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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 pro...
Contexts in source publication
Context 1
... collection began in September 2011 and was completed in May 2018. The published study protocol [18] outlines all study procedures. Briefly, Np swabs were collected at 1, 2, 4, 6 and 7 months (Fig. 1). Primary endpoint samples were collected at least 28 days post 6-month dose. Ear discharge swabs were collected when discharge was observed during the otoscopic examination or at tympanometry, from both AOMwiP (defined as discharge of pus through a small perforation (hole) in the eardrum within the last 6 weeks) and CSOM (persistent ...
Citations
... We hypothesised that infants receiving PHiD-CV10 compared with those receiving PCV13 as a booster at 12 months of age would have superior outcomes in terms of immunogenicity, nasopharyngeal carriage, OM, respiratory illness, hearing loss, and developmental delay [7]. We have reported coprimary and select secondary outcomes to age 18 months [4,6,8] and OM to age 36 months [9]. ...
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
... 17,21 For each randomised controlled trial (RCT) of antibiotics or pneumococcal conjugate vaccines the nasopharyngeal microbiology, and microbiology of ear discharge from spontaneously perforated ear drums (acute otitis media with perforation) has been critically important in understanding the impact of each intervention on the complex underpinning biology (Fig. 1). 4,12,[22][23][24] Clinical outcomes alone tell us about clinical failure or success, but not why there is failure or success. Without microbiology we would be assuming clinical failure might be attributed to antimicrobial resistance (AMR), a higher virulence of strains in this population, viral interactions or high density bacterial load. ...
... Unfortunately, in this population, the microbiology again revealed the challenge of preventing otitis media. Acquisition of nasopharyngeal NTHi and non-vaccine serotypes 22 was associated with OM onset within weeks of birth in all PCV schedule groups. 18,34 Follow up to 3 years of age showed that OM persists causing chronic disabling hearing loss throughout early years for an average of 80% children. ...
Where would we be without microbiology in tackling the high prevalence of otitis media (OM; middle ear infection) and disabling hearing loss that disadvantage Australian First Nations children living in remote communities? Understanding the microbiology of OM in this population has been critical in directing innovative clinical trials research and developing appropriate evidence-based practice guidelines. While these processes are critical to reducing disadvantage associated with OM and disabling hearing loss, a remaining seemingly insurmountable gap has remained, threatening progress in improving the lives of children with ear and hearing problems. That gap is created by the crisis in primary health care workforce in remote communities. Short stay health professionals and fly-in fly-out specialist services are under-resourced to manage the complex needs of the community, including prevention and treatment of otitis media and hearing loss rehabilitation. Hence the rationale for the Hearing for Learning Initiative – a workforce enhancement model to improve sustainability, cultural appropriateness, and effectiveness of evidence-based ear and hearing health care for young children in remote settings. This paper summarises the role of microbiology in the pathway to the Hearing for Learning Initiative.
... Australian Aboriginal children have the highest rate of otitis media disease in the world, and the reality of an "Otitis Media Vaccine" has long been investigated. Studies from Australia found that, while the introduction of the PCV reduced the rate of ear infections for the targeted pneumococcal serotypes, ear disease remained high due to being replaced by previously less common non-vaccine pneumococcal serotypes, and persistence of other pathogens causing middle ear infections (predominantly non-typeable Haemophilus influenzae) [5,6]. Researchers note that such replacement has not been considered for invasive pneumococcal disease (IPD). ...
Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3 years of age and it is a common reason for doctor’s visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable H. influenza, and M. catarrhalis remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against S. pneumoniae, non-typeable H. influenza, and M. catarrhalis are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media.
Objectives
Indigenous children in Australia experience high burden of persistent otitis media (OM) from very early age. The aim was to identify distinct trajectories of OM in children up to age 10–12 years and examine the association with socio-economic determinants.
Study design
A multistage clustered national panel survey.
Methods
The study analysed the birth cohort of the Longitudinal Study of Indigenous Children from 2008 to 2018, comprising 11 study waves. Group-based trajectory modelling was used to identify different trajectories of OM outcome. Multinomial logistic regression was applied to examine the relationship between trajectories and individual, household and community-level socio-economic determinants.
