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Limited data from Asia are available on long-term effects of pneumococcal conjugate vaccine introduction on pneumococcal carriage. Here we assess the impact of 13-valent pneumococcal conjugate vaccine (PCV13) introduction on nasopharyngeal pneumococcal carriage prevalence, density and antimicrobial resistance. Cross-sectional carriage surveys were conducted pre-PCV13 (2015) and post-PCV13 introduction (2017 and 2022). Pneumococci were detected and quantified by real-time PCR from nasopharyngeal swabs. DNA microarray was used for molecular serotyping and to infer genetic lineage (Global Pneumococcal Sequence Cluster). The study included 1461 infants (5-8 weeks old) and 1489 toddlers (12-23 months old) enrolled from family health clinics. We show a reduction in PCV13 serotype carriage (with non-PCV13 serotype replacement) and a reduction in the proportion of samples containing resistance genes in toddlers six years post-PCV13 introduction. We observed an increase in pneumococcal nasopharyngeal density. Serotype 15 A, the most prevalent non-vaccine-serotype in 2022, was comprised predominantly of GPSC904;9. Reductions in PCV13 serotype carriage will likely result in pneumococcal disease reduction. It is important for ongoing surveillance to monitor serotype changes to potentially inform new vaccine development.
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Portador Sadio , Nasofaringe , Infecções Pneumocócicas , Vacinas Pneumocócicas , Streptococcus pneumoniae , Vacinas Conjugadas , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Humanos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/classificação , Lactente , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/imunologia , Nasofaringe/microbiologia , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Portador Sadio/prevenção & controle , Mongólia/epidemiologia , Estudos Transversais , Vacinas Conjugadas/imunologia , Feminino , Masculino , Sorogrupo , Prevalência , SorotipagemRESUMO
The use of pneumococcal conjugate vaccine (PCV) schedules with fewer doses are being considered to reduce costs and improve access, particularly in low- and middle-income countries. While several studies have assessed their immunogenicity, there are limited data on their potential for long-term immune protection, as assessed by pneumococcal serotype-specific memory B cell (Bmem) responses. This current study reports secondary outcome data that aims to compare Bmem responses following reduced-dose (0 + 1 and 1 + 1) schedules of PCV10 and PCV13 in Vietnamese infants from our randomised-controlled trial (trial registration number NCT03098628). Following vaccination at 12 months of age, Bmem levels for most serotypes peaked seven days post-vaccination and were higher in magnitude for the 1 + 1 than 0 + 1 schedules and for PCV13 than PCV10. Furthermore, Bmem did not wane as rapidly as IgG levels by 24 months of age. Further studies are needed to assess the use of Bmem as markers of long-term protection against pneumococcal carriage and disease, which is crucial to generate data for immunisation program decision-making.
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Esquemas de Imunização , Células B de Memória , Infecções Pneumocócicas , Vacinas Pneumocócicas , Streptococcus pneumoniae , Humanos , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vietnã , Lactente , Streptococcus pneumoniae/imunologia , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/imunologia , Células B de Memória/imunologia , Feminino , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/administração & dosagem , Masculino , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/sangue , Vacinação/métodos , Pré-Escolar , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , SorogrupoRESUMO
Pleural empyema is a serious complication of pneumonia in children. Negative bacterial cultures commonly impede optimal antibiotic therapy. To improve bacterial identification, we developed a molecular assay and evaluated its performance compared with bacterial culture. Our multiplex-quantitative PCR to detect Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae was assessed using bacterial genomic DNA and laboratory-prepared samples (n = 267). To evaluate clinical performance, we conducted the Molecular Assessment of Thoracic Empyema (MATE) observational study, enrolling children hospitalised with empyema. Pleural fluids were tested by bacterial culture and multiplex-qPCR, and performance determined using a study gold standard. We determined clinical sensitivity and time-to-organism-identification to assess the potential of the multiplex-qPCR to reduce the duration of empiric untargeted antibiotic therapy. Using spiked samples, the multiplex-qPCR demonstrated 213/215 (99.1%) sensitivity and 52/52 (100%) specificity for all organisms. During May 2019-March 2023, 100 children were enrolled in the MATE study; median age was 3.9 years (IQR 2-5.6). A bacterial pathogen was identified in 90/100 (90%) specimens by multiplex-qPCR, and 24/100 (24%) by bacterial culture (P <0.001). Multiplex-qPCR identified a bacterial cause in 68/76 (90%) culture-negative specimens. S. pneumoniae was the most common pathogen, identified in 67/100 (67%) specimens. We estimate our multiplex-qPCR would have reduced the duration of untargeted antibiotic therapy in 61% of cases by a median 20 days (IQR 17.5-23, range 1-55). Multiplex-qPCR significantly increased pathogen detection compared with culture and may allow for reducing the duration of untargeted antibiotic therapy.
