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Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial.

ABSTRACT: INTRODUCTION:WHO recommends the use of pneumococcal conjugate vaccine (PCV) as a priority. However, there are many countries yet to introduce PCV, especially in Asia. This trial aims to evaluate different PCV schedules and to provide a head-to-head comparison of PCV10 and PCV13 in order to generate evidence to assist with decisions regarding PCV introduction. Schedules will be compared in relation to their immunogenicity and impact on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae. METHODS AND ANALYSIS:This randomised, single-blind controlled trial involves 1200 infants recruited at 2 months of age to one of six infant PCV schedules: PCV10 in a 3+1, 3+0, 2+1?or two-dose schedule; PCV13 in a 2+1?schedule; and controls that receive two doses of PCV10 and 18 and 24 months. An additional control group of 200 children is recruited at 18 months that receive one dose of PCV10 at 24 months. All participants are followed up until 24 months of age. The primary outcome is the post-primary series immunogenicity, expressed as the proportions of participants with serotype-specific antibody levels??0.35?µg/mL for each serotype in PCV10. ETHICS AND DISSEMINATION:Ethical approval has been obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153) 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:NCT01953510; Pre-results.

SUBMITTER: Temple B

PROVIDER: S-EPMC6009474 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial.

Temple Beth B Toan Nguyen Trong NT Uyen Doan Y DY Balloch Anne A Bright Kathryn K Cheung Yin Bun YB Licciardi Paul P Nguyen Cattram Duong CD Phuong Nguyen Thi Minh NTM Satzke Catherine C Smith-Vaughan Heidi H Vu Thi Que Huong TQH Huu Tran Ngoc TN Mulholland Edward Kim EK

BMJ open 20180608 6

<h4>Introduction</h4>WHO recommends the use of pneumococcal conjugate vaccine (PCV) as a priority. However, there are many countries yet to introduce PCV, especially in Asia. This trial aims to evaluate different PCV schedules and to provide a head-to-head comparison of PCV10 and PCV13 in order to generate evidence to assist with decisions regarding PCV introduction. Schedules will be compared in relation to their immunogenicity and impact on nasopharyngeal carriage of <i>Streptococcus pneumonia ...[more]

PMID: 29884695

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Project description:BackgroundPneumococcal 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.MethodsPVS-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.DiscussionAnalysis 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 registrationInternational Standard Randomised Controlled Trial Number 72821613 .

Project description:BackgroundData are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.MethodsIn this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3-18 months depending on group allocation, within 27-43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 μg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.FindingsBetween Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A-D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9-88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9-82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1-13·6]) and 23F (90·6% [95% CI 86·6-93·7] vs 77·6% [71·8-82·2]; 12·9% [90% CI 7·7-18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F.InterpretationA two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life.FundingAustralian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.

Project description:Streptococcus pneumoniae is a leading cause of pneumonia, the most common cause of childhood death. Papua New Guinean children experience high rates of nasopharyngeal pneumococcal colonization within weeks of birth, predisposing them to pneumococcal disease. In a trial to determine the safety and immunogenicity of early infant vaccination with 7-valent pneumococcal conjugate vaccine (7vPCV), we investigated the impact of early schedules on pneumococcal carriage. Infants were randomized at birth to receive 7vPCV in a 0-1-2-month (n = 101) or a 1-2-3-month (n = 105) schedule or no 7vPCV (n = 106). All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. We cultured nasopharyngeal swabs (NPS) collected at ages 1, 2, 3, 4 weeks and 3, 9, 18 months, and middle ear discharge if present. Pneumococcal serotypes were identified by the Quellung reaction. A total of 1761 NPS were cultured. The prevalence of pneumococcal carriage was 22% at 1 week of age, rising to 80% by age 3 months and remained >70% thereafter, with high-density carriage in 42% of pneumococcus-positive samples. We identified 63 different serotypes; 43% of isolates from controls were 13vPCV serotypes. There were no significant differences in 7vPCV serotype carriage between 7vPCV recipients and controls at any age (22% vs. 31% at 9 months, p = 0.2). At age 9 months the prevalence of non-7vPCV carriage was 17% higher in 7vPCV recipients (48%) than in controls (25%, p = 0.02). More non-7vPCV serotypes were isolated from ear discharge in 16 7vPCV recipients than from 4 controls (48% vs. 25%, p = 0.13). The limited impact of neonatal or accelerated infant 7vPCV schedules on vaccine serotype carriage is probably due to the early onset of dense carriage of a broad range of pneumococcal serotypes. While serotype-independent pneumococcal vaccines are needed in high-risk populations, the underlying environmental factors and sources of infection must be investigated. http://clinicaltrials.gov/ct2/show/NCT00219401.

Project description:BackgroundHeterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development.MethodsCom-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration.FindingsIn April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies.InterpretationHeterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics.Isrctn27841311 EudraCT:2021-001275-16.

Project description:This study describes the effects of the introduction of universal infant pneumococcal conjugate vaccination in 2006 on invasive pneumococcal disease (IPD) among children and adults in Germany with a focus on the dynamics of serotype distribution in vaccinated and non-vaccinated age groups. Over a period of 22 years (1992-2014), microbiological diagnostic laboratories from all over Germany have been sending isolates of IPD cases to the German National Reference Center for Streptococci on a voluntary basis. Streptococcus pneumoniae isolates were serotyped using Neufeld's Quellung method. Among children <16 years, the proportion of PCV7 serotypes among isolates from IPD cases decreased from 61.8% before vaccination (1997-2006) to 23.5% in the early vaccination period (2007-2010; p = 1.30E-72) and sank further to 5.2% in the late vaccination period (2010-2014; p = 4.59E-25). Similar reductions were seen for the separate age groups <2 years, 2-4 years and 5-15 years. Among adults, the proportion of PCV7 serotypes decreased from 43.4% in the pre-vaccination period (1992-2006) to 24.7% (p = 3.78E-88) in the early vaccination period and 8.2% (p = 5.97E-161) in the late vaccination period. Both among children and among adults, the non-PCV7 serotypes 1, 3, 7F and 19A significantly increased in the early vaccination period. After the switch from PCV7 to PVC10/PCV13 for infant vaccination in 2010, serotypes 1, 6A and 7F significantly decreased. A decrease in serotype 19A was only observed in 2013-2014, as compared to 2010-2011 (children p = 4.16E-04, adults p = 6.98E-06). Among adults, serotype 3, which strongly increased in the early vaccination period (p = 4.44E-15), remained at a constant proportion in the late vaccination period. The proportion of non-PCV13 vaccine serotypes increased over the whole vaccination period, with serotypes 10A, 12F, 23B, 24F and 38 most significantly increasing among children and serotypes 6C, 12F, 15A, 22F and 23B increasing among adults. Eight years of childhood pneumococcal conjugate vaccination have had a strong effect on the pneumococcal population in Germany, both among the target group for vaccination as well as among older children and adults.

Dataset Information

Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial.

Publications

Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial.

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