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Background Aboriginal children in Northern Australia have a high burden of otitis media, driven by early and persistent nasopharyngeal carriage of otopathogens, including non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). In this context, does a combined mixed primary series of Synflorix and Prevenar13 provide better protection against nasopharyngeal carriage of NTHi and Spn serotypes 3, 6A and 19A than either vaccine alone? Methods Aboriginal infants (n = 425) were randomised to receive Synflorix™ (S, PHiD-CV10) or Prevenar13™ (P, PCV13) at 2, 4 and 6 months (_SSS or _PPP, respectively), or a 4-dose early mixed primary series of PHiD-CV10 at 1, 2 and 4 months and PCV13 at 6 months of age (SSSP). Nasopharyngeal swabs were collected at 1, 2, 4, 6 and 7 months of age. Swabs of ear discharge were collected from tympanic membrane perforations. Findings At the primary endpoint at 7 months of age, the proportion of nasopharyngeal (Np) swabs positive for PCV13-only serotypes 3, 6A, or 19A was 0%, 0.8%, and 1.5% in the _PPP, _SSS, and SSSP groups respectively, and NTHi 55%, 52%, and 52% respectively, and no statistically significant vaccine group differences in other otopathogens at any age. The most common serotypes (in order) were 16F, 11A, 10A, 7B, 15A, 6C, 35B, 23B, 13, and 15B, accounting for 65% of carriage. Ear discharge swabs (n = 108) were culture positive for NTHi (52%), S. aureus (32%), and pneumococcus (20%). Conclusions Aboriginal infants experience nasopharyngeal colonisation and tympanic membrane perforations associated with NTHi, non-PCV13 pneumococcal serotypes and S. aureus in the first months of life. Nasopharyngeal carriage of pneumococcus or NTHi was not significantly reduced in the early 4-dose combined SSSP group compared to standard _PPP or _SSS schedules at any time point. Current pneumococcal conjugate vaccine formulations do not offer protection from early onset NTHi and pneumococcal colonisation in this high-risk population.

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.

Background The prevalence of otitis media (OM) and related hearing loss has remained persistently high among some groups of Australian Aboriginal children who are also reported to have poor academic outcomes. The general literature remains inconclusive about the association between OM-related hearing loss and academic performance in primary school. This study aimed to investigate this association in Aboriginal children living in the Northern Territory (NT) of Australia. Methods A retrospective, observational cohort study was conducted for 2208 NT Aboriginal children, aged about 8 years, living in remote and very remote communities. The explanatory variable was audiometrically determined hearing level as recorded in the Remote Hearing Assessment dataset. The outcome variable consisted of scale scores in the five domains of the National Assessment Program – Literacy and Numeracy (NAPLAN) for Year 3. Other linked datasets used in the study included school attendance records, perinatal records and community level information on relative remoteness, socioeconomic disadvantage and housing crowdedness. Fixed effects linear regression models were used for statistical analyses. Results Compared with children with normal hearing and after controlling for a range of covariates, children with mild hearing impairment (HI) scored lower in Writing and Spelling by 15.0 points (95% CI: − 22.4 to − 7.6, p p = 0.037), equivalent to 7.3 and 2.1% of the mean score, respectively. Children with moderate or worse HI scored lower in Writing and Numeracy by 13.4 points (95% CI, − 24.8 to − 1.9, p = 0.022) and 15.2 points (95% CI, − 27.6 to − 2.7, p = 0.017), both equivalent to 6.3% of the mean score the respective domain. Other factors associated with poorer NAPLAN results included being male, lower Year 2 school attendance, low birthweight, average household size> 5 persons, living in a very remote community and speaking English as a second language. Conclusions OM-related HI was independently associated with poorer early year academic achievement in Aboriginal children living in remote NT communities. Interventions to improve academic outcomes for Aboriginal children must incorporate actions to address the negative impact associated with HI through early detection, effective treatment and ongoing support for affected children.

AIM To investigate the association between hearing impairment (HI) and measures of early childhood development in Aboriginal children at age 5 years. METHODS An observational cohort study (n = 1037) of children aged 4.0-7.3 years (median 5.4 years), living in remote Northern Territory (NT) communities, was conducted using multiple linked administrative datasets, including the NT Perinatal Data Register, Remote Hearing Assessment records (2007-2015) and Australian Early Development Censuses (AEDC, 2009, 2012 and 2015). Outcome measures were summary and domain-specific AEDC results using both dichotomous and continuous variables (domain scores). RESULTS Compared with normal hearing children, after adjustment for selected confounding factors, those with moderate or worse HI had an adjusted odds ratio of 1.69 (95% confidence interval (CI), 1.03-2.77) for being developmentally vulnerable in two or more of the five AEDC domains. Children with mild HI and those with moderate to worse HI had lower domain score sum by -1.60 (95% CI, -3.02 to -0.18) and - 2.40 (95% CI, -4.50 to -0.30), respectively. There was also evidence for an association between HI and poorer outcomes in the 'language and cognitive skills', 'communication skills and general knowledge' and 'physical health and wellbeing' domains. CONCLUSIONS Otitis media-related HI is associated with increased risk for poorer outcomes in early childhood development and this risk appears to increase with higher levels of HI. Prevention and early treatment of otitis media will reduce both the disease and the associated negative impact on early child development, especially the development of language, cognitive and communication skills and physical health and wellbeing.

Objective: To investigate the association between hearing impairment (HI) and Year 1 school attendance in Aboriginal children in the Northern Territory (NT) of Australia. Methods: Observational cohort study (n=3,744) by analysing linked individual‐level information for Aboriginal children from the NT Government school attendance records, NT Perinatal Register and Remote Hearing Assessment dataset, and community level data for relative remoteness, socioeconomic disadvantage and housing crowdedness. Results: Children with unilateral hearing loss, mild HI and moderate or worse HI had significantly lower Year 1 attendance than those with normal hearing, attending 5.6 (95%CI, −9.10 ∼−2.10), 4.0 (95%CI, −7.17 ∼−0.90) and 6.1 (95%CI, −10.71 ∼−1.49) days fewer, respectively. Other variables that yielded significant association were: male gender, having attended preschool less than 20% of available days, speaking English as second language, twin birth and average household size >5. Conclusions: Aboriginal children with any level of HI are likely to have lower school attendance rates in Year 1 than their peers with normal hearing. Implications for public health: In this population, where the prevalence of otitis media and accompanying HI remains extremely high, the early detection and management of hearing loss on entry into primary school should be included in the measures to improve school attendance.

Background Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to Methods ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 to Results Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events. Conclusions An additional dose of Rotarix administered to Australian Aboriginal infants 6 to Clinical Trials Registration NCT02941107.