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Empiema Pleural , Reação em Cadeia da Polimerase Multiplex , Humanos , Pré-Escolar , Empiema Pleural/microbiologia , Empiema Pleural/tratamento farmacológico , Empiema Pleural/diagnóstico , Masculino , Feminino , Reação em Cadeia da Polimerase Multiplex/métodos , Criança , Haemophilus influenzae/genética , Haemophilus influenzae/isolamento & purificação , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pyogenes/genética , Streptococcus pyogenes/isolamento & purificação , Lactente , Hospitalização , Antibacterianos/uso terapêutico , Sensibilidade e Especificidade , DNA Bacteriano/genéticaRESUMO
BACKGROUND: Data available for RSV and influenza infections among children < 2 years in Mongolia are limited. We present data from four districts of Ulaanbaatar from April 2015 to June 2021. METHODS: This study was nested in an enhanced surveillance project evaluating pneumococcal conjugate vaccine (PCV13) impact on the incidence of hospitalized lower respiratory tract infections (LRTIs). Our study was restricted to children aged < 2 years with arterial O2 saturation < 93% and children with radiological pneumonia. Nasopharyngeal (NP) swabs collected at admission were tested for RSV and influenza using qRT-PCR. NP swabs of all patients with radiological pneumonia and of a subset of randomly selected NP swabs were tested for S. pneumoniae (S.p.) by qPCR and for serotypes by culture and DNA microarray. RESULTS: Among 5705 patients, 2113 (37.0%) and 386 (6.8%) had RSV and influenza infections, respectively. Children aged 2-6 months had a higher percentage of very severe RSV infection compared to those older than 6 months (42.2% versus 31.4%, p-value Fisher's exact = 0.001). S.p. carriage was detected in 1073/2281 (47.0%) patients. Among S.p. carriage cases, 363/1073 (33.8%) had S.p. and RSV codetection, and 82/1073 (7.6%) had S.p. and influenza codetection. S.p. codetection with RSV/influenza was not associated with more severe LRTIs, compared to only RSV/influenza cases. CONCLUSION: In Mongolia, RSV is an important pathogen causing more severe LRTI in children under 6 months of age. Codetection of RSV or influenza virus and S.p. was not associated with increased severity.
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Influenza Humana , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Mongólia/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Lactente , Influenza Humana/epidemiologia , Influenza Humana/virologia , Feminino , Masculino , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/isolamento & purificação , Pré-Escolar , Nasofaringe/virologia , Recém-Nascido , Incidência , Hospitalização/estatística & dados numéricos , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/classificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologiaRESUMO
INTRODUCTION: Postnatal depression affects up to one in six new mothers in Australia each year, with significant impacts on the woman and her family. Prevention strategies can be complicated by a woman's reluctance to seek professional help. Peer support is a promising but inadequately tested early intervention. Very few trials have reported on the efficacy of peer support in the perinatal period and no study has been undertaken in Australia. We will explore if proactive telephone-based peer (mother-to-mother) support, provided to women identified as being at high risk of postnatal depression, impacts on clinically significant depressive symptomatology at 6 months postpartum. METHODS AND ANALYSIS: This is a protocol for a single-blinded, multi-centre, randomised controlled trial conducted in Melbourne, Australia. Eligible women will be recruited from either the postnatal units of two maternity hospitals, or around 4 weeks postpartum at maternal and child health centres within two metropolitan council areas. A total of 1060 (530/group) women will be recruited and randomly allocated (1:1 ratio) to either-usual care, to receive the standard community postpartum services available to them, or the intervention group, to receive proactive telephone-based support from a peer volunteer for 6 months, in addition to standard community services. PRIMARY OUTCOME: clinically significant depressive symptomatology at 6 months postpartum as measured using the Edinburgh Postnatal Depression Scale. SECONDARY OUTCOMES: symptoms of anxiety and/or stress, health-related quality of life, loneliness, perception of partner support, self-rated parenting, child health and development, infant feeding and health service use. The cost-effectiveness of the intervention relative to standard care will also be assessed. ETHICS AND DISSEMINATION: Ethics approval has been obtained from La Trobe University, St. Vincent's Hospital, the Royal Women's Hospital, Northern Health, Victorian Department of Health and Human Services and Victorian Department of Education and Training. Written informed consent will be obtained from all participants before randomisation. Trial results will be disseminated through peer-reviewed publications, conference presentations and a higher degree thesis. TRIAL REGISTRATION NUMBER: ACTRN12619000684123; Australian New Zealand Clinical Trials Registry.
