Efficacy against pneumococcal carriage and the immunogenicity of reduced-dose (0 + 1 and 1 + 1) PCV10 and PCV13 schedules in Ho Chi Minh City, Viet Nam: a parallel, single-blind, randomised controlled trial

Abstract

Background: Interest in reduced-dose pneumococcal conjugate vaccine (PCV) schedules is growing, but data on their ability to provide direct and indirect protection are scarce. We evaluated 1 + 1 (at 2 months and 12 months) and 0 + 1 (at 12 months) schedules of PCV10 or PCV13 in a predominately unvaccinated population.

Methods: In this parallel, single-blind, randomised controlled trial, healthy infants aged 2 months were recruited from birth records in three districts in Ho Chi Minh City, Vietnam, and assigned (4:4:4:4:9) to one of five groups: PCV10 at 12 months of age (0 + 1 PCV10), PCV13 at 12 months of age (0 + 1 PCV13), PCV10 at 2 months and 12 months of age (1 + 1 PCV10), PCV13 at 2 months and 12 months of age (1 + 1 PCV13), and unvaccinated control. Outcome assessors were masked to group allocation, and the infants' caregivers and those administering vaccines were not. Nasopharyngeal swabs collected at 6 months, 12 months, 18 months, and 24 months were analysed for pneumococcal carriage. Blood samples collected from a subset of participants (200 per group) at various timepoints were analysed by ELISA and opsonophagocytic assay. The primary outcome was the efficacy of each schedule against vaccine-type carriage at 24 months, analysed by intention to treat for all those with a nasopharyngeal swab available. This trial is registered at ClinicalTrials.gov, NCT03098628.

Findings: 2501 infants were enrolled between March 8, 2017, and July 24, 2018 and randomly assigned to study groups (400 to 0 + 1 PCV10, 400 to 0 + 1 PCV13, 402 to 1 + 1 PCV10, 401 to 1 + 1 PCV13, and 898 to control). Analysis of the primary endpoint included 341 participants for 0 + 1 PCV10, 356 0 + 1 PCV13, 358 1 + 1 PCV10, 350 1 + 1 PCV13, and 758 control. At 24 months, a 1 + 1 PCV10 schedule reduced PCV10-type carriage by 58% (95% CI 25 to 77), a 1 + 1 PCV13 schedule reduced PCV13-type carriage by 65% (42 to 79), a 0 + 1 PCV10 schedule reduced PCV10-type carriage by 53% (17 to 73), and a 0 + 1 PCV13 schedule non-significantly reduced PCV13-type carriage by 25% (-7 to 48) compared with the unvaccinated control group. Reactogenicity and serious adverse events were similar across groups.

Interpretation: A 1 + 1 PCV schedule greatly reduces vaccine-type carriage and is likely to generate substantial herd protection and provide some degree of individual protection during the first year of life. Such a schedule is suitable for mature PCV programmes or for introduction in conjunction with a comprehensive catch-up campaign, and potentially could be most effective given as a mixed regimen (PCV10 then PCV13). A 0 + 1 PCV schedule has some effect on carriage along with a reasonable immune response and could be considered for use in humanitarian crises or remote settings.

Funding: Bill & Melinda Gates Foundation.

Translation: For the Vietnamese translation of the abstract see Supplementary Materials section.

Figure 1

Trial profile Reasons for non-eligibility: 75 had significant medical history, 22 lived or had planned to move outside study area, 15 were outside enrolment age, and 11 had already received their routine 2-month vaccines. Reasons for withdrawal: 184 moved away and were lost to follow-up, 55 voluntarily withdrew, 44 received PCV outside the study, 20 refused study procedure, 3 died, and 12 withdrew for other reasons. Six participants did not have a sample collected at 18 months, a further 66 samples were not analysed for the following reasons: if the swabs were not handled appropriately (two 6-month swabs were inadvertently put in the same tube, one each from the two PCV10 groups), if pneumococcal carriage status could not be determined (n=2, both from the control group at 18 months), or if a serotype could not be determined (n=62). PCV=pneumococcal conjugate vaccine. PCV10=10-valent PCV. PCV13=13-valent PCV. NPS=nasopharyngeal swab.

Figure 2

Vaccine efficacy against vaccine-type pneumococcal carriage Carriage prevalence and percent reduction in carriage of vaccine serotypes comparing each vaccine schedule with unvaccinated participants. Lines represent carriage prevalence with shaded bands showing 95% CI. Text above points shows the percent reduction (95% CI) in carriage in the vaccinated group compared with unvaccinated participants. The percent reduction is equivalent to the vaccine efficacy against carriage, calculated as (1 – prevalence ratio) × 100. At 6 months and 12 months (1 + 1 comparisons), data for unvaccinated participants came from the two 0 + 1 groups combined; at 18 and 24 months (all comparisons), data for unvaccinated participants come from the control group. PCV=pneumococcal conjugate vaccine. PCV10=10-valent PCV. PCV13=13-valent PCV.

Figure 3

Serotype-specific GMCs (95% CI) over time Error bars indicate 95% CI. Data for unvaccinated participants comes from the two 0 + 1 groups combined at 3 months (blood sample collected at 2 months in 0 + 1 PCV10 and at 3 months in 0 + 1 PCV13) and 12 months and from the control group at 24 months. GMC=geometric mean concentration of IgG antibody. PCV=pneumococcal conjugate vaccine. PCV10=10-valent PCV. PCV13=13-valent PCV.