IntroductionOtitis media (OM) is a common childhood illness, often resolving without intervention and acute and long-term complications are rare. However, Australian Aboriginal and Torres Strait Islander infants and children experience a high burden of OM and are at high risk of complications (tympanic membrane perforation and chronic infections). Bacterial OM is commonly associated with Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis. BIGDATA is a data asset combining over 25 years of microbiology and OM surveillance research from the Ear Health Research Program at Menzies School of Health Research (Northern Territory, Australia), including 11 randomized controlled trials, four cohort studies, eight surveys in over 30 remote communities (including data from Western Australia), and five surveys of urban childcare centers including Aboriginal and Torres Strait Islander and non-Indigenous children. Outcome measures include clinical examinations (focusing on OM), antibiotic prescriptions, pneumococcal vaccination, modifiable risk factors such as smoking and household crowding, and nasopharyngeal and ear discharge microbiology including antimicrobial resistance testing.Methods and AnalysisThe initial series of projects are planned to address the following key knowledge gaps: (i) otitis media prevalence and severity over pre pneumococcal conjugate vaccines (PCVs) and three eras of increasing PCV valency; (ii) impact of increasing valency PCVs on nasopharyngeal carriage dynamics of pneumococcal serotypes, and antimicrobial resistance; (iii) impact of increasing valency PCVs on nasopharyngeal carriage dynamics and antimicrobial resistance of other otopathogens; and (iv) serotype specific differences between children with acute OM and OM with effusion or without OM. These data will be utilized to identify research gaps, providing evidence-based prioritization for ongoing research.Ethics and DisseminationData asset creation and priority analyses were approved by the Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research (EC00153, 18-3281), the Child and Adolescent Health Service Human Research Ethics Committee and Western Australian Aboriginal Health Ethics Committee. Dissemination will be through peer review publication and conference presentations.

BackgroundThe oral rotavirus vaccine, Rotarix (GlaxoSmithKline), is licensed for use in infants as two doses in the first six months of life. For infants living in settings with high child-mortality, and also for rural and remote Australian Aboriginal infants, clinical protection conferred by two doses of Rotarix appears to be reduced. We assessed the effect of an additional dose of Rotarix on vaccine immune responses among Aboriginal children who are 6 to < 12 months old.MethodsORVAC is a two-stage, double-blind, randomised, placebo-controlled trial conducted across regional urban and remote locations of Australia’s Northern Territory. Aboriginal children 6 to < 12 months old who had received one or two prior doses of Rotarix were randomised 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological endpoint was seroresponse defined as an anti-rotavirus IgA level ≥ 20 AU/mL, approximately one month following Rotarix or placebo. ClinicalTrials.gov (NCT02941107).FindingsBetween March 2018 and August 2020, 253 infants were enrolled. Of these, 178 infants (70%) had analysable serological results after follow-up; 89 randomised to Rotarix and 89 to placebo. The proportion with a seroresponse was 85% after Rotarix compared to 71% after placebo; the probability of a higher rate of seroresponse in the Rotarix than the placebo arm was 99%. There were no occurrences of intussusception or any serious adverse events attributed to Rotarix or placebo in the 28 days following the additional dose of Rotarix or placebo.InterpretationAn additional dose of Rotarix among Australian Aboriginal infants 6 to < 12 months old increased the proportion with a vaccine seroresponse. If it can be proven that this translates into better protection against disease, scheduling an additional dose may be a viable strategy for further reducing the global burden of rotavirus disease.FundingNHMRC (GNT1086952).Research in contextEvidence before this studyRotavirus vaccine programs have reduced the global burden of gastroenteritis disease among young children, but rotavirus still causes >200,000 child deaths each year. A recent systematic review in the Lancet Global Health found that the effectiveness of oral rotavirus vaccines is variable, from 45 – 58% in settings with high child mortality to 83%-85% in settings with low child mortality. In high child mortality settings there is also evidence of waning effectiveness after 12 months old. Reduced vaccine effectiveness has also been reported among Australian Aboriginal children. Previous trials have failed to demonstrate improved rotavirus vaccine effectiveness with strategies such as withholding breastfeeding, or co-administering vaccines with probiotics or zinc. Pre-licensure studies of Rotarix in Africa did not clearly indicate whether a three-dose Rotarix schedule had benefit over a two-dose schedule, although all vaccine doses were given before infants were six months old when maternal antibodies may impede vaccine responses. Trials in Bangladesh and Mali found that a third Rotarix dose given after 6 months old improved the immune response to vaccine.Added value of this studyIn the first stage of our novel two-stage randomised clinical trial, we showed that scheduling an additional Rotarix dose for remote Australian Aboriginal infants after 6 months old increased the proportion with evidence of vaccine seroresponse.Implications of all the available evidenceScheduling an additional dose of Rotarix after 6 months old is feasible, and trials in three settings have now demonstrated that it improves immune responses. Trials should now be conducted in a number of high burden settings to determine whether this strategy results in improved clinical protection against severe gastroenteritis.

Background Almost all Aboriginal children in remote communities have persistent bilateral otitis media affecting hearing and learning throughout early childhood and school years, with consequences for social and educational outcomes, and later employment opportunities. Current primary health care and specialist services do not have the resources to meet the complex needs of these children. Method/design This stepped-wedge cluster randomised trial will allocate 18 communities to one of five 6-monthly intervention start dates. Stratification will be by region and population size. The intervention (Hearing for Learning Initiative, HfLI) consists of six 20-h weeks of training (delivered over 3 months) that includes Certificate II in Aboriginal Primary Health Care (3 modules) and competencies in ear and hearing data collection (otoscopy, tympanometry and hearScreen), plus 3 weeks of assisted integration into the health service, then part-time employment as Ear Health Facilitators to the end of the trial. Unblinding will occur 6 months prior to each allocated start date, to allow Community Reference Groups to be involved in co-design of the HfLI implementation in their community. Relevant health service data will be extracted 6-monthly from all 18 communities. The primary outcome is the difference in proportion of children (0 to 16 years of age) who have at least one ear assessment (diagnosis) documented in their medical record within each 6-month period, compared to control periods (no HfLI). Secondary outcomes include data on sustainability, adherence to evidence-based clinical guidelines for otitis media, including follow-up and specialist referrals, and school attendance. Structured interviews with staff working in health and education services, Ear Health Trainees, Ear Health Facilitators and families will assess process outcomes and the HfLI broader impact. Discussion The impact of training and employment of Ear Health Facilitators on service enhancement will inform the health, education and employment sectors about effectiveness of skills and job creation that empowers community members to contribute to addressing issues of local importance, in this instance ear and hearing health of children. Trial registration ClinicalTrials.gov NCT03916029. Registered on 16 April 2019.

Background Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins. Methods Healthy 18–45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies. Results There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A–neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F–specific interferon γ–secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose. Conclusions In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns. Clinical Trials Registration NCT02491463., We investigated the safety and immunogenicity of a novel chimpanzee-adenovirus-155 vaccine against respiratory syncytial virus (RSV; ChAd155-RSV). In healthy adults with previous natural RSV exposure, ChAd155-RSV generated antigen-specific humoral and cellular immune responses without raising significant safety concerns.