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Depressão Pós-Parto , Mães , Grupo Associado , Apoio Social , Telefone , Adulto , Feminino , Humanos , Ansiedade/prevenção & controle , Austrália , Depressão Pós-Parto/prevenção & controle , Mães/psicologia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-CegoRESUMO
Objectives: Limited data indicate a beneficial effect of pneumococcal conjugate vaccines (PCVs) on respiratory syncytial virus (RSV) and influenza infections in young children. We evaluated the impact of 13-valent PCV (PCV13) introduction on the incidence of severe lower respiratory tract infections (LRTIs) associated with RSV or influenza in hospitalized children. Methods: Our study was restricted to children aged <2 years with arterial oxygen saturation <93% and children with radiologically confirmed pneumonia nested in a pneumonia surveillance project in four districts of Ulaanbaatar city, Mongolia. We tested nasopharyngeal swabs collected on admission for RSV and influenza using quantitative reverse transcription-polymerase chain reaction. The impact of PCV13 on the incidence of LRTI outcomes associated with RSV or with influenza for the period April 2015-March 2020 was estimated. Incidence rate ratios comparing pre- and post-vaccine periods were estimated for each outcome for each district using negative binomial models and for all districts combined with a mixed-effects negative binomial model. Adjusted models accounted for seasonality. Sensitivity analyses were conducted to assess the robustness of our findings. Results: Among 5577 tested cases, the adjusted incidence rate ratios showed a trend toward a reduction in RSV-associated outcomes: all LRTIs (0.77, 95% confidence interval [CI] 0.44-1.36), severe LRTIs (0.88, 95% CI 0.48-1.62), very severe LRTIs (0.76, 95% CI 0.42-1.38), and radiologically confirmed pneumonia (0.66, 95% CI 0.32-1.38) but inconsistent trends in outcomes associated with influenza. Conclusions: No significant reductions were observed in any outcomes associated with RSV and influenza after PCV introduction.
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RATIONALE: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). METHODS AND DESIGN: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10-14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. PURPOSE: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. TRIAL REGISTRATION: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . PROTOCOL: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions-none.
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Vacina contra Febre Amarela , Febre Amarela , Humanos , Lactente , Esquemas de Imunização , Vacinas Pneumocócicas , Estudos Prospectivos , Streptococcus pneumoniae , Vacinação/métodos , Vacinas ConjugadasRESUMO
Starting in June 2016, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced into the routine immunization program of Mongolia by using a 2+1 dosing schedule, phased by district. We used prospective hospital surveillance to evaluate the vaccine's effect on pneumonia incidence rates among children 2-59 months of age over a 6-year period. Of 17,607 children with pneumonia, overall adjusted incidence rate ratios showed decreased primary endpoint pneumonia, very severe pneumonia, and probable pneumococcal pneumonia until June 2021. Results excluding and including the COVID-19 pandemic period were similar. Pneumonia declined in 3 districts that introduced PCV13 with catch-up campaigns but not in the 1 district that did not. After PCV13 introduction, vaccine-type pneumococcal carriage prevalence decreased by 44% and nonvaccine-type carriage increased by 49%. After PCV13 introduction in Mongolia, the incidence of more specific pneumonia endpoints declined in children 2-59 months of age; additional benefits were conferred by catch-up campaigns.
