Immunogenicity of a single-dose compared with a two-dose primary series followed by a booster dose of ten-valent or 13-valent pneumococcal conjugate vaccine in South African children: an open-label, randomised, non-inferiority trial

Abstract

Background: Routine childhood immunisation with pneumococcal conjugate vaccine (PCV) has changed the epidemiology of pneumococcal disease across age groups, providing an opportunity to reconsider PCV dosing schedules. We aimed to evaluate the post-booster dose immunogenicity of ten-valent (PCV10) and 13-valent (PCV13) PCVs between infants randomly assigned to receive a single-dose compared with a two-dose primary series.

Methods: We did an open-label, non-inferiority, randomised study in HIV-unexposed infants at a single centre in Soweto, South Africa. Infants were randomly assigned to receive one priming dose of PCV10 or PCV13 at ages 6 weeks (6w + 1 PCV10 and 6w + 1 PCV13 groups) or 14 weeks (14w + 1 PCV10 and 14w + 1 PCV13 groups) or two priming doses of PCV10 or PCV13, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10 and 2 + 1 PCV13 groups); all participants then received a booster dose of PCV10 or PCV13 at 40 weeks of age. The primary endpoint was geometric mean concentrations (GMCs) of serotype-specific IgG 1 month after the booster dose, which was assessed in all participants who received PCV10 or PCV13 as per the assigned randomisation group and for whom laboratory results were available at that timepoint. The 1 + 1 vaccine schedule was considered non-inferior to the 2 + 1 vaccine schedule if the lower bound of the 96% CI for the GMC ratio was greater than 0·5 for at least ten PCV13 serotypes and eight PCV10 serotypes. Safety was a secondary endpoint. This trial is registered with ClinicalTrials.gov (NCT02943902) and is ongoing.

Findings: Of 1695 children assessed, 600 were enrolled and randomly assigned to one of the six groups between Jan 9 and Sept 20, 2017; 542 were included in the final analysis of the primary endpoint (86-93 per group). For both PCV13 and PCV10, a 1+1 dosing schedule (either beginning at 6 or 14 weeks) was non-inferior to a 2 + 1 schedule. For PCV13, the lower limit of the 96% CI for the ratio of GMCs between the 1 + 1 and 2 + 1 groups was higher than 0·5 for ten serotypes in the 6w+1 group (excluding 6B, 14, and 23F) and 11 serotypes in the 14w + 1 group (excluding 6B and 23F). For PCV10, the lower limit of the 96% CI for the ratio of GMCs was higher than 0·5 for all ten serotypes in the 6w+1 and 14w + 1 groups. 84 serious adverse events were reported in 72 (12%) of 600 participants. 15 occurred within 28 days of vaccination, but none were considered to be related to PCV injection. There were no cases of culture-confirmed invasive pneumococcal disease.

Interpretation: The non-inferiority in post-booster immune responses following a single-dose compared with a two-dose primary series of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes.

Funding: The Bill & Melinda Gates Foundation (OPP1 + 152352).

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile Participants reincluded are indicated with a + symbol. Infants were randomly assigned to receive one primary dose of PCV10 or PCV13 at age 6 weeks (6w + 1 PCV10 and PCV13 groups) or 14 weeks (14w + 1 PCV10 and PCV13 groups) or two primary doses, one each at ages 6 weeks and 14 weeks (2 + 1 groups). All infants received a booster dose at age 40 weeks. PCV10=ten-valent pneumococcal conjugate vaccine. PCV13=13-valent pneumococcal conjugate vaccine.

Figure 2

Serum IgG 1 month post booster with PCV13 following a single-dose or two-dose primary series (A) GMCs of serotype-specific IgG antibodies (error bars indicate 96% CIs). (B) Ratio of serotype-specific GMCs. The vertical dashed line at 0·5 indicates the non-inferiority margin; for the 1 + 1 vaccine schedule to be non-inferior to the 2 + 1 schedule, the lower bound of the 96% CI for the ratio of GMCs had to be higher than 0·5 for at least ten of the 13 vaccine serotypes. The serotype-specific IgG GMC was higher in the 1 + 1 group than in the 2 + 1 group if the lower bound of the 96% CI was above 1, whereas the serotype-specific IgG GMC was lower in the 1 + 1 group than in the 2 + 1 group if the upper bound of the 96% CI was less than 1 (note that the limits have been rounded in this figure). Infants received one primary dose of PCV13 at age 6 weeks (6w + 1 PCV13) or 14 weeks (14w + 1 PCV13) or two primary doses, one each at ages 6 weeks and 14 weeks (2 + 1 PCV13). All infants received a booster dose of PCV13 at age 40 weeks. PCV13=13-valent pneumococcal conjugate vaccine. GMC=geometric mean concentration.

Figure 3

Serum IgG 1 month post booster with PCV10 following a single-dose or two-dose primary series (A) GMCs of serotype-specific IgG antibodies (error bars indicate 96% CIs). (B) Ratio of serotype-specific GMCs. The vertical dashed line at 0·5 indicates the non-inferiority margin; for the 1 + 1 vaccine schedule to be non-inferior to the 2 + 1 schedule, the lower bound of the 96% CI for the ratio of GMCs had to be higher than 0·5 for at least eight of the ten vaccine serotypes. The serotype-specific IgG GMC was higher in the 1 + 1 group than in the 2 + 1 group if the lower bound of the 96% CI was above 1, whereas the serotype-specific IgG GMC was lower in the 1 + 1 group than in the 2 + 1 group if the upper bound of the 96% CI was less than 1 (note that the limits have been rounded in this figure). Infants received one primary dose of PCV10 at age 6 weeks (6w + 1 PCV10) or 14 weeks (14w + 1 PCV10) or two primary doses, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10). All infants received a booster dose of PCV10 at age 40 weeks. PCV10=ten-valent pneumococcal conjugate vaccine. GMC=geometric mean concentration. *Serotypes included in the 13-valent but not the ten-valent pneumococcal conjugate vaccine.

Figure 4

Percentage of infants with serotype-specific serum IgG concentrations ≥0·35 μg/mL 1 month after a single-dose or two-dose primary series with PCV13 (A) or PCV10 (B) Error bars show 96% CI (note that the limits have been rounded in this figure). Infants received one primary dose of PCV10 or PCV13 at age 6 weeks (6w + 1 PCV10 or PCV13) or 14 weeks (14w + 1 PCV10 or PCV13) or two primary doses, one each at ages 6 weeks and 14 weeks (2 + 1 groups). PCV13=13-valent pneumococcal conjugate vaccine. PCV10=ten-valent pneumococcal conjugate vaccine. *Serotypes included in PCV13 but not in PCV10.

Figure 5

Serum IgG GMCs pre-booster dose with PCV13 (A) or PCV10 (B) following a single-dose or two-dose primary series Error bars show 96% CIs (note that the limits have been rounded in this figure). Infants received one primary dose of PCV10 or PCV13 at age 6 weeks (6w + 1 PCV10 or PCV13) or 14 weeks (14w + 1 PCV10 or PCV13) or two primary doses, one each at ages 6 weeks and 14 weeks (2 + 1 groups), plus booster doses at age 40 weeks. PCV13=13-valent pneumococcal conjugate vaccine. PCV10=ten-valent pneumococcal conjugate vaccine. GMC=geometric mean concentration. *Serotypes included in PCV13 but not in PCV10.