Paediatrics (RCH) - Research Publications
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ItemNo long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine(Elsevier, 2016-06)Background: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. Objective: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. Methods: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. Results: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. Conclusion: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.
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ItemNo Preview AvailableEffect of a 2+1 schedule of ten-valent versus 13-valent pneumococcal conjugate vaccine on pneumococcal carriage: Results from a randomised controlled trial in Vietnam(ELSEVIER SCI LTD, 2021-04-15)BACKGROUND: Pneumococcal conjugate vaccines (PCVs) generate herd protection by reducing nasopharyngeal (NP) carriage. Two PCVs, PCV10 and PCV13, have been in use for over a decade, yet there are few data comparing their impact on carriage. Here we report their effect on carriage in a 2+1 schedule, compared with each other and with unvaccinated controls. METHODS: Data from four groups within a parallel, open-label randomised controlled trial in Ho Chi Minh City contribute to this article. Three groups were randomised to receive a 2+1 schedule of PCV10 (n = 250), a 2+1 schedule of PCV13 (n = 251), or two doses of PCV10 at 18 and 24 months (controls, n = 197). An additional group (n = 199) was recruited at 18 months to serve as controls from 18 to 24 months. NP swabs collected at 2, 6, 9, 12, 18, and 24 months were analysed (blinded) for pneumococcal carriage. This study aimed to determine if PCV10 and PCV13 have a differential effect on pneumococcal carriage, a secondary outcome of the trial. We also describe the serotype distribution among unvaccinated participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953510. FINDINGS: Compared with unvaccinated controls, a 2+1 schedule of PCV10 reduced PCV10-type carriage by 45-62% from pre-booster through to 24 months of age, and a 2+1 schedule of PCV13 reduced PCV13-type carriage by 36-49% at 12 and 18 months of age. Compared directly with each other, there were few differences between the vaccines in their impact on carriage. Vaccine serotypes accounted for the majority of carriage in unvaccinated participants. INTERPRETATION: Both PCV10 and PCV13 reduce the carriage of pneumococcal vaccine serotypes. The introduction of either vaccine would have the potential to generate significant herd protection in this population. FUNDING: National Health and Medical Research Council of Australia, Bill & Melinda Gates Foundation.
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ItemSynergism and Antagonism of Bacterial-Viral Coinfection in the Upper Respiratory Tract(AMER SOC MICROBIOLOGY, 2022-02-23)Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal coinfections with respiratory syncytial virus (RSV). Here, we developed a novel infant mouse model of coinfection using pneumonia virus of mice (PVM), a murine analogue of RSV, to examine the dynamics of coinfection in the upper respiratory tract, an anatomical niche that is essential for host-to-host transmission and progression to disease. Coinfection increased damage to the nasal tissue and increased production of the chemokine CCL3. Nasopharyngeal pneumococcal density and shedding in nasal secretions were increased by coinfection. In contrast, coinfection reduced PVM loads in the nasopharynx, an effect that was independent of pneumococcal strain and the order of infection. We showed that this "antagonistic" effect was absent using either ethanol-killed pneumococci or a pneumococcal mutant deficient in capsule production and incapable of nasopharyngeal carriage. Colonization with a pneumococcal strain naturally unable to produce capsule also reduced viral loads. The pneumococcus-mediated reduction in PVM loads was caused by accelerated viral clearance from the nasopharynx. Although these synergistic and antagonistic effects occurred with both wild-type pneumococcal strains used in this study, the magnitude of the effects was strain dependent. Lastly, we showed that pneumococci can also antagonize influenza virus. Taken together, our study has uncovered multiple novel facets of bacterial-viral coinfection. Our findings have important public health implications, including for bacterial and viral vaccination strategies in young children. IMPORTANCE Respiratory bacterial-viral coinfections (such as pneumococci and influenza virus) are often synergistic, resulting in enhanced disease severity. Although colonization of the nasopharynx is the precursor to disease and transmission, little is known about bacterial-viral interactions that occur within this niche. In this study, we developed a novel mouse model to examine pneumococcal-viral interactions in the nasopharynx with pneumonia virus of mice (PVM) and influenza. We found that PVM infection benefits pneumococci by increasing their numbers in the nasopharynx and shedding of these bacteria in respiratory secretions. In contrast, we discovered that pneumococci decrease PVM numbers by accelerating viral clearance. We also report a similar effect of pneumococci on influenza. By showing that coinfections lead to both synergistic and antagonistic outcomes, our findings challenge the existing dogma in the field. Our work has important applications and implications for bacterial and viral vaccines that target these microbes.