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Pandemias , Pneumonia Pneumocócica , Criança , Humanos , Vacinas Conjugadas , Incidência , Mongólia/epidemiologia , Estudos Prospectivos , Pneumonia Pneumocócica/epidemiologia , Pneumonia Pneumocócica/prevenção & controleRESUMO
Background: COVID-19 vaccine booster doses restore vaccine effectiveness lost from waning immunity and emerging variants. Fractional dosing may improve COVID-19 booster acceptability and uptake and will reduce the per-dose cost of COVID-19 booster programmes. We sought to quantify the immunogenicity, reactogenicity, and safety of a half-dose BNT162b2 (Pfizer-BioNTech) booster relative to the standard formulation. Methods: This randomised, controlled, non-inferiority trial recruited adults in Mongolia primed with a two-dose homologous ChAdOx1 nCov-19 (Oxford-AstraZeneca, n = 129 participants), BBIBP-CorV (Sinopharm (Beijing), n = 399), or Gam-COVID-Vac (Gamaleya, n = 70) schedule. Participants were randomised (1:1) to receive a 15 µg (half-dose) or 30 µg (full-dose) BNT162b2 booster. Participants and study staff assessing reactogenicity were blinded up to day 28. Co-primary endpoints were Wuhan-Hu-1 anti-spike S1 IgG seroresponse 28 days post-boosting and reactogenicity within 7 days of boosting. The non-inferiority margin for the absolute difference in seroresponse was -10%. Differences in seroresponse were estimated from logistic regression with marginal standardisation. Geometric mean ratios of IgG were also estimated. ClinicalTrials.gov Identifier: NCT05265065. Findings: Between May 27th and September 30th, 2022, 601 participants were randomized to full-dose BNT162b2 (n = 300) or half-dose (n = 301). 598 were included in safety analyses, and 587 in immunological analyses. The frequency of grade 3-4 reactions was similar between arms (half-dose: 4/299 [1.3%]; full-dose: 6/299 [2.0%]). Across all severity grades, half-dose recipients reported fewer local and systemic reactions (60% versus 72% and 25% versus 32%, respectively). Seroresponse was 84.7% (250/295) and 86.6% (253/292) in the half-dose and full-dose arms, respectively (Difference: -2.8%; 95% CI -7.7, 2.1). Geometric mean IgG titres were similar in those receiving full and half-dose boosters for the ChAdOx1 and BBIBP-CorV primed groups, but lower in the half-dose arm in Gam-COVID-Vac-primed participants (GMR: 0.71; 95% CI 0.54, 0.93). Interpretation: Half-dose BNT162b2 boosting elicited an immune response that was non-inferior to a full-dose, with fewer reactions, in adults primed with ChAdOx1 nCov-19 or BBIBP-CorV. Half-dose boosting may not be suitable in adults primed with Gam-COVID-Vac. Half-dose BNT162b2 boosting may be considered in populations primed with ChAdOx1 nCov-19 or BBIBP-CorV. Funding: Coalition for Epidemic Preparedness Innovations (CEPI).
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Multiple imputation (MI) is a popular method for handling missing data. Auxiliary variables can be added to the imputation model(s) to improve MI estimates. However, the choice of which auxiliary variables to include is not always straightforward. Several data-driven auxiliary variable selection strategies have been proposed, but there has been limited evaluation of their performance. Using a simulation study we evaluated the performance of eight auxiliary variable selection strategies: (1, 2) two versions of selection based on correlations in the observed data; (3) selection using hypothesis tests of the "missing completely at random" assumption; (4) replacing auxiliary variables with their principal components; (5, 6) forward and forward stepwise selection; (7) forward selection based on the estimated fraction of missing information; and (8) selection via the least absolute shrinkage and selection operator (LASSO). A complete case analysis and an MI analysis using all auxiliary variables (the "full model") were included for comparison. We also applied all strategies to a motivating case study. The full model outperformed all auxiliary variable selection strategies in the simulation study, with the LASSO strategy the best performing auxiliary variable selection strategy overall. All MI analysis strategies that we were able to apply to the case study led to similar estimates, although computational time was substantially reduced when variable selection was employed. This study provides further support for adopting an inclusive auxiliary variable strategy where possible. Auxiliary variable selection using the LASSO may be a promising alternative when the full model fails or is too burdensome.
