Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial.

BACKGROUND: Data 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. METHODS: In 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. FINDINGS: Between 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. INTERPRETATION: A 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. FUNDING: Australian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.

Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial.

BACKGROUND: Few data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13. METHODS: In this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 µg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510. FINDINGS: Of 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 µg/mL did not differ between groups at the 10% level for any serotype (PCV10-PCV13 risk difference -2·1% [95% CI -4·8 to -0·1] for serotype 1; -1·3% [-3·7 to 0·6] for serotype 4; -3·4% [-6·8 to -0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; -1·3% [-3·7 to 0·6] for serotype 7F; -1·6% [-5·1 to 1·7] for serotype 9V; 0·0% [-2·7 to 2·9] for serotype 14; -2·1% [-5·3 to 0·9] for serotype 18C; 0·0% [-2·2 to 2·3] for serotype 19F; and -11·6% [-18·2 to -4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups. INTERPRETATION: PCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings. FUNDING: National Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.