Background Nontypeable Haemophilus influenzae (NTHi) is one of the main respiratory pathogens associated with otitis media and lung infections in Australian Indigenous children. PHiD-CV10, the 10-valent pneumococcal conjugate vaccine containing H. influenzae protein D was used in the Northern Territory infant vaccination schedule for two years from October 2009. Methods NTHi isolates from nasopharyngeal and ear discharge samples collected before, during and after the PHiD-CV10 era were screened for the hpd gene by PCR. Target amplicon sequence, extracted from available genomic sequence data, was analysed to identify variability in this region. Results There was no statistically significant difference in the proportion of hpd#3-PCR negative isolates from each era; overall 7% and 6% of nasopharyngeal and ear discharge isolates were negative, respectively. The nucleotide sequence data supported the hpd-PCR findings; truncations of the hpd gene precluding amplification and presumably expression of protein D were observed in approximately 7% of available genomes. Conclusions In the Northern Territory of Australia, a population at high risk of NTHi-associated infection, PHiD-CV10 use did not select for hpd-PCR negative isolates.

Background Chronic suppurative otitis media (CSOM) is a significant health issue affecting Aboriginal Australians. Long-term hearing loss can cause communication problems, educational disadvantage, and social isolation. Current standard treatment for CSOM in our region is twice daily dry mopping of the pus from the ear canal followed by instillation of ciprofloxacin antibiotic ear drops for up to 16 weeks, or until the discharge resolves for a period of 3 days. The treatment is long, laborious and fails to resolve ear discharge in 70% of cases in remote communities. Bacterial pathogens also persist. Povidone-iodine ear wash is the preferred method of clearing ear discharge in Western Australia. However, evidence of its effectiveness is lacking. In systematic reviews, topical antibiotics (ciprofloxacin) have been shown to be more effective than oral antibiotics or topical antiseptics. Currently, it is unclear whether there are any benefits of combining these treatments. Methods This protocol describes a 2 × 2 factorial randomised controlled trial of two different interventions (povidone-iodine ear wash and oral cotrimoxazole), given as adjunctive therapy to standard treatment for CSOM. 280 children, between 2 months and 17 years of age, Indigenous or non-Indigenous, living in participating Northern Territory (NT) communities are randomised to standard treatment (dry mopping and ciprofloxacin drops) plus one of two topical treatments (dilute povidone-iodine ear wash or no wash) and one of two oral medication treatments (16 weeks of cotrimoxazole or placebo). Discussion Current treatment of CSOM in our region shows that eradication of bacterial pathogens from the middle ear space and dry ears is often not achieved. This trial will evaluate the efficacy of adjunctive treatments of antiseptic ear washes and oral antibiotics. Clinical, microbiological and hearing outcomes will be reported. Trial registration This trial (ACTRN12614000234617) was registered with ANZCTR on 05 April 2014.

Background Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months. Methods In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2–4-6 months (_PPP), Synflorix™ (S) at 2–4-6 months (_SSS), or Synflorix™ at 1–2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM). Results Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM. Conclusions Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life. Trial registration ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.govNCT01174849 registered 04/08/2010.

Aim Australian Aboriginal and Torres Strait Islander children have among the highest rates of otitis media (OM) and associated conductive hearing loss in the world. OM begins early in life and is well-documented in the research literature. In contrast, audiology data for the infant and toddler age-groups are limited. This review aimed to summarise the recent literature on hearing loss among Aboriginal and Torres Strait Islander infants and toddlers. Methods Systematic literature review. PubMed and ScienceDirect databases were searched for relevant journal articles. Key search terms were “Aboriginal”, “children”, “hearing loss”, “otitis media”, and their relevant synonyms. Journal articles published before 2000 were excluded. Results Only two journal articles met review inclusion criteria. Ear disease and associated conductive hearing loss was significantly higher among Aboriginal and Torres Strait Islander than non-Aboriginal and Torres Strait Islander children. No intervention studies were found. Conclusions More research is needed to evaluate hearing health outcomes of medical (including surgical) and audiological interventions in this high-risk population.

Maternal urogenital human papillomavirus (HPV) infection may place neonates at risk of HPV acquisition and subsequently lower respiratory infections as HPV can influence development of immunity. The respiratory HPV prevalence is not known in remote‐dwelling Aboriginal infants, who are at high risk of respiratory infection and where the population prevalence of urogenital HPV in women is high. These data are necessary to inform HPV vaccination regimens. A retrospective analysis using PCR specific for HPV was performed on 64 stored nasopharyngeal swabs from remote‐dwelling Aboriginal infants < 6 months of age, with and without hospitalised pneumonia. HPV DNA was not detected in any specimen. Despite the negative result, we cannot exclude a role for HPV in respiratory infections affecting infants in this population; however, our data do not support HPV as an important contributor to acute respiratory infection in remote‐dwelling Aboriginal children., In populations at high risk of urogenital HPV infection, newborns are at risk of acquiring HPV which may lead to impaired immunity and increased risk of chest infection. In our study, infant nose swabs were HPV negative suggesting that HPV isn’t a common child health issue in this population.

IntroductionStreptococcus 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 analysesOur 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 disseminationEthics 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 numberNCT01735084.

Background Culture-independent sequencing methods are increasingly used to investigate the microbiota associated with human mucosal surfaces, including sites that have low bacterial load in healthy individuals (e.g. the lungs). Standard microbiota methods developed for analysis of high bacterial load specimens (e.g. stool) may require modification when bacterial load is low, as background contamination derived from sterile laboratory reagents and kits can dominate sequence data when few bacteria are present. Main body Bacterial load in respiratory specimens may vary depending on the specimen type, specimen volume, the anatomic site sampled and clinical parameters. This review discusses methodological issues inherent to analysis of low bacterial load specimens and recommends strategies for successful respiratory microbiota studies. The range of methods currently used to process DNA from low bacterial load specimens, and the strategies used to identify and exclude background contamination are also discussed. Conclusion Microbiota studies that include low bacterial load specimens require additional tests to ensure that background contamination does not bias the results or interpretation. Several methods are currently used to analyse the microbiota in low bacterial load respiratory specimens; however, there is scant literature comparing the effectiveness and biases of different methods. Further research is needed to define optimal methods for analysing the microbiota in low bacterial load specimens.

Acute lower respiratory infection (ALRI) is a major cause of hospitalization for Indigenous children in remote regions of Australia. The associated microbiology remains unclear. Our aim was to determine whether the microbes present in the nasopharynx before an ALRI were associated with its onset. A retrospective case-control/crossover study among Indigenous children aged up to 2 years. ALRI cases identified by medical note review were eligible where nasopharyngeal swabs were available: (1) 0–21 days before ALRI onset (case); (2) 90–180 days before ALRI onset (same child controls); and (3) from time and age-matched children without ALRI (different child controls). PCR assays determined the presence and/or load of selected respiratory pathogens. Among 104 children (182 recorded ALRI episodes), 120 case-same child control and 170 case-different child control swab pairs were identified. Human adenoviruses (HAdV) were more prevalent in cases compared to same child controls (18 vs 7%; OR = 3.08, 95% CI 1.22–7.76, p = 0.017), but this association was not significant in cases versus different child controls (15 vs 10%; OR = 1.93, 95% CI 0.97–3.87 (p = 0.063). No other microbes were more prevalent in cases compared to controls. Streptococcus pneumoniae (74%), Haemophilus influenzae (75%) and Moraxella catarrhalis (88%) were commonly identified across all swabs. In a pediatric population with a high detection rate of nasopharyngeal microbes, HAdV was the only pathogen detected in the period before illness presentation that was significantly associated with ALRI onset. Detection of other potential ALRI pathogens was similar between cases and controls. Electronic supplementary material The online version of this article (10.1007/s10096-018-3314-7) contains supplementary material, which is available to authorized users.

