at the first episode, nor for OM episode frequency (all ps > 0.05). Regardless of the timing or frequency of episodes, children with OM episodes are at risk of poor literacy and numeracy attainment. Aboriginal children with OM appeared to be particularly at risk of poor literacy and numeracy achievement. Intervention to reduce the prevalence of otitis media in young children, and early treatment of OM, are important for limiting the negative effects on academic outcomes.

The 2001 Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Islander populations were revised in 2010. This 2020 update by the Centre of Research Excellence in Ear and Hearing Health of Aboriginal and Torres Strait Islander Children used for the first time the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Background: Nasopharyngeal colonisation with nontypeable Haemophilus influenzae (NTHi) is associated with development of infections including pneumonia and otitis media. The 10-valent pneumococcal conjugate vaccine (PCV10) uses NTHi Protein D (PD) as a carrier. Papua New Guinean children have exceptionally early and dense NTHi carriage, and high rates of NTHi-associated disease. Vaccination with PCV10 could potentially reduce NTHi carriage and disease in this population by inducing a NTHi PD immune response. Methods: Serum and nasopharyngeal swabs were collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age. Children received PCV10 (n = 55) or PCV13 (not containing NTHi PD) (n = 46) at 1, 2 and 3 months of age. NTHi carriage density was measured in swabs by qPCR. Serum PD-IgG levels were measured by bead-based immunoassay. Results: Papua New Guinean children did naturally develop PD-IgG antibodies whose levels were increased at 4 months of age with PCV10 vaccination at 1-2-3 months. Despite this, most children were colonised with NTHi by 4 months of age (similar to 95%) regardless of being vaccinated with PCV10 or PCV13, and PCV10 had no impact on NTHi carriage density. Conclusion: Early vaccination of infants with PCV10 elicited a robust PD antibody response but this had no impact on NTHi carriage. (C) 2021 The Authors. Published by Elsevier Ltd.

Abstract Background Pneumonia is the leading cause of death in young children globally and is prevalent in the highlands of Papua New Guinea (PNG). We investigated clinical predictors of severe pneumonia to inform local treatment guidelines in this resource-limited setting. Methods Between 2013 and 2020, prospective studies were undertaken enrolling children <5 years presenting with pneumonia to health-care facilities in Goroka Town, Eastern Highlands Province. Physical examination findings and blood cultures were collected. Logistic regression analyses were performed to determine predictors of hypoxaemia (oxygen saturation <90% on presentation), bacteraemia and death. Results There were 2067 cases of pneumonia, hypoxaemia was detected in 36.1%. Bacteraemia was identified in 47/1943 (2.4%) blood cultures. Of 1444 children followed up, 18 (1.2%) died. Central cyanosis (odds ratio 3.82, 95% CI 2.55-5.71) and reduced breath sounds (2.77, 2.17-3.53) independently predicted hypoxaemia; altered consciousness (21.44, 3.91-117.48), bronchial breathing (10.49, 2.01-54.63) and apnoea (2.54, 1.26-5.14) independently predicted bacteraemia; and altered consciousness (20.95, 2.32-189.00), reduced skin turgor (14.43 (4.79-43.49) and central cyanosis (5.96, 2.13-16.66) independently predicted death. Conclusions In children with pneumonia in the PNG highlands, those with central cyanosis, apnoea, bronchial breathing, altered consciousness or reduced skin turgor are at greatest risk of severe outcomes. Ongoing training of health care workers is essential to ensure these signs are recognised and appropriate management promptly instituted. Key messages Prompt recognition of signs of severity is likely to lead to better outcomes for children in PNG with pneumonia. These findings will inform future modifications to local treatment guidelines.

Background Development of vaccines to prevent disease and death from Streptococcus pneumoniae, and nontypeable Haemophilus influenzae (NTHi), the main pathogens that cause otitis media, pneumonia, meningitis and sepsis, are a global priority. Children living in low and lower-middle income settings are at the highest risk of contracting and dying from these diseases. Improved vaccines with broader coverage are required. Data on the natural development of antibodies to putative vaccine antigens, especially in high-risk settings, can inform the rational selection of the best antigens for vaccine development. Methods Serum IgG titres to four pneumococcal proteins (PspA1, PspA2, CbpA, and Ply) and five NTHi antigens (P4, P6, OMP26, rsPilA and ChimV4) were measured in sera collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age using multiplexed bead-based immunoassays. Carriage density of S. pneumoniae and H. influenzae were assessed by quantitative PCR on genomic DNA extracted from nasopharyngeal swabs using species-specific primers and probes. All data were log-transformed for analysis using Student’s unpaired t-tests with geometric mean titre (GMT) or density (GMD) calculated with 95% confidence intervals (CI). Results Serum -pneumococcal protein-specific IgG titres followed a “U” shaped pattern, with a decrease in presumably maternally-derived IgG titres between 1 and 4 months of age and returning to similar levels as those measured at 1 month of age by 24 months of age. In contrast, NTHi protein-specific IgG titres steadily increased with age. There was no correlation between antibody titres and carriage density for either pathogen. Conclusion This longitudinal study indicates that the waning of maternally- derived antibodies that is usually observed in infants, after infants does not occur for NTHi antigens in Papua New Guinean infants. Whether NTHi antigen IgG can be transferred maternally remains to be determined. Vaccines that are designed to specifically increase the presence of protective NTHi antibodies in the first few months of life may be most effective in reducing NTHi disease. Clinical Trial Registration https://clinicaltrials.gov/, identifier NCT01619462.

Introduction Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.Methods and analyses Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.Ethics and dissemination Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.Trial registration number NCT01735084.

Introduction: Invasive pneumococcal disease remains a major cause of hospitalization and death in Papua New Guinean (PNG) children. We assessed mucosal IgA and IgG responses in PNG infants vaccinated with pneumococcal conjugate vaccine (PCV) followed by a pneumococcal polysaccharide vaccine (PPV) booster. Methods: Infants received 7-valent PCV (7vPCV) in a 0-1-2 (neonatal) or 1-2-3-month (infant) schedule, or no 7vPCV (control). At age 9 months all children received 23-valent PPV (23vPPV). IgA and IgG to 7vPCV and non-7vPCV (1, 5, 7F, 19A) serotypes were measured in saliva collected at ages 1, 2, 3, 4, 9, 10 and 18 months (131 children, 917 samples). Correlations were studied between salivary and serum IgG at 4, 10 and 18 months. Results: Salivary IgA and IgG responses overall declined in the first 9 months. Compared to non-7vPCV recipients, salivary IgA remained higher in 7vPCV recipients for serotypes 4 at 3 months, 6B at 3 months (neonatal), and 14 at 3 (neonatal), 4 and 9 months (infant); and for salivary IgG for serotypes 4 at 3, 4 and 9 months, 6B at 9 months, 14 at 4 (neonatal) and 9 months, 18C at 3, 4, and 9 (infant) months, and 23F at 4 months. Following 23vPPV, salivary 7vPCV-specific IgA and IgG increased in 7vPCV-vaccinated children but not in controls; and salivary IgA against non-PCV serotypes 5 and 7F increased in 7vPCV recipients and non-recipients. Salivary and serum IgG against 7vPCV-serotypes correlated in 7vPCV-vaccinated children at 4 and 10 months of age. Conclusions: PCV may protect high-risk children against pneumococcal colonization and mucosal disease by inducing mucosal antibody responses and priming for mucosal immune memory that results in mucosal immune responses after booster PPV. Saliva can be a convenient alternative sample to serum to study PCV-induced systemic IgG responses. (C) 2020 The Authors. Published by Elsevier Ltd.