Hearing loss in Australian First Nations children at 6-monthly assessments from age 12 to 36 months: Secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.

BACKGROUND: In 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 FINDINGS: In 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. CONCLUSIONS: In 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 REGISTRATION: ClinicalTrials.gov NCT01735084 and NCT01174849.

Clinical predictors of hypoxic pneumonia in children from the Eastern Highlands Province, Papua New Guinea: secondary analysis of two prospective observational studies.

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 flaring 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 flaring or grunting, age-specific tachycardia, wheezing, parent-reported 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. Funding: Funded by Pfizer Global and the Bill & Melinda Gates Foundation.

Ear and hearing outcomes in Aboriginal infants living in an urban Australian area: the Djaalinj Waakinj birth cohort study.

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.

Pneumococcal carriage, serotype distribution, and antimicrobial susceptibility in Papua New Guinean children vaccinated with PCV10 or PCV13 in a head-to-head trial.

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 µg/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC ≥ 8 µg/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19-2/38 µg/mL) and 16.9% full resistance (MIC ≥ 4/76 µg/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. The study is registered with ClinicalTrials.gov (CTN NCT01619462).

Early onset of otitis media is a strong predictor of subsequent disease in urban Aboriginal infants: Djaalinj Waakinj cohort study.

AIM: Australian 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. METHODS: Between 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. RESULTS: The 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). CONCLUSION: Approximately 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.

Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study.

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. FUNDING: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention.

Distinct Streptococcus pneumoniae cause invasive disease in Papua New Guinea.

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.

Immunogenicity, otitis media, hearing impairment, and nasopharyngeal carriage 6-months after 13-valent or ten-valent booster pneumococcal conjugate vaccines, stratified by mixed priming schedules: PREVIX_COMBO and PREVIX_BOOST randomised controlled trials.

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 µg/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. FUNDING: National Health and Medical Research Council (NHMRC).

Effectiveness of 13-valent pneumococcal conjugate vaccine against hypoxic pneumonia and hospitalisation in Eastern Highlands Province, Papua New Guinea: An observational cohort study.

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.

Children with Secondary Care Episodes for Otitis Media Have Poor Literacy and Numeracy Outcomes: A Data Linkage Study.

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.

Lack of effectiveness of 13-valent pneumococcal conjugate vaccination against pneumococcal carriage density in Papua New Guinean infants.

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 (~7.0 log10genome 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.

Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life.

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.

PCV10 elicits Protein D IgG responses in Papua New Guinean children but has no impact on NTHi carriage in the first two years of life.

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 (~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. TRIAL REGISTRATION: ClinicalTrials.gov CTN NCT01619462.

Otitis media guidelines for Australian Aboriginal and Torres Strait Islander children: summary of recommendations.

INTRODUCTION: 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. MAIN RECOMMENDATIONS: We performed systematic reviews of evidence across prevention, diagnosis, prognosis and management. We report ten algorithms to guide diagnosis and clinical management of all forms of otitis media. The guidelines include 14 prevention and 37 treatment strategies addressing 191 questions. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINES: A GRADE approach is used. Targeted recommendations for both high and low risk children. New tympanostomy tube otorrhoea section. New Priority 5 for health services: annual and catch-up ear health checks for at-risk children. Antibiotics are strongly recommended for persistent otitis media with effusion in high risk children. Azithromycin is strongly recommended for acute otitis media where adherence is difficult or there is no access to refrigeration. Concurrent audiology and surgical referrals are recommended where delays are likely. Surgical referral is recommended for chronic suppurative otitis media at the time of diagnosis. The use of autoinflation devices is recommended for some children with persistent otitis media with effusion. Definitions for mild (21-30 dB) and moderate (> 30 dB) hearing impairment have been updated. New "OMapp" enables free fast access to the guidelines, plus images, animations, and multiple Aboriginal and Torres Strait Islander language audio translations to aid communication with families.

An observational study of the reactogenicity and immunogenicity of 13-valent pneumococcal conjugate vaccine in women of childbearing age in Papua New Guinea.

BACKGROUND: Maternal immunization with pneumococcal conjugate vaccine (PCV) may protect young infants in high-risk settings against the high risk of pneumococcal infections in early life. The aim of this study was to determine the safety and immunogenicity of 13-valent PCV (PCV13) in healthy women of childbearing age in PNG. METHODS: As part of this observational study, 50 non-pregnant women of childbearing age (18-45 yrs. old) living in the highlands of PNG were vaccinated with a single dose of PCV13. Local and systemic reactogenicity were assessed 24-48 h after vaccination. Venous blood samples were collected before and 1 month after vaccination to measure PCV13 serotype-specific IgG antibody concentrations. RESULTS: No severe adverse effects were reported during the 1-month follow-up period. IgG antibody concentrations significantly increased after vaccination for all PCV13 serotypes. One month after vaccination IgG antibody levels ≥2.5 µg/mL were reached in at least 75% of women for all PCV13 serotypes, except serotype 3, and ≥ 5 µg/mL in at least 75% of women for 7 serotypes (serotypes 6B, 9 V, 14, 18C, 19A, 19F and 23F). CONCLUSION: PCV13 is safe and immunogenic in women of childbearing age living in a high-risk setting in PNG. This supports the implementation of studies to investigate the safety and immunogenicity of maternal PCV vaccination in high-risk settings as a strategy to protect infants in these settings against the high risk of pneumococcal infections in early life. TRIAL REGISTRATION: NCT04183322 . Registered 3 December 2019 - Retrospectively registered.

