Paediatrics (RCH) - Research Publications

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    Aetiology of childhood pneumonia in low- and middle-income countries in the era of vaccination: a systematic review.
    von Mollendorf, C ; Berger, D ; Gwee, A ; Duke, T ; Graham, SM ; Russell, FM ; Mulholland, EK ; ARI review group, (International Global Health Society, 2022-07-23)
    Background: This systematic review aimed to describe common aetiologies of severe and non-severe community acquired pneumonia among children aged 1 month to 9 years in low- and middle-income countries. Methods: We searched the MEDLINE, EMBASE, and PubMed online databases for studies published from January 2010 to August 30, 2020. We included studies on acute community-acquired pneumonia or acute lower respiratory tract infection with ≥1 year of continuous data collection; clear consistent case definition for pneumonia; >1 specimen type (except empyema studies where only pleural fluid was required); testing for >1 pathogen including both viruses and bacteria. Two researchers reviewed the studies independently. Results were presented as a narrative summary. Quality of evidence was assessed with the Quality Assessment Tool for Quantitative Studies. The study was registered on PROSPERO [CRD42020206830]. Results: We screened 5184 records; 1305 duplicates were removed. The remaining 3879 titles and abstracts were screened. Of these, 557 articles were identified for full-text review, and 55 met the inclusion criteria - 10 case-control studies, three post-mortem studies, 11 surveillance studies, eight cohort studies, five cross-sectional studies, 12 studies with another design and six studies that included patients with pleural effusions or empyema. Studies which described disease by severity showed higher bacterial detection (Streptococcus pneumoniae, Staphylococcus aureus) in severe vs non-severe cases. The most common virus causing severe disease was respiratory syncytial virus (RSV). Pathogens varied by age, with RSV and adenovirus more common in younger children. Influenza and atypical bacteria were more common in children 5-14 years than younger children. Malnourished and HIV-infected children had higher rates of pneumonia due to bacteria or tuberculosis. Conclusions: Several viral and bacterial pathogens were identified as important targets for prevention and treatment. Bacterial pathogens remain an important cause of moderate to severe disease, particularly in children with comorbidities despite widespread PCV and Hib vaccination.
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    Prevalence and Determinants of Vaginal Infection With Human Papillomavirus Among Female University Students in Vietnam
    Van Trang, N ; Prem, K ; Toh, ZQ ; Ha, BTV ; Lan, PTN ; Tran, HP ; Pham, QD ; Van Khuu, N ; Jit, M ; Luu, DT ; Ly, LTK ; Van, C ; Le-Ha, T-D ; Bright, K ; Garland, SM ; Anh, DD ; Mulholland, K (INT INST ANTICANCER RESEARCH, 2022-01-01)
    BACKGROUND/AIM: Cervical cancer is the second most common malignancy among women in Vietnam, but the country is yet to introduce a national human papillomavirus (HPV) vaccine programme targeted at adolescents. We determined HPV prevalence and HPV vaccine knowledge among female university students in Vietnam. PATIENTS AND METHODS: We surveyed and screened 1,491 female university students in Hanoi, Hue, and Ho Chi Minh City for their sexual behaviours, HPV knowledge and low- and high-risk HPV infection. RESULTS: The prevalence of any HPV infection and any high-risk HPV infection were 4.2% (95%CI=3.3%-5.4%) and 3.4% (95%CI=2.5%-4.4%), respectively. Being sexually active [adjusted prevalence ratio (aPR): 6.22; 95%CI=3.4-11.37] and having ever been pregnant (aPR: 4.82; 95%CI=1.93-12.04) were positively associated with high-risk HPV infection. Whilst 60% of participants had heard of HPV vaccine, only 4.6% had received the vaccine. CONCLUSION: The low HPV prevalence found in university students in Vietnam indicates that they can benefit from HPV vaccination, along with a well-designed HPV health promotion programme.
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    Effect 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
    Temple, B ; Nation, ML ; Vo, TTD ; Beissbarth, J ; Bright, K ; Dunne, EM ; Hinds, J ; Pham, TH ; Lai, J ; Nguyen, CD ; Ortika, BD ; Phan, T ; Ho, NLT ; Nguyen, TT ; Uyen, DY ; Satzke, C ; Smith-Vaughan, H ; Tran, NH ; Mulholland, K (ELSEVIER SCI LTD, 2021-04-07)
    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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    Can early measles vaccination control both measles and respiratory syncytial virus infections?
    Do, LAH ; Toh, ZQ ; Licciardi, PV ; Mulholland, EK (Elsevier BV, 2022-02)
    Measles virus and respiratory syncytial virus (RSV) are two important global health pathogens causing substantial morbidity and mortality worldwide. The current measles vaccination schedule has the first dose given at 9-12 months of age and the second dose given at 15-18 months of age. Measles outbreaks have been associated with an increase in severe RSV infections in children younger than 6 months, probably as a result of measles-induced immunosuppression. A resurgence in measles cases was already occurring before the COVID-19 pandemic, which has affected global immunisation programmes, resulting in millions of children, mostly in low-income and middle-income countries (LMICs), missing out on their measles vaccine. This will leave many children living in the most vulnerable of circumstances highly susceptible to measles and RSV infections when current COVID-19 public health control measures are lifted. This Viewpoint discusses these issues and highlights the need for urgent action to address this looming crisis. The use of early measles vaccination at 4 months of age could be an effective strategy to prevent severe morbidity and death from both measles and RSV infections in many LMICs.
