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.

The effectiveness of maternal pertussis vaccination for protecting Aboriginal and Torres Strait Islander infants against infection, 2012-2017: a retrospective cohort study.

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

Evaluating the role of asymptomatic throat carriage of Streptococcus pyogenes in impetigo transmission in remote Aboriginal communities in Northern Territory, Australia: a retrospective genomic analysis.

BACKGROUND: Streptococcus pyogenes, or group A Streptococcus (GAS), infections contribute to a high burden of disease in Aboriginal Australians, causing skin infections and immune sequelae such as rheumatic heart disease. Controlling skin infections in these populations has proven difficult, with transmission dynamics being poorly understood. We aimed to identify the relative contributions of impetigo and asymptomatic throat carriage to GAS transmission. METHODS: In this genomic analysis, we retrospectively applied whole genome sequencing to GAS isolates that were collected as part of an impetigo surveillance longitudinal household survey conducted in three remote Aboriginal communities in the Northern Territory of Australia between Aug 6, 2003, and June 22, 2005. We included GAS isolates from all throats and impetigo lesions of people living in two of the previously studied communities. We classified isolates into genomic lineages based on pairwise shared core genomes of more than 99% with five or fewer single nucleotide polymorphisms. We used a household network analysis of epidemiologically and genomically linked lineages to quantify the transmission of GAS within and between households. FINDINGS: We included 320 GAS isolates in our analysis: 203 (63%) from asymptomatic throat swabs and 117 (37%) from impetigo lesions. Among 64 genomic lineages (encompassing 39 emm types) we identified 264 transmission links (involving 93% of isolates), for which the probable source was asymptomatic throat carriage in 166 (63%) and impetigo lesions in 98 (37%). Links originating from impetigo cases were more frequent between households than within households. Households were infected with GAS for a mean of 57 days (SD 39 days), and once cleared, reinfected 62 days (SD 40 days) later. Increased household size and community presence of GAS and scabies were associated with slower clearance of GAS. INTERPRETATION: In communities with high prevalence of endemic GAS-associated skin infection, asymptomatic throat carriage is a GAS reservoir. Public health interventions such as vaccination or community infection control programmes aimed at interrupting transmission of GAS might need to include consideration of asymptomatic throat carriage. FUNDING: Australian National Health and Medical Research Council.

Inequity of antenatal influenza and pertussis vaccine coverage in Australia: the Links2HealthierBubs record linkage cohort study, 2012-2017.

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

Timing and temporal trends of influenza and pertussis vaccinations during pregnancy in three Australian jurisdictions: The Links2HealthierBubs population-based linked cohort study, 2012-2017.

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

Novel Human Parechovirus 3 Diversity, Recombination, and Clinical Impact Across 7 Years: An Australian Story.

BACKGROUND: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV3-AR strain and its association with severe HPeV infections. METHODS: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in 2 Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific polymerase chain reaction was designed and utilized to screen all clinical and community HPeV3-positive samples. RESULTS: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3' end of the nonstructural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed that most (>75%) hospitalized HPeV3 cases involved the AR strain in the first 3 clinical outbreaks, with declining prevalence in the 2019-2020 season. The AR strain was not statistically associated with increased clinical severity among hospitalized infants. CONCLUSIONS: HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

Evidence of maternal transfer of antigen-specific antibodies in serum and breast milk to infants at high-risk of S. pneumoniae and H. influenzae disease.

Introduction: Children in low-mid income countries, and First Nations children in high-income countries, experience disproportionately high rates of Streptococcus pneumoniae and Haemophilus influenzae infections and diseases including pneumonia and otitis media. We previously observed that infants from Papua New Guinea had no evidence of waning maternal immunity for H. influenzae-specific antibodies. In this study, we assessed S. pneumoniae and H. influenzae antibody titres in Australian First Nation mothers and infants to determine antigen-specific antibody ontogenies and whether H. influenzae antibody titres in infants were due to low maternal antibody titres or lack of placental transfer. Methods: Breast milk, infant nasopharyngeal swabs and ear assessment data were collected 1-, 2-, 7-months post-birth as well as maternal, cord and 7-month-old infant sera, from 85 Australian Aboriginal and Torres Strait Islander mother-infant pairs. Serum IgG and breast milk IgG and IgA antibody titres to S. pneumoniae antigens (PspA1, PspA2, CbpA, Ply) and H. influenzae antigens (PD, ChimV4, OMP26, rsPilA) were measured. Results: IgG titres in maternal and cord sera were similar for all antigens, except Ply (higher in cord; p=0.004). Sera IgG titres at 7-months of age were lower than cord sera IgG titres for all S. pneumoniae antigens (p<0.001). Infant sera IgG titres were higher than cord sera for H. influenzae PD (p=0.029), similar for OMP26 (p=0.817) and rsPilA (p=0.290), and lower for ChimV4 (p=0.004). Breast milk titres were similar for all antigens at 1, 2 and 7-months except OMP26 IgA (lower at 7-months than 1-month; p=0.035), PspA2 IgG (p=0.012) and Ply IgG that increased by 7-months (p=0.032). One third of infants carried nontypeable Haemophilus influenzae (NTHi), 45% carried S. pneumoniae and 52% had otitis media (OM) observed at least once over the 7-months. 73% of infants who carried either S. pneumoniae or NTHi, also had otitis media observed. Conclusions: Similarities between maternal and cord IgG titres, and absence of waning, support a lack of maternal H. influenzae IgG antibodies available for cross-placental transfer. Increased maternal anti-PD IgG could offer some protection from early carriage with NTHi, and maternal immunisation strategies should be considered for passive-active immunisation of infants to protect against S. pneumoniae and H. influenzae diseases. Trial registration: ClinicalTrials.gov NCT00714064 and NCT00310349.