The RTS,S/AS01 malaria vaccine (Mosquirix) reduces the incidence of Plasmodium falciparum malaria and is intended for routine administration to infants in Sub-Saharan Africa. We evaluated the immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix) and human rotavirus vaccine (HRV; Rotarix) when co-administered with RTS,S/AS01 (www.clinicaltrials.gov NCT01345240) in African infants. 705 healthy infants aged 8–12 weeks were randomized to receive three doses of either RTS,S/AS01 or licensed hepatitis B (HBV; Engerix B) vaccine (control) co-administered with diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type-b-conjugate vaccine (DTaP/Hib) and trivalent oral poliovirus vaccine at 8–12-16 weeks of age, because DTaP/Hib was not indicated before 8 weeks of age. The vaccination schedule can still be considered broadly applicable because it was within the age range recommended for EPI vaccination. PHiD-CV or HRV were either administered together with the study vaccines, or after a 2-week interval. Booster doses of PHiD-CV and DTaP/Hib were administered at age 18 months. Non-inferiority of anti-HBV surface antigen antibody seroprotection rates following co-administration with RTS,S/AS01 was demonstrated compared to the control group (primary objective). Pre-specified non-inferiority criteria were reached for PHiD-CV (for 9/10 vaccine serotypes), HRV, and aP antigens co-administered with RTS,S/AS01 as compared to HBV co-administration (secondary objectives). RTS,S/AS01 induced a response to circumsporozoite protein in all groups. Pain and low grade fever were reported more frequently in the PHiD-CV group co-administered with RTS,S/AS01 than PHiD-CV co-administered with HBV. No serious adverse events were considered to be vaccine-related. RTS,S/AS01 co-administered with pediatric vaccines had an acceptable safety profile. Immune responses to RTS,S/AS01 and to co-administered PHiD-CV, pertussis antigens and HRV were satisfactory.

Background: Nontypeable Haemophilus influenzae (NTHi), the most common bacterial lower airway infection in children with protracted bacterial bronchitis, is associated with progression to bronchiectasis. We determined whether vaccination with 10-valent pneumococcal NTHi protein-D conjugate vaccine (PHiD-CV) reduced NTHi lower airway infection compared to children not PHiD-CV-vaccinated. Our unique childhood vaccination schedule and prospective 9-year bronchoalveolar lavage (BAL) collection provided an exclusive opportunity to examine this hypothesis. Methods: Paired BAL fluids and nasopharyngeal (NP) swabs were collected from 543 children (2007–2016) undergoing bronchoscopy for chronic cough. Children who received a primary course of ≥2 doses of one pneumococcal conjugate vaccine (PCV) and

Otitis media (OM) is a common condition in Australia. It represents a spectrum of diseases from otitis media with effusion (OME) to chronic suppurative otitis media. For all the OM diagnoses, Australian Indigenous children have higher rates of early onset, severe and persistent disease. OME is the most common form of OM and often occurs after an upper respiratory tract infection. It can be difficult to diagnose (and often goes unrecognised). Hearing loss is the most important complication. The middle-ear effusion impedes the movement of the tympanic membrane and causes a conductive hearing loss of around 25 dB. Around 20% will have a hearing loss exceeding 35 dB. Children with early onset, persistent, bilateral OME and hearing loss (or speech delay) are most likely to benefit from interventions. However, the impact of all the effective treatment options is modest. Giving advice about effective communication strategies for young children is always appropriate. The best evidence from randomised trials supports not using antihistamines and/or decongestants, considering a trial of antibiotics and referral for tympanostomy tubes. Despite the availability of evidence-based guidelines, giving advice about treatment is a challenge because recommendations vary according to condition, age, risk of complications and parental preference. While most children with OME can be effectively managed in primary care, we need to get children who meet the criteria for simple ear, nose and throat procedures that improve hearing on to ear, nose and throat surgery waiting lists. Long delays in hearing support may contribute to life-long social and economic disadvantage.

Streptococcus pneumoniae (pneumococcus) is the main cause of bacterial pneumonia worldwide and has been studied extensively in this context. However, its role in chronic endobronchial infections and accompanying lower airway neutrophilic infiltration has received little attention. Severe and recurrent pneumonia are risk factors for chronic suppurative lung disease (CSLD) and bronchiectasis; the latter causes considerable morbidity and, in some populations, premature death in children and adults. Protracted bacterial bronchitis (PBB) is another chronic endobronchial infection associated with substantial morbidity. In some children, PBB may progress to bronchiectasis. Although nontypeable Haemophilus influenzae is the main pathogen in PBB, CSLD and bronchiectasis, pneumococci are isolated commonly from the lower airways of children with these diagnoses. Here we review what is known currently about pneumococci in PBB, CSLD and bronchiectasis, including the importance of pneumococcal nasopharyngeal colonization and how persistence in the lower airways may contribute to the pathogenesis of these chronic pulmonary disorders. Antibiotic treatments, particularly long-term azithromycin therapy, are discussed together with antibiotic resistance and the impact of pneumococcal conjugate vaccines. Important areas requiring further investigation are identified, including immune responses associated with pneumococcal lower airway infection, alone and in combination with other respiratory pathogens, and microarray serotyping to improve detection of carriage and infection by multiple serotypes. Genome wide association studies of pneumococci from the upper and lower airways will help identify virulence and resistance determinants, including potential therapeutic targets and vaccine antigens to treat and prevent endobronchial infections. Much work is needed, but the benefits will be substantial.

BACKGROUND: Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults. METHODS: Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3μg/ml but 4.0μg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N=20) and Indigenous (N=60) and non-Indigenous adults (N=25) receiving their first 23vPPV dose. RESULTS: All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p=0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (-27%, 95% CI: -43% to -11%; p=0.01) and 90% (-38%, 95% CI: -60% to -16%; p=0.006) of serotypes with a positive response. CONCLUSION: Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV.