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ItemThe impact of 10-valent pneumococcal vaccine introduction on invasive disease in Fiji(ELSEVIER, 2022-03)BACKGROUND: In 2012, Fiji introduced the 10-valent pneumococcal conjugate vaccine (PCV10). We assessed the impact of PCV10 on invasive pneumococcal disease (IPD), probable bacterial or pneumococcal meningitis (PBPM), meningitis and sepsis 3-5 years post-introduction. METHODS: Laboratory-confirmed IPD and PBPM cases were extracted from national laboratory records. ICD-10-AM coded all-cause meningitis and sepsis cases were extracted from national hospitalisation records. Incidence rate ratios were used to compare outcomes pre/post-PCV10, stratified by age groups: 1-23m, 2-4y, 5-9y, 10-19y, 20-54y, ≥55y. To account for different detection and serotyping methods in the pre-and post-PCV10 period, a Bayesian inference model estimated serotype-specific changes in IPD, using pneumococcal carriage and surveillance data. FINDINGS: There were 423 IPD, 1,029 PBPM, 1,391 all-cause meningitis and 7,611 all-cause sepsis cases. Five years post-PCV10 introduction, IPD declined by 60% (95%CI: 37%, 76%) in children 1-23m months old, and in age groups 2-4y, 5-9y, 10-19y although confidence intervals spanned zero. PBPM declined by 36% (95%CI: 21%, 48%) among children 1-23 months old, and in all other age groups, although some confidence intervals spanned zero. Among children <5y of age, PCV10-type IPD declined by 83% (95%CI; 70%, 90%) and with no evidence of change in non-PCV10-type IPD (9%, 95%CI; -69, 43%). There was no change in all-cause meningitis or sepsis. Post-PCV10, the most common serotypes in vaccine age-eligible and non-age eligible people were serotypes 8 and 23B, and 3 and 7F, respectively. INTERPRETATIONS: Our study demonstrates the effectiveness of PCV10 against IPD in a country in the Asia-Pacific of which there is a paucity of data. FUNDING: This study was support by the Department of Foreign Affairs and Trade of the Australian Government and Fiji Health Sector Support Program (FHSSP). FHSSP is implemented by Abt JTA on behalf of the Australian Government.
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ItemImmunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to vietnamese children at 18 months of age(ELSEVIER, 2021-11)BACKGROUND: This study investigated the immunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to 18-month-old Vietnamese children. This information is important for countries considering catch-up vaccination during PCV introduction and in the context of vaccination during humanitarian crises. METHODS: Two groups of PCV-naïve children within the Vietnam Pneumococcal Project received PCV10 (n=197) or no PCV (unvaccinated; n=199) at 18 months of age. Blood samples were collected at 18, 19, and 24 months of age, and nasopharyngeal swabs at 18 and 24 months of age. Immunogenicity was assessed by measuring serotype-specific IgG, opsonophagocytosis (OPA) and memory B cells (Bmem). Pneumococci were detected and quantified using real-time PCR and serotyped by microarray. FINDINGS: At 19 months of age, IgG and OPA responses were higher in the PCV10 group compared with the unvaccinated group for all PCV10 serotypes and cross-reactive serotypes 6A and 19A. This was sustained out to 24 months of age, at which point PCV10-type carriage was 60% lower in the PCV10 group than the unvaccinated group. Bmem levels increased between 18 and 24 months of age in the vaccinated group. INTERPRETATION: We demonstrate strong protective immune responses in vaccinees following a single dose of PCV10 at 18 months of age, and a potential impact on herd protection through a substantial reduction in vaccine-type carriage. A single dose of PCV10 in the second year of life could be considered as part of catch-up campaigns or in humanitarian crises to protect children at high-risk of pneumococcal disease.