Discord between presence of follicular conjunctivitis and Chlamydia trachomatis infection in a single Torres Strait Island community: a cross-sectional survey.

OBJECTIVE: Recent surveys identified trachomatous inflammation - follicular (TF) at endemic levels in the Torres Strait Islands; however, local health staff do not report trachomatous trichiasis (TT) in adults. We undertook a cross-sectional survey involving eye examination and microbiological testing to better understand this disconnect. METHODS: We examined 169 of 207 (82%) residents and collected ocular swabs for polymerase chain reaction (PCR) testing for Chlamydia trachomatis. Other viral PCR tests and bacterial culture were also performed. RESULTS: TF prevalence in children aged 5-9 years was 23% (7/30). No ocular C. trachomatis was identified by PCR. For the 72 participants (43%) with follicles, bacterial culture was positive for 11 (15%) individuals. No individual had trachomatous trichiasis. CONCLUSIONS: Follicular conjunctivitis consistent with TF was prevalent but ocular C. trachomatis and cicatricial trachoma were absent. Non-chlamydial infections or environmental causes of follicular conjunctivitis may be causing TF in this community. IMPLICATIONS FOR PUBLIC HEALTH: In similar settings, reliance on simplified clinical assessment alone may lead to an overestimation of the public health problem posed by trachoma. Consideration should be given to incorporating C. trachomatis PCR, and in certain settings, a detailed clinical exam could be performed by an experienced ophthalmologist during prevalence surveys.

Drivers of the summer influenza epidemic in New South Wales, 2018-19.

OBJECTIVES: To assess the extent to which the 2018-19 New South Wales summer influenza epidemic was associated with overseas or domestic travel and with seasonal influenza vaccination status. DESIGN, SETTING: Unmatched case-control study, based on an online survey distributed from the NSW Notifiable Conditions Information Management System (NCIMS) to people for whom mobile phone numbers were available. PARTICIPANTS: A case was defined as a person with notified laboratory-confirmed influenza with onset of illness between 1 December 2018 and 21 March 2019. People with notified pertussis infections (confirmed or probable) were selected as controls. MAIN OUTCOME MEASURES: Notified influenza infection, by travel and contact with unwell overseas travellers in the week before onset of illness and seasonal influenza vaccination status (as the primary exposures). RESULTS: Valid survey responses were provided by 648 of 2806 invited people with notified influenza (23%) and 257 of 796 invited people with notified pertussis (32%). The demographic characteristics of the respondents were similar to those of the source population (7251 cases, 2254 controls). During the first two months of the summer of 2018-19, notified influenza was more likely for people who had travelled overseas or had contact with an ill overseas traveller in the week before symptom onset (adjusted OR [aOR], 6.99; 95% CI, 3.59-13.6), but not during the second two months (aOR, 1.63; 95% CI, 0.79-3.35). Influenza vaccination status was not associated with the likelihood of notified influenza. CONCLUSIONS: Travel-related factors were early drivers of the 2018-19 NSW summer influenza epidemic; local transmission sustained the outbreak despite unfavourable conditions later in summer. Our findings prompted re-evaluation of recommendations for pre-travel vaccination in NSW. The role of travel in out-of-season influenza outbreaks should be considered in other temperate zones.

National predictors of influenza vaccine uptake in pregnancy: the FluMum prospective cohort study, Australia, 2012-2015.