Summary Background Evidence is mounting that price discounts can be effective in improving diet. This study examined the effectiveness of a 20% price discount on food and drink purchases with and without consumer education in remote Indigenous Australia. Methods A 20% discount on fruit, vegetables, water, and artificially sweetened soft drinks was applied for 24 weeks in 20 communities in remote Indigenous Australia where the community store was managed by the Arnhem Land Progress Aboriginal Corporation (ALPA) or Outback Stores (OBS) in a stepped-wedge randomised trial. Communities were randomly allocated to a fixed framework of five sets of four stratified by store association; ten stores (two in each set) were randomly assigned to receive consumer education. A store from each of the ALPA and OBS store groups (contained in separate opaque envelopes) was selected, and stores in turn continued to be consecutively allocated to the fixed store set framework, starting with the first store slot in the first store set, until all stores had been allocated. The effect of the discount on the weight of fruit and vegetables purchased (the primary endpoint) was assessed using weekly store sales data and mixed models per protocol. We did sensitivity analyses by repeating the analyses with the outliers included and repeating the analyses for the primary outcome measure removing each store one at a time. This trial was registered with Australian New Zealand Clinical Trials Registry, number ACTRN12613000694718. Findings Weekly store sales data on all food and drink products sold in 20 stores were collected from July 1, 2012, to Dec 28, 2014. Price discount alone was associated with a 12·7% (95% CI 4·1–22·1) increase in purchases in grams of fruit and vegetables combined (primary outcome), and a 19·8% (6·2–35·1) increase post discount (after vs before); an effect of 12 g and 18 g per capita per day. Sensitivity analyses did not modify the results for the primary outcome measure. Interpretation A 20% discount can only increase fruit and vegetable purchases to help protect against obesity and diet related disease to a certain extent. Large discounts might have a greater impact than small discounts. Creative merchandising approaches to consumer education could also be considered alongside fiscal interventions to achieve marked improvements in diet. Funding Australian National Health and Medical Research Council.

Background: The burden of acute lower respiratory infection (ALRI) in Indigenous children of Australia's Northern Territory is among the highest globally. No published data exists on the effect of pneumococcal conjugate vaccine (PCV) introduction on ALRIs in this population beyond 2005. The aim of this study was to describe the rates of ALRI admissions to hospital in Indigenous infants in the Northern Territory from 2006 to 2015, across three periods of different PCV use. We hypothesised that broader valency PCVs would be more effective against hospitalisations for pneumonia. Methods: We did a retrospective population-based cohort study of Indigenous infants born in the Northern Territory followed up until age 12 months. Data were from administrative hospital and perinatal datasets. International classification of diseases codes (tenth revision, Australian modification; ICD-10AM) were used to identify respiratory hospitalisations of interest: all-cause ALRI, all-cause pneumonia, bacterial pneumonia, viral pneumonia, influenza-like illness (ILI), respiratory syncytial virus ALRI (RSV-ALRI), and pneumococcal ALRI. Incidence rates were compared between PCV eras (7-valent PCV [PCV7], 2006–09; 10-valent PCV [PCV10], 2009–11; and 13-valent PCV [PCV13], 2011–15) using interrupted time trend analysis and negative binomial regression. Findings: For children born between Jan 1, 2006, and Dec 31, 2015, 4138 ALRI episodes (31% of all hospitalisations) occurred among 2888 (20%) of the 14 594 infants. The overall ALRI hospitalisation rate was 29·7 episodes per 100 child-years. Prominent risk factors associated with ALRI hospitalisation were living in a remote community or the Central desert region, being born preterm or with low birthweight. ALRI rates were lowest in the PCV13 era, in association with a significant reduction in bacterial pneumonia hospitalisations in the PCV13 era compared with the PCV10 (incidence rate ratio 0·68, 95% CI 0·57–0·81) and PCV7 (0·70, 0·60–0·81) eras. In contrast, RSV-ALRI rates were 4·9 episodes per 100 child-years in each era. Interpretation: A 30% reduction in bacterial-coded pneumonia hospitalisations in the Northern Territory during the era of PCV13 immunisation supports its ongoing use in the region. Despite the reduction, one in five Indigenous infants born in the region continue to be hospitalised with an ALRI in their first year of life. Future gains require multifaceted environmental and biomedical approaches. Funding: National Health and Medical Research Council of Australia.

IntroductionRotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to Methods and analysisThis Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to 20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confirmed gastroenteritis/diarrhoea, and rotavirus notification. Analysis will be based on Bayesian inference with adaptive sample size.Ethics, registration and disseminationEthics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifications to this protocol will be updated.Trial registration numberNCT02941107; Pre-results.

Background International studies provide evidence of an association between child disabilities, including hearing impairment (HI), and child maltreatment. There are high prevalences of ear disease with associated HI, and child maltreatment among Australian Aboriginal children, but the link between HI and child maltreatment is unknown. This study investigates the association between HI and child maltreatment for Aboriginal children living in the Northern Territory (NT) of Australia. Methods This was a retrospective cohort study of 3895 Aboriginal school-aged children (born between 1999 and 2008) living in remote NT communities. The study used linked individual-level information from health, education and child protection services. The outcome variables were child maltreatment notifications and substantiations. The key explanatory variable, HI, was based on audiometric assessment. The Kaplan–Meier estimator method was used in univariate analysis; Cox proportional hazards regression was used in multivariable analysis. Results A majority of the study cohort lived in very remote (94.5%) and most disadvantaged (93.1%) regions. Among all children in the study cohort, 56.1% had a record of either HI or unilateral hearing loss (UHL), and for those with a history of contact with child protection services (n = 2757), 56.7% had a record of HI/UHL (n = 1564). In the 1999–2003 birth cohort, by age 12 years, 53.5% of children with a record of moderate or worse HI had at least one maltreatment notification, compared to 47.3% of children with normal hearing. In the 2004–2008 cohort, the corresponding results were 83.4 and 71.7% respectively. In multivariable analysis, using the full cohort, children with moderate or worse HI had higher risk of any child maltreatment notification (adjusted Hazard Ratios (adjHR): 1.16, 95% CI:1.04–1.30), notification for neglect (adjHR:1.17, 95% CI:1.04–1.31) and substantiation (adjHR:1.20, 95% CI:1.04–1.40), than children with normal hearing. In the 2004–2008 birth cohort, children with moderate or worse HI had higher risk of a substantiated episode of physical abuse (adjHR:1.47, 95% CI:1.07–2.03) than children with normal hearing. Conclusion Our findings demonstrate the urgent need for HI and child maltreatment prevention strategies through raised community awareness and inter-agency collaboration. Effective information-sharing between service providers is a critical first step to a public health approach in child protection.

Background High prevalence of chronic middle ear disease has persisted in Australian Aboriginal children, and the related hearing impairment (HI) has been implicated in a range of social outcomes. This study investigated the association between HI in early childhood and youth offending. Method This was a retrospective cohort study of 1533 Aboriginal children (born between 1996 and 2001) living in remote Northern Territory communities. The study used linked individual-level information from health, education, child protection and youth justice services. The outcome variable was a youth being “found guilty of an offence”. The key explanatory variable, hearing impairment, was based on audiometric assessment. Other variables were: child maltreatment notifications, Year 7 school enrolment by mother, Year 7 school attendance and community ‘fixed- effects’. The Cox proportional hazards model was used to estimate the association between HI and youth offending; and the Royston R2 measure to estimate the separate contributions of risk factors to youth offending. Results The proportion of hearing loss was high in children with records of offence (boys: 55.6%, girls: 36.7%) and those without (boys: 46.1%; girls: 49.0%). In univariate analysis, a higher risk of offending was found among boys with moderate or worse HI (HR: 1.77 [95% CI: 1.05–2.98]) and mild HI (HR: 1.54 [95% CI:1.06–2.23]). This association was attenuated in multivariable analysis (moderate HI, HR: 1.43 [95% CI:0.78–2.62]; mild HI, HR: 1.37 [95% CI: 0.83–2.26]). No evidence for an association was found in girls. HI contributed 3.2% and 6.5% of variation in offending among boys and girls respectively. Factors contributing greater variance included: community ‘fixed-effects’ (boys: 14.6%, girls: 36.5%), child maltreatment notification (boys: 14.2%, girls: 23.9%) and year 7 school attendance (boys: 7.9%; girls 12.1%). Enrolment by mother explained substantial variation for girls (25.4%) but not boys (0.2%). Conclusion There was evidence, in univariate analysis, for an association between HI and youth offending for boys however this association was not evident after controlling for other factors. Our findings highlight a range of risk factors that underpin the pathway to youth-offending, demonstrating the urgent need for interagency collaboration to meet the complex needs of vulnerable children in the Northern Territory.