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ItemPrevalence of Streptococcus pneumoniae in conjunctival flora and association with nasopharyngeal carriage among children in a Vietnamese community(NATURE PORTFOLIO, 2021-01-11)Conjunctival pneumococcal serotypes among members of a community have not been investigated well. We determined the prevalence and association of Streptococcus pneumoniae in the nasopharynx and conjunctiva among children in a community before pneumococcal conjugate vaccine introduction. In October 2016, conjunctival and nasopharyngeal swabs were collected from children (< 24 months old) and nasopharyngeal swabs from mothers in Nha Trang, Vietnam. Quantitative lytA PCR and DNA microarray were performed to detect and serotype S. pneumoniae. The association between S. pneumoniae in the nasopharynx and conjunctiva was evaluated using multivariable logistic regression model. Among 698 children, 62 (8.9%, 95% CI 6.9-11.2%) were positive for S. pneumoniae in the conjunctiva. Non-encapsulated S. pneumoniae were most commonly identified, followed by serotypes 6A, 6B, and 14. Nasopharyngeal and conjunctival detection were positively associated (aOR 47.30, 95% CI 24.07-92.97). Low birth-weight, day-care attendance, and recent eye symptoms were independently associated with S. pneumoniae detection in the conjunctiva (aOR 11.14, 95% CI 3.76-32.98, aOR 2.19, 95% CI 1.45-3.31, and aOR 3.59, 95% CI 2.21-5.84, respectively). Serotypes and genotypes in the conjunctiva and nasopharynx matched in 87% of the children. Three mothers' nasopharyngeal pneumococcal samples had matched serotype and genotype with their child's in the conjunctiva and nasopharynx. S. pneumoniae presence in nasopharynx and conjunctiva were strongly associated. The high concordance of serotypes suggests nasopharyngeal carriage may be a source of transmission to the conjunctiva.
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ItemSimplified 0+1 and 1+1 pneumococcal vaccine schedules in Ho Chi Minh City, Vietnam: protocol for a randomised controlled trial(BMJ PUBLISHING GROUP, 2021-11)INTRODUCTION: Reduced-dose schedules offer a more efficient and affordable way to use pneumococcal conjugate vaccines (PCVs). Such schedules rely primarily on the maintenance of herd protection. The Vietnam Pneumococcal Trial II (VPT-II) will evaluate reduced-dose schedules of PCV10 and PCV13 utilising an unvaccinated control group. Schedules will be compared in relation to their effect on nasopharyngeal carriage and immunogenicity. METHODS AND ANALYSIS: VPT-II is a single-blind open-label randomised controlled trial of 2500 infants in three districts of Ho Chi Minh City, Vietnam. Eligible infants have no clinically significant maternal or perinatal history and are born at or after 36 weeks' gestation. Participants are recruited at 2 months of age and randomly assigned (4:4:4:4:9) using block randomisation, stratified by district, to one of five groups: four intervention groups that receive PCV10 in a 0+1 (at 12 months) or 1+1 (at 2 and 12 months) schedule or PCV13 in the same 0+1 or 1+1 schedule; and a control group (that receives a single dose of PCV10 at 24 months). Participants are followed up to 24 months of age. The primary outcome is vaccine-type pneumococcal carriage at 24 months of age. Secondary outcomes are carriage at 6, 12 and 18 months of age and the comparative immunogenicity of the different schedules in terms of antibody responses, functional antibody responses and memory B cell responses. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the Royal Children's Hospital Melbourne and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences and published in peer-reviewed open access journals. TRIAL REGISTRATION NUMBER: NCT03098628.
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ItemDirect and indirect effects of 13-valent pneumococcal conjugate vaccine on pneumococcal carriage in children hospitalised with pneumonia from formal and informal settlements in Mongolia: an observational study(ELSEVIER, 2021-10)BACKGROUND: Within Ulaanbaatar, Mongolia, risk factors for pneumonia are concentrated among children living in informal settlements comprised of temporary shelters (gers). We used pneumococcal carriage surveillance among children from formal and informal settlements hospitalised with pneumonia to evaluate the direct and indirect effects of 13-valent pneumococcal conjugate vaccine (PCV13) against vaccine-type (VT) pneumococcal carriage following a phased introduction of PCV13. METHODS: We enrolled and collected nasopharyngeal swabs from children 2-59 months of age presenting to hospital. Pneumococci were detected using lytA qPCR and serotyped using microarray on a random monthly selection of swabs between November 2015 and March 2019 from two districts in Ulaanbaatar. PCV13 status was determined using written records. We quantified the associations between individual PCV13 status (direct effects) and district-level PCV13 coverage (indirect effects) and VT carriage using generalised estimating equations and explored interactions by settlement type. FINDINGS: A total of 1 292 swabs from 6 046 participants were tested for pneumococci. Receipt of PCV13 and increasing PCV13 coverage independently reduced the risk of VT carriage. For each percent increase in PCV13 coverage, the adjusted odds of VT carriage decreased by 1•0% (OR 95% CI 0•983-0•996; p=0•001), with a predicted decrease in VT carriage rate from 29•1% to 13•1% as coverage reached 100%. There was a trend towards a slower decline within informal settlements (p=0•100). Adjusted PCV13 vaccine effectiveness against VT carriage was 39•1% (95% CI 11•4-58•1%, p=0•009). INTERPRETATION: Substantial indirect effects were observed following PCV13 introduction, including among children living within informal settlements. FUNDING: Bill & Melinda Gates Foundation; Gavi, the Vaccine Alliance.