OBJECTIVE: Ascertain predictors of inactivated influenza vaccine (IIV) uptake in pregnancy in mother-infant pairs from six Australian sites over four consecutive influenza seasons (2012-2015). METHODS: Prospective observational cohort study calculating proportions of unvaccinated and vaccinated pregnancies. Multivariable logistic regression calculating adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) to determine demographic, pregnancy and birth characteristics as predictors of IIV uptake in pregnancy. RESULTS: Uptake of IIV was 36% (n=3,651/9,878) with only 3-4% during the first trimester. Validation of IIV receipt was obtained for 77% of vaccinated participants. Predictors of IIV uptake in pregnancy were: healthcare provider recommendation to have IIV during pregnancy (aOR 7.04 [95%CI 5.83-8.50]): GP (aOR 4.12 [95%CI 3.43-4.98]), obstetrician (aOR 4.41 [95%CI 3.45-5.64]), midwife (aOR 1.88 [95%CI 1.51-2.36]); previous IIV within 12 months of their current pregnancy (aOR 2.87 [95%CI 2.36-3.50]); and pertussis vaccination during the current pregnancy (aOR 4.88 [95%CI 4.08-5.83]). Conclusions and implications for public health: Healthcare provider discussions with pregnant women about the risks associated with influenza infection during pregnancy and early infancy and evidence about the safety and effectiveness of IIV are required. Recommending and offering IIV in pregnancy needs to be included in these discussions to improve uptake.

Investigating inequities in cardiovascular care and outcomes for Queensland Aboriginal and Torres Strait Islander people: protocol for a hospital-based retrospective cohort data linkage project.

INTRODUCTION: Cardiovascular disease (CVD) represents a significant burden of disease for Aboriginal and Torres Strait Islander people, a population that continues to experience a lower life expectancy than other Australians. The aim of the Better Cardiac Care Data Linkage project is to describe patient care pathways and to identify disparities in care and health outcomes between Aboriginal and Torres Strait Islander people and other Queensland residents diagnosed with CVD in the state of Queensland. METHODS: This is a population-based retrospective cohort study using linked regional, state and national health and administrative data collections to describe disparities in CVD healthcare in primary and secondary prevention settings and during hospitalisation. The CVD cohort will be identified from the Queensland Hospital Admitted Patient Data Collection for admissions that occurred between 1 July 2010 and 31 June 2016 and will include relevant International Classification of Disease codes for ischaemic heart disease, congestive heart failure, stroke, acute rheumatic fever and rheumatic heart disease. Person-level data will be linked by Data Linkage Queensland and the Australian Institute of Health and Welfare (AIHW) in accordance with ethical and public health approvals to describe the patient journey prior to, during and post the hospital admission. ANALYSIS: This project will focus largely on descriptive epidemiological measures and multivariate analysis of clinical care standards and outcomes for Aboriginal and Torres Strait Islander people compared with other Queenslanders, including identification of risk factors for suboptimal care and change over time. Variation in care pathways and patient outcomes will be compared by Indigenous status, sex, age group, remoteness of residence, year of index hospitalisation and socioeconomic status. Cox models for time-to-event data and mixed models or generalised estimating equations for longitudinal data will be used to measure change over time where temporal effects exist. ETHICS AND DISSEMINATION: Ethical approval has been granted by Human Research Ethics Committees of the Prince Charles Hospital (HREC/15/QPCH/289) and the AIHW (EO2016-1-233). The Northern Territory Department of Health and Menzies School of Health Research have also provided reciprocal ethical approval of the project (HREC 2019-3490). The deidentified results will be summarised in a report and shared with investigators, advisory groups, Queensland Health and key stakeholders. Findings will be disseminated through workshops, conferences and will be published in peer-reviewed journals.

Impact of Meningococcal B (4CMenB) Vaccine on Pharyngeal Neisseria meningitidis Carriage Density and Persistence in Adolescents.