Introduction Respiratory syncytial virus (RSV) is the leading viral cause of acute lower respiratory infections globally, accounting for high morbidity and mortality burden among children aged less than 5 years. As candidate RSV vaccine trials in pregnant women and infants are underway a greater understanding of RSV epidemiology is now needed, especially in paediatric populations with high rates of acute and chronic respiratory disease. The objective was to identify RSV prevalence in children living in northern Australia, a region with a high respiratory disease burden. Methods Data were sourced from 11 prospective studies (four hospital and seven community-based) of infants and children with acute and chronic respiratory illnesses, as well as otitis media, conducted between 1996 and 2017 inclusive. The data from northern Australian children in these trials were extracted and, where available and consented, their nasopharyngeal swabs (biobanked at -80oC) were tested by polymerase chain reaction assays for RSV-A and B, 16 other viruses and atypical respiratory bacterial pathogens. Results Overall, 1127 children were included. Their median age was 1.8 years (interquartile range 0.5-4.9); 58% were male and 90% Indigenous, with 81% from remote communities. After human rhinoviruses (HRV), RSV was the second most prevalent virus (15%, 95% confidence interval (CI) 13-18). RSV prevalence was greatest amongst children aged less than 2 years hospitalised with bronchiolitis (47%, 95%CI 41.4-52.4), with more than two-thirds with RSV aged less than 6 months. In contrast, the prevalence of RSV was only 1-3.5% in other age groups and settings. In one-third of RSV cases, another respiratory virus was also detected. Individual viruses other than RSV and HRV were uncommon (0-9%). Conclusion Combined data from 11 hospital and community-based studies of children aged less than 18 years who lived in communities with a high burden of acute and chronic respiratory illness showed that RSV was second only to HRV as the most prevalent virus detected across all settings. RSV was the most frequently detected virus in infants hospitalised with bronchiolitis, including those aged less than 6 months. In contrast, RSV was uncommonly detected in children in community settings. In northern Australia, effective maternal and infant RSV vaccines could substantially reduce RSV bronchiolitis-related hospitalisations, including admissions of Indigenous infants from remote communities.

BackgroundImportant ear problems can affect the outer ear, the middle ear and the inner ear. Globally, the greatest burden of disease is due to ear conditions that are associated with otorrhoea and hearing loss.MethodsThis study reviewed the literature on the prevention and treatment of common ear conditions that are most relevant to settings with high rates of ear disease and limited resources. The grading of recommendations assessment, development and evaluation (‘GRADE’) approach was utilised to assess interventions.ResultsAccurate diagnosis of ear disease is challenging. Much of the preventable burden of ear disease is associated with otitis media. Nine otitis media interventions for which there is moderate to high certainty of effect were identified. While most interventions only provide modest benefit, the impact of treatment is more substantial in children with acute otitis media with perforation and chronic suppurative otitis media.ConclusionDisease prevention through good hygiene practices, breastfeeding, reducing smoke exposure, immunisation and limiting noise exposure is recommended. Children with acute otitis media with perforation, chronic suppurative otitis media, complications of otitis media, and significant hearing loss should be prioritised for medical treatment.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17\xC2\xA0months) and 6537 infants (enrolled at 6-12\xC2\xA0weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score \xE2\x89\xA42 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Background:­­­­ For Indigenous infants living in Australia’s Northern Territory (NT) acute lower respiratory infections (ALRIs) are a leading cause of hospitalisation and preventable mortality. The study describes the burden of ALRI hospitalisation in this population from 2006 to 2015 with contrast between three periods of different pneumococcal conjugate vaccine (PCV) use. Methods: We conducted a historical cohort study of NT Indigenous infants born between 1st January 2006 and 31st December 2015 and followed until age 12 months. Data were from administrative hospital and perinatal datasets. International classification of diseases codes were used to identify respiratory hospitalisations of interest: all cause ALRI, all cause pneumonia, bacterial pneumonia, viral pneumonia, influenza-like illness (ILI), respiratory syncytial virus ALRI (RSV-ALRI) and pneumococcal ALRI. Incidence rates were compared between PCV eras (7-valent PCV-PCV7, 2006-2009; PCV10, 2009-2011; PCV13, 2011-2015) using interrupted time trend analysis and negative binomial regression. Findings: Over the study period 4138 ALRI episodes (31% of all hospitalisations) occurred among 2888 of the 14594 infants (20% of the cohort). The overall ALRI hospitalisation rate was 29.7 episodes per 100 child-years. Prominent risk factors associated with ALRI hospitalisation were living in a remote community or the Central desert region, being born preterm or with low birth weight. ALRI rates were lowest in the PCV13 era in association with a significant reduction in bacterial pneumonia hospitalisations in the PCV13 relative to the PCV10 (IRR 0∙68, 95% CI 0∙57-0∙81) and PCV7 (IRR 0∙70, 95% CI 0∙60-0∙81) eras. In contrast, RSV-ALRI rates were 4∙9 episodes per 100 child-years in each era. Interpretation: We found a 30% reduction in bacterial-coded pneumonia hospitalisation episodes during the era of PCV13 use. Despite this, one in five NT Indigenous infants continue to be hospitalised with an ALRI in their first year of life. RSV associated ALRI rates were high and remained unchanged over a decade. Funding Statement: This work was supported by the National Health and Medical Research Council (NHMRC) of Australia. MJB was funded by an NHMRC Early Career Fellowship (1088733) and NHMRC-funded `Hot North - Improving Health Outcomes in the Tropical North’ Fellowship (1131932). JB is supported by a NHMRC scholarship (1150901) and a NHMRC-funded Centre of Research Excellence in Ear and Hearing Health of Aboriginal and Torres Strait Islander children scholarship (1078557). VMO none. SJP was supported by a NHMRC Peter Doherty Early Career Fellowship (1113302). AJL was supported by NHMRC Fellowship (1020561), the NHMRC-funded Centre of Research Excellence in Ear and Hearing Health of Aboriginal and Torres Strait Islander Children (1078557), The Balnaves Foundation, the Northern Territory Government and the Australian Government. PSM none. RMA none. LM was supported by an Australian Postgraduate Award through Charles Darwin University and an Enhanced Living scholarship through Menzies School of Health Research towards a Doctor of Philosophy degree. RW none. ABC is supported by Australia’s NHMRC Practitioner Fellowship (1058213) and a Children’s Hospital Foundation Fellowship, Queensland (50286). Declaration of Interests: The authors stated: "None exist." Ethics Approval Statement: This project was approved by the Human Research Ethics Committee of the NT Department of Health and Menzies School of Health Research (HREC 2015-2406).