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    Synergism and Antagonism of Bacterial-Viral Coinfection in the Upper Respiratory Tract
    Manna, S ; McAuley, J ; Jacobson, J ; Nguyen, CD ; Ullah, MA ; Sebina, I ; Williamson, V ; Mulholland, EK ; Wijburg, O ; Phipps, S ; Satzke, C ; Rosenberg, HF (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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    The impact of 10-valent pneumococcal vaccine introduction on invasive disease in Fiji.
    Reyburn, R ; Tuivaga, EJ ; Ratu, FT ; Dunne, EM ; Nand, D ; Kado, J ; Jenkins, K ; Tikoduadua, L ; Jenney, A ; Howden, BP ; Ballard, SA ; Fox, K ; Devi, R ; Satzke, C ; Rafai, E ; Kama, M ; Flasche, S ; Mulholland, EK ; Russell, FM (Elsevier BV, 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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    Preliminary report from the World Health Organisation Chest Radiography in Epidemiological Studies project
    Mahomed, N ; Fancourt, N ; de Campo, J ; de Campo, M ; Akano, A ; Cherian, T ; Cohen, OG ; Greenberg, D ; Lacey, S ; Kohli, N ; Lederman, HM ; Madhi, SA ; Manduku, V ; McCollum, ED ; Park, K ; Luis Ribo-Aristizabal, J ; Bar-Zeev, N ; O'Brien, KL ; Mulholland, K (SPRINGER, 2017-10-01)
    Childhood pneumonia is among the leading infectious causes of mortality in children younger than 5 years of age globally. Streptococcus pneumoniae (pneumococcus) is the leading infectious cause of childhood bacterial pneumonia. The diagnosis of childhood pneumonia remains a critical epidemiological task for monitoring vaccine and treatment program effectiveness. The chest radiograph remains the most readily available and common imaging modality to assess childhood pneumonia. In 1997, the World Health Organization Radiology Working Group was established to provide a consensus method for the standardized definition for the interpretation of pediatric frontal chest radiographs, for use in bacterial vaccine efficacy trials in children. The definition was not designed for use in individual patient clinical management because of its emphasis on specificity at the expense of sensitivity. These definitions and endpoint conclusions were published in 2001 and an analysis of observer variation for these conclusions using a reference library of chest radiographs was published in 2005. In response to the technical needs identified through subsequent meetings, the World Health Organization Chest Radiography in Epidemiological Studies (CRES) project was initiated and is designed to be a continuation of the World Health Organization Radiology Working Group. The aims of the World Health Organization CRES project are to clarify the definitions used in the World Health Organization defined standardized interpretation of pediatric chest radiographs in bacterial vaccine impact and pneumonia epidemiological studies, reinforce the focus on reproducible chest radiograph readings, provide training and support with World Health Organization defined standardized interpretation of chest radiographs and develop guidelines and tools for investigators and site staff to assist in obtaining high-quality chest radiographs.
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    Evaluating Functional Immunity Following Encapsulated Bacterial Infection and Vaccination
    Toh, ZQ ; Higgins, RA ; Mazarakis, N ; Abbott, E ; Nathanielsz, J ; Balloch, A ; Mulholland, K ; Licciardi, PV (MDPI, 2021-06-01)
    Encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis cause significant morbidity and mortality in young children despite the availability of vaccines. Highly specific antibodies are the primary mechanism of protection against invasive disease. Robust and standardised assays that measure functional antibodies are also necessary for vaccine evaluation and allow for the accurate comparison of data between clinical studies. This mini review describes the current state of functional antibody assays and their importance in measuring protective immunity.
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    Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study
    Mackenzie, GA ; Osei, I ; Salaudeen, R ; Secka, O ; D'Alessandro, U ; Clarke, E ; Schmidt-Chanasit, J ; Licciardi, P ; Nguyen, C ; Greenwood, B ; Mulholland, K (BMC, 2022-01-15)
    BACKGROUND: Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. METHODS: PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative '1+1' schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard '3+0' schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. DISCUSSION: Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number 72821613 .
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    Immunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to vietnamese children at 18 months of age
    Higgins, RA ; Temple, B ; Vo, TTD ; Phan, T ; Nguyen, TT ; Spry, L ; Zheng, QT ; Nation, ML ; Ortika, BD ; Uyen, DY ; Cheung, YB ; Nguyen, CD ; Bright, K ; Hinds, J ; Balloch, A ; Smith-Vaughan, H ; Tran, NH ; Mulholland, K ; Satzke, C ; Licciardi, P (ELSEVIER, 2021-09-20)
    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.