BACKGROUND: Higher density of Neisseria meningitidis carriage may be associated with transmission of the meningococcus. Our aim was to establish the impact of meningococcal B (4CMenB) vaccine on N. meningitidis carriage density. METHODS: We compared 4CMenB vaccine to control among 913 South Australian students aged approximately 15-18 years in a cluster randomized trial who had N. meningitidis carriage at 12 months. Oropharyngeal swabs were collected at baseline and 12 months later to detect N. meningitidis carriage. Colony-forming units per milliliter (CFU/mL) were estimated by generating a standard curve that plotted quantitative polymerase chain reaction cycle threshold values against log-normalized CFU. RESULTS: Among the 913 students with N. meningitidis carriage at 12 months, there was no difference in mean carriage density between the vaccinated (n = 434; 3.80 log CFU/mL [standard deviation {SD}, 1.29]) and control group (n = 479; 3.73 log CFU/mL [SD, 1.30]; P = .51). Higher N. meningitidis carriage density at baseline was associated with an increase in the odds of persistent carriage at 12 months (n = 504; odds ratio [OR] per 1.0 log CFU/mL increase in density, 1.36 [95% confidence interval {CI}, 1.17-1.58]; P < .001). Students with baseline carriage who were vaccinated had decreased persistent N. meningitidis carriage at 12 months compared to unvaccinated students (81/260 [31%] vs 105/244 [43%]; OR, 0.60 [95% CI, .40-.90]; P = .01). CONCLUSIONS: 4CMenB vaccine did not reduce carriage density of N. meningitidis 12 months postvaccination, despite increased carriage clearance. Higher carriage density is likely to enable transmission through prolonged periods of population exposure. CLINICAL TRIALS REGISTRATION: NCT03089086.

Strongyloides stercoralis seropositivity is not associated with increased symptoms in a remote Aboriginal community.

BACKGROUND: Strongyloides stercoralis is a soil-transmitted helminth, endemic in remote Aboriginal and Torres Strait Islander communities in northern Australia with estimates of prevalences up to 60%. Hyperinfection in the setting of immunosuppression is a rare, but well recognised cause of significant morbidity and mortality. However, the morbidity associated with chronic uncomplicated infection is less well characterised. AIMS: To measure the prevalence of symptoms potentially attributable to S. stercoralis infection and their association with seropositivity. METHODS: This retrospective matched case-control study reviewed records of primary healthcare presentations for symptoms in the 12 months before and after an ivermectin mass drug administration (MDA) in a remote Aboriginal community. RESULTS: One hundred and seventy-five S. stercoralis seropositive cases were matched with 175 seronegative controls. The most frequently reported symptom overall in the 12 months prior to the MDA was cough followed by abdominal pain, weight loss/malnutrition, diarrhoea and pruritis. Seropositive cases were not more likely than matched controls to have symptoms typically attributed to strongyloidiasis. In the seropositive cohort, we found no difference in symptoms in the 12 months before and after an ivermectin MDA despite a reduction in seroprevalence. CONCLUSION: We found no evidence to suggest that S. stercoralis seropositivity was associated with increased symptoms when compared to matched seronegative controls. Treatment with ivermectin did not reduce symptoms in seropositive cases. Without evidence to support that population-based screening or treatment programmes reduce symptoms, the emphasis must remain on identifying and managing those few individuals with immunosuppression that predisposes them to potentially life-threatening hyperinfection.

Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis.

BACKGROUND: Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage. METHODS: A search within PubMed, Embase, Scopus, and unpublished studies up to 1 February 2020 was conducted. RESULTS: After removal of duplicates, 8565 studies were screened and 27 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio [OR], 0.13 [95% confidence interval {CI}, .07-.23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR, 0.35 [95% CI, .25-.48]), and meningococcal A, C, W, Y (MenACWY) vaccines against group ACWY IMD (OR, 0.31 [95% CI, .20-.49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0.25 [95% CI, .19-.36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR], 0.88 [95% CI, .66-1.18]), unlike monovalent C vaccines (RR, 0.50 [95% CI, .26-.97]). 4CMenB vaccine had no effect on group B carriage (RR, 1.12 [95% CI, .90-1.40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR, 0.98 [95% CI, .53-1.79]). CONCLUSIONS: Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant MenB vaccines, which has implications for immunization strategies. CLINICAL TRIALS REGISTRATION: CRD42018082085 (PROSPERO).

Estimation of the force of infection and infectious period of skin sores in remote Australian communities using interval-censored data.

Prevalence of impetigo (skin sores) remains high in remote Australian Aboriginal communities, Fiji, and other areas of socio-economic disadvantage. Skin sore infections, driven primarily in these settings by Group A Streptococcus (GAS) contribute substantially to the disease burden in these areas. Despite this, estimates for the force of infection, infectious period and basic reproductive ratio-all necessary for the construction of dynamic transmission models-have not been obtained. By utilising three datasets each containing longitudinal infection information on individuals, we estimate each of these epidemiologically important parameters. With an eye to future study design, we also quantify the optimal sampling intervals for obtaining information about these parameters. We verify the estimation method through a simulation estimation study, and test each dataset to ensure suitability to the estimation method. We find that the force of infection differs by population prevalence, and the infectious period is estimated to be between 12 and 20 days. We also find that optimal sampling interval depends on setting, with an optimal sampling interval between 9 and 11 days in a high prevalence setting, and 21 and 27 days for a lower prevalence setting. These estimates unlock future model-based investigations on the transmission dynamics of skin sores.