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ItemIndirect effects of 13-valent pneumococcal conjugate vaccine on pneumococcal carriage in children hospitalised with acute respiratory infection despite heterogeneous vaccine coverage: an observational study in Lao People's Democratic Republic(BMJ PUBLISHING GROUP, 2021-06)INTRODUCTION: Empiric data on indirect (herd) effects of pneumococcal conjugate vaccines (PCVs) in settings with low or heterogeneous PCV coverage are limited. The indirect effects of PCV, which benefits both vaccinated and non-vaccinated individuals, are mediated by reductions in vaccine-type (VT) carriage (a prerequisite for disease). The aim of this study among hospitalised children in Lao People's Democratic Republic (Lao PDR) is to determine the effectiveness of a 13-valent PCV (PCV13) against VT pneumococcal nasopharyngeal carriage (direct effects) and the association between village-level PCV13 coverage and VT carriage (indirect effects). METHODS: Pneumococcal nasopharyngeal carriage surveillance commenced in December 2013, shortly after PCV13 introduction (October 2013). We recruited and swabbed children aged 2-59 months admitted to hospital with acute respiratory infection. Pneumococci were detected using lytA quantitative real-time PCR and serotyped using microarray. PCV13 status and village-level PCV13 coverage were determined using written immunisation records. Associations between both PCV13 status and village-level PCV13 coverage and VT carriage were calculated using generalised estimating equations, controlling for potential confounders. RESULTS: We enrolled 1423 participants and determined PCV13 coverage for 368 villages (269 863 children aged under 5 years). By 2017, median village-level vaccine coverage reached 37.5%, however, the IQR indicated wide variation among villages (24.1-56.4). Both receipt of PCV13 and the level of PCV13 coverage were independently associated with a reduced odds of VT carriage: adjusted PCV13 effectiveness was 38.1% (95% CI 4.1% to 60.0%; p=0.032); and for each per cent increase in PCV13 coverage, the estimated odds of VT carriage decreased by 1.1% (95% CI 0.0% to 2.2%; p=0.056). After adjustment, VT carriage decreased from 20.0% to 12.8% as PCV13 coverage increased from zero to 60% among under 5. CONCLUSIONS: Despite marked heterogeneity in PCV13 coverage, we found evidence of indirect effects in Lao PDR. Individual vaccination with PCV13 was effective against VT carriage.
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ItemNasopharyngeal Pneumococcal Colonization Density Is Associated With Severe Pneumonia in Young Children in the Lao People's Democratic Republic(OXFORD UNIV PRESS INC, 2022-04-01)BACKGROUND: No studies have explored the association between pneumococcal nasopharyngeal density and severe pneumonia using the World Health Organization (WHO) 2013 definition. In Lao People's Democratic Republic (Lao PDR), we determine the association between nasopharyngeal pneumococcal density and severe pneumonia in children. METHODS: A prospective observational study was undertaken at Mahosot Hospital, Vientiane, from 2014 to mid-2018. Children <5 years admitted with acute respiratory infections (ARIs) were included. Clinical and demographic data were collected alongside nasopharyngeal swabs for pneumococcal quantification by lytA real-time quantitative polymerase chain reaction. Severe pneumonia was defined using the 2013 WHO definition. For pneumococcal carriers, a logistic regression model examined the association between pneumococcal density and severe pneumonia, after adjusting for potential confounders including demographic and household factors, 13-valent pneumococcal conjugate vaccine status, respiratory syncytial virus co-detection, and preadmission antibiotics. RESULTS: Of 1268 participants with ARI, 32.3% (n = 410) had severe pneumonia and 36.9% (n = 468) had pneumococcal carriage. For pneumococcal carriers, pneumococcal density was positively associated with severe pneumonia (adjusted odds ratio, 1.4 [95% confidence interval, 1.1-1.8]; P = .020). CONCLUSIONS: Among children with ARIs and pneumococcal carriage, pneumococcal carriage density was positively associated with severe pneumonia in Lao PDR. Further studies may determine if pneumococcal density is a useful marker for pneumococcal conjugate vaccine impact on childhood pneumonia.