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Simulação por ComputadorRESUMO
Background: Few studies have assessed the potential indirect effects of childhood pneumococcal conjugate vaccine (PCV) programs on the adult pneumonia burden in resource-limited settings. We evaluated the impact of childhood PCV13 immunisation on adult all-cause pneumonia following a phased program introduction from 2016. Methods: We conducted a time-series analysis to assess changes in pneumonia hospitalisation incidence at four district hospitals in Mongolia. Adults (≥18 years) that met the clinical case definition for all-cause pneumonia were enrolled. A negative binomial mixed-effects model was used to assess the impact of PCV13 introduction on monthly counts of pneumonia admissions from January 2015-February 2022. We also performed a restricted analysis excluding the COVID-19 pandemic period. All models were stratified by age and assessed separately. Additional analyses assessed the robustness of our findings. Findings: The average annual incidence of all-cause pneumonia hospitalisation was highest in adults 65+ years (62.81 per 10,000 population) and declined with decreasing age. After adjusting for the COVID-19 pandemic period, we found that rates of pneumonia hospitalisation remained largely unchanged over time. We did not observe a reduction in pneumonia hospitalisation in any age group. Results from restricted and sensitivity analyses were comparable to the primary results, finding limited evidence of a reduced pneumonia burden. Interpretation: We did not find evidence of indirect protection against all-cause pneumonia in adults following childhood PCV13 introduction. Direct pneumococcal vaccination and other interventions should be considered to reduce burden of pneumonia among older adults. Funding: Pfizer clinical research collaboration agreement (contract number: WI236621).
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BACKGROUND: Case-cohort studies are conducted within cohort studies, with the defining feature that collection of exposure data is limited to a subset of the cohort, leading to a large proportion of missing data by design. Standard analysis uses inverse probability weighting (IPW) to address this intended missing data, but little research has been conducted into how best to perform analysis when there is also unintended missingness. Multiple imputation (MI) has become a default standard for handling unintended missingness and is typically used in combination with IPW to handle the intended missingness due to the case-control sampling. Alternatively, MI could be used to handle both the intended and unintended missingness. While the performance of an MI-only approach has been investigated in the context of a case-cohort study with a time-to-event outcome, it is unclear how this approach performs with a binary outcome. METHODS: We conducted a simulation study to assess and compare the performance of approaches using only MI, only IPW, and a combination of MI and IPW, for handling intended and unintended missingness in the case-cohort setting. We also applied the approaches to a case study. RESULTS: Our results show that the combined approach is approximately unbiased for estimation of the exposure effect when the sample size is large, and was the least biased with small sample sizes, while MI-only and IPW-only exhibited larger biases in both sample size settings. CONCLUSIONS: These findings suggest that a combined MI/IPW approach should be preferred to handle intended and unintended missing data in case-cohort studies with binary outcomes.
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Estudos de Coortes , Humanos , Interpretação Estatística de Dados , Probabilidade , Viés , Simulação por ComputadorRESUMO
(1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to its high cost and requirement for multiple intramuscular injections, its use has been limited mostly to high-income countries. Following our previous study showing the successful lung deposition of aerosolised palivizumab in lambs, this current study evaluated the "proof-of-principle" effect of aerosolised palivizumab delivered as a therapeutic to neonatal lambs following RSV infection. (2) Methods: Neonatal lambs were intranasally inoculated with RSV-A2 on day 0 (day 3 post-birth) and treated with aerosolised palivizumab 3 days later (day 3 post-inoculation). Clinical symptoms, RSV viral load and inflammatory response were measured post-inoculation. (3) Results: Aerosolised therapeutic delivery of palivizumab did not reduce RSV viral loads in the nasopharynx nor the bronchoalveolar lavage fluid, but resulted in a modest reduction in inflammatory response at day 6 post-inoculation compared with untreated lambs. (4) Conclusions: This proof-of-principle study shows some evidence of aerosolised palivizumab reducing RSV inflammation, but further studies using optimized protocols are needed in order to validate these findings.
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Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Animais , Ovinos , Palivizumab , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Antivirais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Introduction: The WHO currently recommends giving pneumococcal conjugate vaccines (PCVs) as three doses - either three doses in infancy with Pentavalent vaccine (3p+0), or two doses in infancy followed by a booster around 12 months (2p+1). However, their high price is a barrier to introduction and sustainability in low and middle-income countries. We hypothesize that a schedule with a single priming and a booster dose (1p+1) may maintain similar levels of protection for the community by sustaining herd immunity, once circulation of vaccine types has been controlled. Methods and analysis: We will conduct a cluster randomized trial with four intervention arms (1p+1, 0p+1, 2p+1, 3p+0) and three unvaccinated clusters in the 27 communes of Nha Trang, central Vietnam. A PCV catch-up vaccination campaign to all children under three years of age will be performed at the start of the trial. The primary endpoint is non-inferiority of the1p+1 schedule if compared to the WHO standard 2p+1 and 3p+0 schedules in reducing vaccine serotype carriage prevalence in infants. We will also explore impact of 0p+1 schedule. A baseline and annual pneumococcal carriage surveys of 6480 participants per survey covering infants, toddlers and their mothers will be conducted. Ethics and dissemination: Ethical approvals were obtained from the ethical review committees of Institute of Tropical Medicine, Nagasaki University (151203149-2) and the Ministry of Health, Vietnam (1915/QD-BYT). The results, interpretation and conclusions will be presented at national and international conferences, and published in peer-reviewed open access journals. Trial registration number: NCT02961231.
