Abstract
SummaryBackgroundData 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.
Highlights
Pneumococcal infections cause invasive diseases and mucosal diseases, and are a major cause of morbidity and mortality in children younger than 5 years globally.[1]
We searched PubMed for publications in English from database inception until Jan 31, 2020, using search terms including but not limited to “pneumococcal conjugate vaccine”, “immunogenicity” and “low- and middle-income country”. At the time this trial was designed (2012), no studies had been published on alternative PCV schedules in low-income and middle-income countries (LMICs) settings
A systematic review of 61 PCV dosing studies published in 2014 found that a three-dose primary series schedule was more immunogenic than two doses for most serotypes
Summary
Pneumococcal infections cause invasive diseases (eg, meningitis and sepsis) and mucosal diseases (eg, pneumonia and otitis media), and are a major cause of morbidity and mortality in children younger than 5 years globally.[1]. We searched PubMed for publications in English from database inception until Jan 31, 2020, using search terms including but not limited to “pneumococcal conjugate vaccine”, “immunogenicity” and “low- and middle-income country” At the time this trial was designed (2012), no studies had been published on alternative PCV schedules in LMIC settings. For many LMICs, in Asia, country-specific data are needed to facilitate a decision on which vaccine schedule to introduce Since submission of this Article, one trial in South Africa compared PCV10 and PCV13 when given as a 1 + 1 (primary dose at age 6 or 14 weeks plus booster dose at age 40 weeks) or as 2 + 1 schedule (at ages 6 and 14 weeks plus booster dose at age 40 weeks). No difference was found in the primary outcome of IgG geometric mean concentration (GMC) and GMC ratio at 1 month after booster between the single dose and two-dose primary schedules
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