Results
This analysis included 894 children with at least three responses on OM over the 11 waves, and the baseline mean age was 15.8 months. Three different trajectories of OM were identified: non-severe OM prone, early/persistent severe OM and late-onset severe OM. Overall, 11.4% of the children had early/persistent severe OM from birth to 7.5 to nine years, while late-onset severe OM consisted of 9.8% of the children who had first OM from age 3.5 to five years. Children in communities with middle and the highest socio-economic outcomes have lower relative risk of early/persistent severe OM (adjusted relative risk ratio = 0.39, 95% confidence interval = 0.22–0.70 and adjusted relative risk ratio = 0.22, 95% confidence interval = 0.09–0.52, respectively) compared to children in communities with lowest socio-economic outcomes.
Conclusion
Efforts to close the gap in the quality of life of Indigenous children must prioritise strategies that prevent severe ear disease (runny ears and perforation), including improved healthcare access, reduced household crowding, and better education, and more employment opportunities.
Background:
Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines.
Methods:
In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, Global Health, Medline, clinicaltrials.gov and trialsearch.who.int up to February 17, 2023 with no language restrictions. Studies were eligible if they presented data comparing the immunogenicity of either PCV7, PCV10 or PCV13 in head-to-head randomised trials of young children under 2 years of age, and provided immunogenicity data for at least one time point after the primary vaccination series or the booster dose. Publication bias was assessed via Cochrane's Risk Of Bias due to Missing Evidence tool and comparison-adjusted funnel plots with Egger's test. Individual participant level data were requested from publication authors and/or relevant vaccine manufacturers. Outcomes included the geometric mean ratio (GMR) of serotype-specific IgG and the relative risk (RR) of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Seroefficacy was defined as the RR of seroinfection. We also estimated the relationship between the GMR of IgG one month after priming and the RR of seroinfection by the time of the booster dose. The protocol is registered with PROSPERO, ID CRD42019124580.
Findings:
47 studies were eligible from 38 countries across six continents. 28 and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. GMRs comparing PCV13 vs PCV10 favoured PCV13 for serotypes 4, 9V, and 23F at 1 month after primary vaccination series, with 1.14- to 1.54- fold significantly higher IgG responses with PCV13. Risk of seroinfection prior to the time of booster dose was lower for PCV13 for serotype 4, 6B, 9V, 18C and 23F than for PCV10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Two-fold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (RR 0.46, 95% CI 0.23-0.96).
Interpretation:
Serotype-specific differences were found in immunogenicity and seroefficacy between PCV13 and PCV10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These findings could be used to compare PCVs and optimise vaccination strategies.
Funding:
The NIHR Health Technology Assessment Programme.
Background
Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organisation. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines.
Methods
In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, Global Health, Medline, clinicaltrials.gov and trialsearch.who.int up to July 2022 (Protocol PROSPERO ID CRD42019124580). Studies were eligible if they presented data comparing the immunogenicity of either PCV7, PCV10 or PCV13 in head-to-head randomised trials for young children, and provided at least one time point after the primary vaccination series and/or one-month after a booster dose. Individual participant level data were requested from publication authors and/or the relevant vaccine manufacturer; aggregate data were extracted if individual data were unavailable. Outcomes included the geometric mean ratio (GMR) of serotype-specific IgG and relative risk (RR) of seroinfection. Seroinfection is defined as a rise in antibody between the primary vaccination series and the booster dose, as evidence of subclinical infection. We also estimated the relationship between the GMR one month after priming and the RR of seroinfection by the time of the booster dose.
Findings
In total 45 studies were eligible from 38 countries across six continents. 27 and 12 studies with data available were included in immunogenicity and seroefficacy analyses respectively. GMRs comparing PCV13 vs PCV10 favoured PCV13 for serotypes 4, 9V, and 23F at 1 month after primary vaccination series, with 1.14- to 1.54- fold significantly higher IgG responses with PCV13. Risk of seroinfection prior to the time of booster dose was lower for PCV13 for serotype 4, 6B, 9V, 18C and 23F than for PCV10. Two-fold higher antibody after primary vaccination was associated with 54% decrease in risk of seroinfection (RR 0.46, 95%CI 0.23-0.96).
Conclusion
Serotype-specific differences were found in immunogenicity and seroefficacy between PCV10 and PCV13. Higher immunogenicity of PCVs are associated with lower risk of subsequent infection. These findings could be further used to compare PCVs and optimise vaccination strategy.