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Background: In 2008/9, Fiji vaccinated >30,000 girls aged 9-12 years with the quadrivalent human papillomavirus (4vHPV) vaccine coverage for at least one dose was >60% (one dose only was 14%, two dose only was 13%, three doses was 35%). We calculated vaccine effectiveness (VE) of one, two and three doses of 4vHPV against oncogenic HPV genotypes 16/18, eight years following vaccination. Methods: A retrospective cohort study was undertaken (2015-2019) in pregnant women ≤23 years old, eligible to receive 4vHPV in 2008/9, with confirmed vaccination status. The study was restricted to pregnant women due to the cultural sensitivity of asking about sexual behavior in Fiji. For each participant a clinician collected a questionnaire, vaginal swab and genital warts examination, a median eight (range 6-11) years post vaccination. HPV DNA was detected by molecular methods. Adjusted VE (aVE) against the detection of vaccine HPV genotypes (16/18), the comparison group of non-vaccine genotypes (31/33/35/39/45/51/52/56/58/59/66/68), and genital warts were calculated. Covariates included in the adjusted model were: age, ethnicity and smoking, according to univariate association with any HPV detection. Findings: Among 822 participants the prevalence of HPV 16/18 in the unvaccinated, one, two and three-dose groups were 13.3% (50/376), 2.5% (4/158), 0% (0/99) and 1.6% (3/189), respectively; and for the non-vaccine high-risk genotypes, the detection rate was similar across dosage groups (33.2%-40.4%, p = 0.321). The aVE against HPV 16/18 for one, two and three doses were 81% (95% CI; 48-93%), 100% (95% CI; 100-100%), and 89% (95% CI; 64-96%), respectively. Prevalence of HPV 16/18 was lower among women with longer time since vaccination. Interpretations: A single dose 4vHPV vaccine is highly effective against HPV genotypes 16 and 18 eight years following vaccination. Our results provide the longest duration of protection for reduced dose 4vHPV schedule in a low- or middle-income country in the Western Pacific region. Funding: This study was supported by the Bill & Melinda Gates Foundation and 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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The COVID-19 pandemic represents an unprecedented challenge for clinical research. The Pneumococcal Vaccine Schedules (PVS) study is a non-inferiority, interventional trial in which infants resident in 68 geographic clusters are randomised to two different schedules for pneumococcal vaccination. From September 2019 onwards, all infants resident in the study area became eligible for trial enrolment at all Expanded Programme on Immunisation (EPI) clinics in the study area. Surveillance for clinical endpoints is conducted at all 11 health facilities in the study area. PVS is conducted as a collaboration between the Medical Research Council Unit The Gambia (MRCG) at LSHTM and the Gambian Ministry of Health (MoH). The COVID-19 pandemic caused many disruptions to PVS. MRCG instructed interventional studies that participant enrolment be suspended on 26 March 2020, and a public health emergency was declared in The Gambia on 28 March 2020. Enrolment in PVS restarted on 1 July 2020 and was suspended again on 5 August 2020 after The Gambia experienced a sharp increase in COVID-19 cases in late July 2020 and restarted again on 1 September 2020. During periods of suspended enrolment of infants at EPI clinics, PVS continued safety surveillance at health facilities, albeit with disruptions. During the periods of suspended enrolment, infants who had been enrolled before 26 March 2020 continued to receive the PCV schedule to which they had been randomly allocated based on their village of residence, whereas all other infants received the standard PCV schedule. Throughout 2020 and 2021, the trial faced numerous technical and operational challenges: disruption to MoH delivery of EPI services and clinical care at health facilities; episodes of staff illness and isolation; disruption of MRCG transport, procurement, communications and human resource management; and also a range of ethical, regulatory, sponsorship, trial monitoring and financial challenges. In April 2021, a formal review concluded that the pandemic had not compromised the scientific validity of PVS and that the trial should continue as per protocol. The continuing challenges that COVID-19 poses to PVS, and other clinical trials will persist for some time.