Background Indigenous children in Australia’s Northern Territory are densely colonised with the pneumococcus within weeks of birth antecedent to a high prevalence of acute lower respiratory infection (ALRI). We assessed the impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPV) in pregnancy against infant ALRI in this setting. Methods In an open label, allocation concealed, outcome-assessor blinded, randomised controlled trial conducted in the Northern Territory of Australia, healthy Indigenous women aged 17–39 years were randomised to receive the 23vPPV during pregnancy (n = 75; 30–36 weeks gestation), at birth (n = 75), or at 7 months post-partum (n = 77). Randomisation was stratified by community of residence. In a secondary analysis, we compared the incidence of ALRI hospitalisations and ALRI clinic presentations (ascertained from electronic medical records) among infants of pregnancy vaccinees versus infants of mothers not vaccinated in pregnancy (controls) in the first year of life. Results ALRI hospitalisation incidence was 12.3 per 100 child-years among infants of pregnancy vaccinees compared with 15.8 per 100 child-years among controls (hazard ratio (HR) 0.77, 95%CI 0.29–2.03). ALRI hospitalisations were more common among remote compared to urban infants (27.7 versus 8.6 per 100 child-years). Stratification by dwelling highlighted a differential antenatal vaccine effect against ALRI hospitalisations (urban HR 2.45, 95%CI 0.60–9.99; remote HR 0.21, 95%CI 0.04–1.08). ALRI clinic presentation incidence was similar among infants of pregnancy vaccinees and controls. Conclusions In this small study, antenatal 23vPPV vaccination was not associated with a reduced incidence of infant ALRI hospitalisations or ALRI clinic presentations during the first year of life. A potential differential effect between urban and remote settings warrants further investigation. Trial registration PneuMum; ClinicalTrials.gov NCT00714064. Electronic supplementary material The online version of this article (10.1186/s41479-018-0057-2) contains supplementary material, which is available to authorized users.

Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya.We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459.Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients).RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes.GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

The efficacy of chocolate agar, versus bacitracin, vancomycin, clindamycin, chocolate agar (BVCCA) for the isolation of non-typeable Haemophilus influenzae (NTHi) from nasopharyngeal swabs was determined. BVCCA cultured NTHi from 97.3% of NTHi-positive swabs, compared to 87.1% for chocolate agar. To maximise culture sensitivity, the use of both media is recommended.

Background Lower respiratory tract infections (LRTIs) are a leading cause of pediatric morbidity and mortality worldwide, with ~650,000 deaths recorded in < 5-year-olds in 2016. Cross-sectional studies on hospitalized LRTIs are available, but longitudinal studies on the total burden of viral LRTIs are scarce. This study (NCT01995175) prospectively collected incident RSV and other viral LRTIs in a multinational cohort. Methods From 2013 to 2017, infants in 8 countries were enrolled at birth and followed for LRTIs up to 2 years of age. Infants with suspected LRTIs were clinically examined and swabbed. Nasal swab samples were tested using quantitative real-time PCR for RSV and multiplex PCR panel for 16 other respiratory viruses/subtypes; bacterial culture was not performed. LRTI and severe LRTI episodes were defined per 2015 WHO LRTI case definitions. Viruses detected from nasal swabs collected from participants with WHO-defined LRTI and severe LRTI episodes are reported. Results The 2401 infants followed experienced 1012 LRTI episodes; 259 of these were severe LRTIs. At least 1 virus was detected from 909 (90%) and 235 (91%) LRTI and severe LRTI episodes, respectively. Enteroviruses/Rhinoviruses (EV/RV, 49%) were detected most frequently in samples collected from LRTI episodes, followed by RSV (22%), parainfluenza (PIV, 14%), human metapneumovirus (hMPV, 8%) and seasonal coronavirus (CoV, 6%). RSV was detected in 39% of samples from LRTI episodes in < 3-month-olds and in 18% of 1-year-olds (Table 1). In a similar trend, RSV was detected in 47% of samples from severe LRTI episodes in < 3-month-olds and in 21% of 1-year-olds (Table 2). Co-infection with another virus was common in CoV-positive samples (67%), while most samples positive for RSV (71%), hMPV (70%), EV/RV (67%) and PIV (58%) had no other virus detected. Table 1. Occurrence of laboratory confirmed respiratory viral infections by viral pathogens identified in nasal swab samples from WHO-defined LRTI episodes Table 2. Occurrence of laboratory confirmed respiratory viral infections by viral pathogens identified in nasal swab samples from WHO-defined severe LRTI episodes Conclusion Respiratory viruses are detected in the majority of LRTIs during the first 2 years of life. RSV likely accounts for much of this overall LRTI burden. Our results suggest that RSV most strongly impacted the very young; it was the most commonly detected virus in severe LRTIs in infants aged < 3 months. RSV was also persistently detected at high levels in samples from LRTIs (22%) and severe LRTIs (28%) in children up to 2 years old. Funding GlaxoSmithKline Biologicals SA Disclosures Ana Ceballos, MD, GSK group of companies (Scientific Research Study Investigator) Jo Ann Colas, MSc, GSK group of companies (Consultant) Luis Cousin, MD, Tecnología en Investigación (Scientific Research Study Investigator) Ilse Dieussaert, IR, GSK group of companies (Employee, Shareholder) Joseph B. Domachowske, MD, Astra Zeneca (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities)GSK group of companies (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities)Merck (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities) Janet A. Englund, MD, AstraZeneca (Scientific Research Study Investigator)GSK group of companies (Scientific Research Study Investigator)Meissa vaccines (Consultant)Merck (Scientific Research Study Investigator)Sanofi Pasteur (Consultant) Sanjay Gandhi, MD, GSK group of companies (Employee) Mélanie Hercor, PhD, GSK group of companies (Employee) Magali de Heusch, PhD, GSK group of companies (Employee) Joanne M. Langley, MD, GSK group of companies (Research Grant or Support)Immunivaccines Inc (Scientific Research Study Investigator, Research Grant or Support)Janssen (Research Grant or Support)Pfizer (Research Grant or Support)Symvivo (Scientific Research Study Investigator, Research Grant or Support)VBI Vaccines (Research Grant or Support) Amanda Leach, MRCPCH, GSK group of companies (Employee) Timo Vesikari, MD, PhD, Denka (Consultant) Sonia K. Stoszek, PhD, GSK group of companies (Employee, Shareholder)