Pneumococcal conjugate vaccine primes mucosal immune responses to pneumococcal polysaccharide vaccine booster in Papua New Guinean children.

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.

10-Valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine (PHiD-CV10) versus 13-valent pneumococcal conjugate vaccine (PCV13) as a booster dose to broaden and strengthen protection from otitis media (PREVIX_BOOST) in Australian Aboriginal children: study protocol for a randomised controlled trial.

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.

Australian Aboriginal children have higher hospitalization rates for otitis media but lower surgical procedures than non-Aboriginal children: A record linkage population-based cohort study.

INTRODUCTION: Otitis media (OM) is one of the most common infectious diseases affecting children globally and the most common reason for antibiotic prescription and paediatric surgery. Australian Aboriginal children have higher rates of OM than non-Aboriginal children; however, there are no data comparing OM hospitalization rates between them at the population level. We report temporal trends for OM hospitalizations and in-hospital tympanostomy tube insertion (TTI) in a cohort of 469,589 Western Australian children born between 1996 and 2012. MATERIALS AND METHODS: We used the International Classification of Diseases codes version 10 to identify hospitalizations for OM or TTI recorded as a surgical procedure. Using age-specific population denominators, we calculated hospitalization rates per 1,000 child-years by age, year and level of socio-economic deprivation. RESULTS: There were 534,674 hospitalizations among 221,588 children hospitalized at least once before age 15 years. Aboriginal children had higher hospitalization rates for OM than non-Aboriginal children (23.3/1,000 [95% Confidence Interval (CI) 22.8,24.0] vs 2.4/1,000 [95% CI 2.3,2.4] child-years) with no change in disparity over time. Conversely non-Aboriginal children had higher rates of TTI than Aboriginal children (13.5 [95% CI 13.2,13.8] vs 10.1 [95% CI 8.9,11.4]). Children from lower socio-economic backgrounds had higher OM hospitalization rates than those from higher socio-economic backgrounds, although for Aboriginal children hospitalization rates were not statistically different across all levels of socio-economic disadvantage. Hospitalizations for TTI among non-Aboriginal children were more common among those from higher socio-economic backgrounds. This was also true for Aboriginal children; however, the difference was not statistically significant. There was a decline in OM hospitalization rates between 1998 and 2005 and remained stable thereafter. CONCLUSION: Aboriginal children and children from lower socio-economic backgrounds were over-represented with OM-related hospitalizations but had fewer TTIs. Despite a decrease in OM and TTI hospitalization rates during the first half of the study for all groups, the disparity between Aboriginal and non-Aboriginal children and between those of differing socioeconomic deprivation remained.

The epidemiological transition in Papua New Guinea: new evidence from verbal autopsy studies.

BACKGROUND: Recent economic growth in Papua New Guinea (PNG) would suggest that the country may be experiencing an epidemiological transition, characterized by a reduction in infectious diseases and a growing burden from non-communicable diseases (NCDs). However, data on cause-specific mortality in PNG are very sparse, and the extent of the transition within the country is poorly understood. METHODS: Mortality surveillance was established in four small populations across PNG: West Hiri in Central Province, Asaro Valley in Eastern Highlands Province, Hides in Hela Province and Karkar Island in Madang Province. Verbal autopsies (VAs) were conducted on all deaths identified, and causes of death were assigned by SmartVA and classified into five broad disease categories: endemic NCDs; emerging NCDs; endemic infections; emerging infections; and injuries. Results from previous PNG VA studies, using different VA methods and spanning the years 1970 to 2001, are also presented here. RESULTS: A total of 868 deaths among adolescents and adults were identified and assigned a cause of death. NCDs made up the majority of all deaths (40.4%), with the endemic NCD of chronic respiratory disease responsible for the largest proportion of deaths (10.5%), followed by the emerging NCD of diabetes (6.2%). Emerging infectious diseases outnumbered endemic infectious diseases (11.9% versus 9.5%). The distribution of causes of death differed across the four sites, with emerging NCDs and emerging infections highest at the site that is most socioeconomically developed, West Hiri. Comparing the 1970-2001 VA series with the present study suggests a large decrease in endemic infections. CONCLUSIONS: Our results indicate immediate priorities for health service planning and for strengthening of vital registration systems, to more usefully serve the needs of health priority setting.