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COVID-19 , Estudos de Equivalência como Asunto , Vacinas Pneumocócicas , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Lactente , COVID-19/prevenção & controle , COVID-19/epidemiologia , Gâmbia/epidemiologia , Pandemias/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , VacinaçãoRESUMO
INTRODUCTION: Observational studies in health-related research often aim to answer causal questions. Missing data are common in these studies and often occur in multiple variables, such as the exposure, outcome and/or variables used to control for confounding. The standard classification of missing data as missing completely at random, missing at random (MAR) or missing not at random does not allow for a clear assessment of missingness assumptions when missingness arises in more than one variable. This presents challenges for selecting an analytic approach and determining when a sensitivity analysis under plausible alternative missing data assumptions is required. This is particularly pertinent with multiple imputation (MI), which is often justified by assuming data are MAR. The objective of this scoping review is to examine the use of MI in observational studies that address causal questions, with a focus on if and how (a) missingness assumptions are expressed and assessed, (b) missingness assumptions are used to justify the choice of a complete case analysis and/or MI for handling missing data and (c) sensitivity analyses under alternative plausible assumptions about the missingness mechanism are conducted. METHODS AND ANALYSIS: We will review observational studies that aim to answer causal questions and use MI, published between January 2019 and December 2021 in five top general epidemiology journals. Studies will be identified using a full text search for the term 'multiple imputation' and then assessed for eligibility. Information extracted will include details about the study characteristics, missing data, missingness assumptions and MI implementation. Data will be summarised using descriptive statistics. ETHICS AND DISSEMINATION: Ethics approval is not required for this review because data will be collected only from published studies. The results will be disseminated through a peer reviewed publication and conference presentations. TRIAL REGISTRATION NUMBER: This protocol is registered on figshare (https://doi.org/10.6084/m9.figshare.20010497.v1).
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Modelos Estatísticos , Projetos de Pesquisa , Humanos , Interpretação Estatística de Dados , Estudos Observacionais como Assunto , Literatura de Revisão como AssuntoRESUMO
Background: WHO recommends a three-dose infant pneumococcal conjugate vaccine (PCV) schedule administered as a two-dose primary series with booster (2 + 1) or a three-dose primary series (3 + 0). Data on carriage impacts of these and further reduced PCV schedules are needed to inform PCV strategies. Here we evaluate the efficacy against carriage of four different PCV10 schedules. Methods: Participants within an open-label, randomised controlled trial in Ho Chi Minh City, Vietnam, were allocated to receive PCV10 in a 3 + 1 (2,3,4,9 months, n = 152), 3 + 0 (2,3,4 months, n = 149), 2 + 1 (2,4,9.5 months, n = 250) or novel two-dose (2,6 months, n = 202) schedule, or no infant doses of PCV (two control groups, n = 197 and n = 199). Nasopharyngeal swabs collected between 2 and 24 months were analysed (blinded) for pneumococcal carriage and serotypes. Trial registration: ClinicalTrials.gov NCT01953510. Findings: Pneumococcal carriage prevalence was low (10.6-14.1% for vaccine-type (VT) at 12-24 months in unvaccinated controls). All four PCV10 schedules reduced VT carriage compared with controls (the 2 + 1 schedule at 12, 18, and 24 months; the 3 + 1 and two-dose schedules at 18 months; and the 3 + 0 schedule at 24 months), with maximum reductions of 40.1%-64.5%. There were no differences in VT carriage prevalence at 6 or 9 months comparing three-dose and two-dose primary series, and no differences at 12, 18, or 24 months when comparing schedules with and without a booster dose. Interpretation: In Vietnamese children with a relatively low pneumococcal carriage prevalence, 3 + 1, 2 + 1, 3 + 0 and two-dose PCV10 schedules were effective in reducing VT carriage. There were no discernible differences in the effect on carriage of the WHO-recommended 2 + 1 and 3 + 0 schedules during the first two years of life. Together with the previously reported immunogenicity data, this trial suggests that a range of PCV schedules are likely to generate significant direct and indirect protection. Funding: NHMRC, BMGF.