Correction: Antibiotic use for Australian Aboriginal children in three remote Northern Territory communities.

[This corrects the article DOI: 10.1371/journal.pone.0231798.].

Acute lower respiratory infections in Indigenous infants in Australia's Northern Territory across three eras of pneumococcal conjugate vaccine use (2006-15): a population-based cohort study.

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.

Antibiotic use for Australian Aboriginal children in three remote Northern Territory communities.

OBJECTIVE: To describe antibiotic prescription rates for Australian Aboriginal children aged <2 years living in three remote Northern Territory communities. DESIGN: A retrospective cohort study using electronic health records. SETTING: Three primary health care centres located in the Katherine East region. PARTICIPANTS: Consent was obtained from 149 mothers to extract data from 196 child records. There were 124 children born between January 2010 and July 2014 who resided in one of the three chosen communities and had electronic health records for their first two years of life. MAIN OUTCOME MEASURES: Antibiotic prescription rates, factors associated with antibiotic prescription and factors associated with appropriate antibiotic prescription. RESULTS: There were 5,675 Primary Health Care (PHC) encounters for 124 children (median 41, IQR 25.5, 64). Of the 5,675 PHC encounters, 1,542 (27%) recorded at least one infection (total 1,777) and 1,330 (23%) had at least one antibiotic prescription recorded (total 1,468). Children had a median five (IQR 2, 9) prescriptions in both their first and second year of life, with a prescription rate of 5.99/person year (95% CI 5.35, 6.63). Acute otitis media was the most common infection (683 records, 38%) and Amoxycillin was the most commonly prescribed antibiotic (797 prescriptions, 54%). Of the 1,468 recorded prescriptions, 398 (27%) had no infection recorded and 116 (8%) with an infection recorded were not aligned with local treatment guidelines. CONCLUSION: Prescription rates for Australian Aboriginal children in these communities are significantly higher than that reported nationally for non-Aboriginal Australians. Prescriptions predominantly aligned with treatment guidelines in this setting where there is a high burden of infectious disease.

Birth outcomes in Aboriginal mother-infant pairs from the Northern Territory, Australia, who received 23-valent polysaccharide pneumococcal vaccination during pregnancy, 2006-2011: The PneuMum randomised controlled trial.

BACKGROUND: Pregnant women and infants <6 months old have a high baseline risk for pneumococcal disease compared to the general population, particularly among Indigenous populations living in poverty and low-resource settings. Efficacy trials of pneumococcal vaccination in pregnancy examining adverse birth outcomes are lacking. AIMS: We report adverse birth events as secondary outcomes from the 'PneuMum' randomised controlled trial of 23-valent pneumococcal polysaccharide vaccination (23vPPV) in pregnancy (August 2006-January 2011). MATERIALS AND METHODS: Australian Aboriginal women aged 17-39 years with singleton uncomplicated pregnancies were randomised (1:2 ratio) to receive 23vPPV or no 23vPPV in pregnancy at 30-36 weeks gestation. We compared risks of stillbirth, preterm birth, low birthweight (LBW), and small for gestational age (SGA) between vaccinated and unvaccinated pregnant women. Cox proportional hazard ratios (HRs) were calculated on an intention-to-treat basis. RESULTS: Among 227 enrolled participants, 75 (33%) received 23vPPV in pregnancy. Risk differences in adverse birth outcomes between 23vPPV vaccinated and unvaccinated pregnant women were; preterm birth 9% vs 4% (HR 2.79; 95% CI 0.94-8.32) P = 0.07; LBW 9% vs 5% (HR 2.09; 95% CI 0.76-5.78) P = 0.15; and SGA 15% vs 17% (HR 1.02; 95% CI 0.50-2.06) P = 0.96. There were no stillbirths. CONCLUSIONS: We found a numerically higher rate of preterm births among women who received 23vPPV in pregnancy compared to unvaccinated pregnant women. Although further investigation with larger participant numbers is needed to better evaluate this safety signal, the contribution of safety results from smaller studies using appropriate data analysis methodologies is critical, particularly as more clinical trials in pneumococcal vaccination in pregnancy are progressing.

A Rationale for Change: An Increase in Invasive Pneumococcal Disease in Fully Vaccinated Children.

Increasing numbers of cases of invasive pneumococcal disease in fully vaccinated children have occurred in Australia since 2013. A review of cases informed a change from a "3 + 0" infant schedule (13-valent pneumococcal conjugate vaccine at 2, 4, and 6 months) to a "2 + 1" schedule (2, 4, and 12 months).