Objective Summarise the published evidence on otitis media and associated hearing loss in low to middle-income countries (LMIC) and disadvantaged populations. Data sources PubMed and other databases. Review methods Firstly, sensitive search strategy using ‘otitis media’, combined with specific key words for each topic of the review, from January 2015 to June 2019. Then, restriction to LMIC and disadvantaged populations. Topics covered included prevention, epidemiology, risk factors, microbiology, prognosis, diagnosis, and treatment. Conclusions There was a high degree of methodological heterogeneity and high risk of bias. The majority of studies were school-based. In Africa, Asia and Oceania (e.g., Australian Aboriginal populations) the prevalence of OM was respectively 8% (range 3-16%), 14% (range 7–22%) and 50% (4–95%). Prevalence of any hearing loss in these regions was 12% (range 8–17%), 12% (range 3–24%), and 26% (range 25–28%) respectively. Risk factors in LMIC and disadvantaged populations included age, gender, exposure to smoke and pollution. Microbiology was reported for otitis media with effusion at time of surgery or ear discharge (acute otitis media with perforation or chronic suppurative otitis media). Specimen handling and processing in hospital laboratories was associated with low detection of S. pneumoniae and H. influenzae. Case series described complicated cases of OM due to M. tuberculosis, multidrug resistance and HIV. QOL studies identified discrimination of persons with OM and hearing loss. Diagnostic methods varied greatly, from naked eye to tympanometry. Treatment interventions were reported from four RCTs. Non-RCTs included evaluations of guidelines, surgery outcomes, access to ENTs. Implications for Clinical Practice Chronic suppurative otitis media, otitis media with effusion and conductive hearing loss are common in LMIC and disadvantaged populations. Paucity of research, poor regional representation, non-standardised methods and low-quality reporting preclude accurate assessment of disease burden in LMIC and disadvantaged populations. Awareness and adherence to reporting Guidelines should be promoted.

This study compared flocked (nylon) swabs and (non-flocked) rayon swabs for the detection of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in nasopharyngeal samples from 20 enrolled Indigenous children under the age of 6 years living in remote Australian Aboriginal communities, and determined which swab the child or parent perceived to be more comfortable. There was no evidence of a significant difference between flocked and rayon swabs in the recovery of common respiratory bacteria. Rayon swabs detected presence of S. pneumoniae (90% cf. 74%, p = 0.375), H. influenzae (79% cf. 74%, p = 1.00) and M. catarrhalis (79% cf. 74%, p = 1.00) at higher rates than the flocked swabs. Analysis of semi-quantitative growth scores also showed no significant differences in either the ranked distributions or medians. Rayon swabs median semi-quantitative growth scores were higher for S. pneumoniae (4 [IQR 1–5] cf. 3 [IQR 0–6], p = 0.699), and H. influenzae (2 [IQR1–5] cf. 1 [IQR0–5], p = 0.946). Sixty percent of participants preferred samples to be taken with flocked swabs. This study demonstrates that microbiological outcomes are not compromised when using flocked or rayon swabs in respiratory bacterial carriage studies in this population. Therefore, cost, methodological consistency across studies, and participant preference can be considered when choosing swab type.

In a phase III trial, the RTS,S/AS01 malaria vaccine produced lower anti-circumsporozoite (CS) antibody titers when co-administered with Expanded Programme on Immunization vaccines (0-, 1- and 2-month schedule) at 6 to 12 weeks compared with 5 to 17 months at first vaccination. Alternative infant immunization schedules within the Expanded Programme on Immunization were investigated.This phase II, open, single-site (Blantyre, Malawi) trial was conducted in infants 1 to 7 days of age. Subjects were equally randomized across 7 groups to receive 3 doses of RTS,S/AS01E at time points that included ≤7 days, 6, 10, 14 and 26 weeks, and 9 months. All RTS,S/AS01E groups plus a control group (without RTS,S/AS01E) received Bacillus Calmette-Guérin + oral poliovirus vaccine at ≤7 days, diphtheria, tetanus, whole-cell pertussis, hepatitis B and Haemophilus influenzae type b vaccine + oral poliovirus vaccine at 6, 10, and 14 weeks and measles vaccine at 9 months; one RTS,S/AS01E group and the control additionally received hepatitis B vaccination at ≤7 days. Serum anti-CS antibody geometric mean concentration (GMC; enzyme-linked immunosorbent assay) and safety were assessed up to age 18 months.Of the 480 infants enrolled, 391 completed the study. No causally related serious adverse event was reported. A higher frequency of fever within 7 days of RTS,S/AS01E vaccination compared with control was observed. Compared with the standard 6-, 10-, 14-week schedule, anti-CS antibody GMC ratios post-dose 3 were significantly higher in the 10-, 14- and 26-week group only (ratio 1.80; 95% confidence interval, 1.24-2.60); RTS,S/AS01E vaccination at ≤7 days and 10 and 14 weeks produced significantly lower anti-CS GMCs (ratio 0.59; 95% confidence interval, 0.38-0.92).Initiation of RTS,S/AS01E vaccination above 6 weeks of age tended to improve anti-CS antibody responses. Neonatal vaccination was well tolerated but produced a comparatively lower immune response.

Although long-term azithromycin decreases exacerbation frequency in bronchiectasis, increased macrolide resistance is concerning. We investigated macrolide resistance determinants in a secondary analysis of a multicenter randomized controlled trial. Indigenous Australian children living in remote regions and urban New Zealand Māori and Pacific Islander children with bronchiectasis were randomized to weekly azithromycin (30 mg/kg) or placebo for up to 24 months and followed post-intervention for up to 12 months. Nurses administered and recorded medications given and collected nasopharyngeal swabs 3–6 monthly for culture and antimicrobial susceptibility testing. Nasopharyngeal carriage of Haemophilus influenzae and Moraxella catarrhalis was significantly lower in azithromycin compared to placebo groups, while macrolide-resistant Streptococcus pneumoniae and Staphylococcus aureus carriage was significantly higher. Australian children, compared to New Zealand children, had higher carriage overall, significantly higher carriage of macrolide-resistant bacteria at baseline (16/38 versus 2/40 children) and during the intervention (69/152 versus 22/239 swabs), and lower mean adherence to study medication (63 % versus 92 %). Adherence ≥70 % (versus

Indigenous Australians experience one of the highest rates of pneumococcal disease globally. In the Northern Territory of Australia, a unique government-funded vaccination schedule for Indigenous Australian adults comprising multiple lifetime doses of the pneumococcal polysaccharide vaccine is currently implemented. Despite this programme, rates of pneumococcal disease do not appear to be declining, with concerns raised over the potential for immune hyporesponse associated with the use of this vaccine. We undertook a study to examine the immunogenicity and immune function of a single and repeat pneumococcal polysaccharide vaccination among Indigenous adults compared to non-Indigenous adults. Our results found that immune function, as measured by opsonophagocytic and memory B-cell responses, were similar between the Indigenous groups but lower for some serotypes in comparison with the non-Indigenous group. This is the first study to document the immunogenicity following repeat 23-valent pneumococcal polysaccharide vaccine administration among Indigenous Australian adults, and reinforces the continued need for optimal pneumococcal vaccination programmes among high-risk populations.