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Nonpharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. Previous studies have proposed the decline is due to reduced pneumococcal transmission or suppression of respiratory viruses, but the mechanism remains unclear. We undertook a secondary analysis of data collected from a clinical trial to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. Nasopharyngeal samples from children aged 24 months were assessed in three periods - one pre-COVID-19 period (n = 1,537) and two periods where NPIs were implemented with increasing stringency (NPI period 1 [NPI-1, n = 307], and NPI period 2 [NPI-2, n = 262]). Pneumococci were quantified using lytA quantitative PCR and serotyped by DNA microarray. Overall, capsular, and nonencapsulated pneumococcal carriage and density were assessed in each NPI period compared with the pre-COVID-19 period using unadjusted log-binomial and linear regression. Pneumococcal carriage was generally stable after the implementation of NPIs. In contrast, overall pneumococcal carriage density decreased by 0.44 log10 genome equivalents/mL (95% confidence interval [CI]: 0.19 to 0.69) in NPI-1 and by 0.84 log10 genome equivalents/mL (95% CI: 0.55 to 1.13) in NPI-2 compared with the pre-COVID-19 period. Reductions in overall pneumococcal density were driven by reductions in capsular pneumococci, with no corresponding reduction in nonencapsulated density. As higher pneumococcal density is a risk factor for disease, the decline in density provides a plausible explanation for the reductions in invasive pneumococcal disease that have been observed in many countries in the absence of a substantive reduction in pneumococcal carriage. IMPORTANCE The pneumococcus is a major cause of mortality globally. Implementation of NPIs during the COVID-19 pandemic led to reductions in invasive pneumococcal disease in many countries. However, no studies have conducted a fully quantitative assessment on the impact of NPIs on pneumococcal carriage density, which could explain this reduction. We evaluated the impact of COVID-19 NPIs on pneumococcal carriage prevalence and density in 2,106 children aged 24 months in Vietnam and found pneumococcal carriage density decreased up to 91.5% after NPI introduction compared with the pre-COVID-19 period, which was mainly attributed to capsular pneumococci. Only a minor effect on carriage prevalence was observed. As respiratory viruses are known to increase pneumococcal carriage density, transmission, and disease, this work suggests that interventions targeting respiratory viruses may have the added benefit of reducing invasive pneumococcal disease and explain the reductions observed following NPI implementation.
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COVID-19 , Infecções Pneumocócicas , Criança , Humanos , Lactente , Streptococcus pneumoniae/genética , COVID-19/epidemiologia , COVID-19/prevenção & controle , Prevalência , Vietnã/epidemiologia , Pandemias/prevenção & controle , SARS-CoV-2 , Portador Sadio/epidemiologia , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controleRESUMO
Background: Community-acquired pneumonia is a leading cause of morbidity and mortality among children and adults worldwide. Adult pneumonia surveillance remains limited in many low- and middle-income settings, resulting in the disease burden being largely unknown. Methods: A retrospective cohort study was conducted by reviewing medical charts for respiratory admissions at four district hospitals in Ulaanbaatar during January 2015-February 2019. Characteristics of community-acquired pneumonia cases were summarized by disease severity and age. To explore factors associated with severe pneumonia, we ran univariable and age-adjusted logistic regression models. Incidence rates were calculated using population denominators. Results: In total, 4290 respiratory admissions met the case definition for clinical pneumonia, including 430 admissions of severe pneumonia. The highest proportion of severe pneumonia admissions occurred in adults >65 years (37.4%). After adjusting for age, there were increased odds of severe pneumonia in males (adjusted odds ratio [aOR]: 1.63; 95% confidence interval [CI]: 1.33-2.00) and those with ≥1 underlying medical condition (aOR: 1.46; 95% CI: 1.14-1.87). The incidence of hospitalized pneumonia in adults ≥18 years increased from 13.49 (95% CI: 12.58-14.44) in 2015 to 17.65 (95% CI: 16.63-18.71) in 2018 per 10,000 population. The incidence of severe pneumonia was highest in adults >65 years, ranging from 9.29 (95% CI: 6.17-13.43) in 2015 to 12.69 (95% CI: 9.22-17.04) in 2018 per 10,000 population. Interpretations: Vaccination and other strategies to reduce the risk of pneumonia, particularly among older adults and those with underlying medical conditions, should be prioritized. Funding: Pfizer clinical research collaboration agreement (contract number: WI236621).