Effect of a Reduced PCV10 Dose Schedule on Pneumococcal Carriage in Vietnam

Abstract

Background: After pneumococcal disease and colonization have been controlled through vaccination campaigns, a reduced pneumococcal conjugate vaccine (PCV) schedule may be sufficient to sustain that control at reduced costs.

Methods: We investigated whether a single primary dose and booster dose (1p+1) of the 10-valent PCV (PCV10) would be noninferior to alternative dose schedules in sustaining control of carriage of pneumococcal serotypes included in the vaccine. In Nha Trang, Vietnam, an area in which PCV had not been used previously, a PCV10 catch-up campaign was conducted in which the vaccine was offered to children younger than 3 years of age, after which a cluster-randomized trial was conducted in which children received PCV10 at 2, 3, and 4 months of age (3p+0 group); at 2, 4, and 12 months of age (2p+1 group); at 2 and 12 months of age (1p+1 group); or at 12 months of age (0p+1 group). Annual carriage surveys in infants (4 to 11 months of age) and toddlers (14 to 24 months of age) were conducted from 2016 through 2020. The primary end point was protection against carriage of vaccine serotypes, evaluated in a noninferiority analysis in the 1p+1 group as compared with the 2p+1 and 3p+0 groups, 3.5 years after vaccine introduction (noninferiority margin, 5 percentage points). Noninferiority of the 0p+1 schedule was also evaluated.

Results: In 2016, before the introduction of PCV10, vaccine-serotype carriage was found in 160 of 1363 infants (11.7%); in 2020, vaccine-serotype carriage was found in 6 of 333 (1.8%), 5 of 340 (1.5%), and 4 of 313 (1.3%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively, indicating noninferiority of 1p+1 to 2p+1 (difference, 0.3 percentage points; 95% confidence interval [CI], -1.6 to 2.2) and to 3p+0 (difference, 0.5 percentage points; 95% CI, -1.4 to 2.4). Similarly, 1p+1 was noninferior to 2p+1 and 3p+0 for protection against vaccine-serotype carriage among toddlers. In 2016, carriage of serotype 6A was found in 99 of 1363 infants (7.3%); in 2020, it was found in 12 of 333 (3.6%), 10 of 340 (2.9%), and 3 of 313 (1.0%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively. The 0p+1 schedule was also noninferior to the other three dose schedules among infants and toddlers, although cross-protection against serotype 6A was less common than with the other vaccination schedules. No PCV10-associated severe adverse effects were observed.

Conclusions: A reduced vaccination schedule involving a single primary dose and booster dose of PCV10 was noninferior to alternative schedules in protecting against vaccine-serotype carriage in infants and toddlers. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02961231.).

Figure 1.

Study site map, proportion of population that received different PCV10 doses by age groups and arms Panel A shows the map of communes in Nha Trang with trial arm cluster allocation (unvaccinated, 0+1, 1p+1, 2p+1, 3p+0); panel B shows the proportion receiving the specified number of doses (dark section of bar) or greater (lighter section of bar) by trial arm and age group. Note that for the 0p+1 infant group, the specified number of doses is 0. Panel C shows the proportion reporting receiving different numbers of doses specified by trial arm and age group.

Figure 2.

Flowchart of enrolment and sample-tested children for the carriage surveys, and enrolment and PCV administration for the catch-up campaign Panel A shows the number of children (infant: 4-11-month, toddler: 14–24-month-old) enrolled in each carriage survey. A total six carriage surveys; 1st: a pre-vaccination baseline carriage survey in all arms in 2016 October, 2nd: a post PCV-10 catchup carriage survey in June 2017 (5 months after the catch-up), and 3rd: annual carriage surveys in November 2017, 4th: October 2018, 5th: October 2019, and 6th: October 2020 were conducted. Panel B shows the number of children enrolled and the PCV10 vaccination coverage in the PCV10 catch-up campaign. *Completion rate (coverage of the catch-up campaign): ([3]/[1]) #Completion rate (coverage of PCV, assuming [2] completed a designated schedule): (([2]+[3])/(1))

Figure 2.

Flowchart of enrolment and sample-tested children for the carriage surveys, and enrolment and PCV administration for the catch-up campaign Panel A shows the number of children (infant: 4-11-month, toddler: 14–24-month-old) enrolled in each carriage survey. A total six carriage surveys; 1st: a pre-vaccination baseline carriage survey in all arms in 2016 October, 2nd: a post PCV-10 catchup carriage survey in June 2017 (5 months after the catch-up), and 3rd: annual carriage surveys in November 2017, 4th: October 2018, 5th: October 2019, and 6th: October 2020 were conducted. Panel B shows the number of children enrolled and the PCV10 vaccination coverage in the PCV10 catch-up campaign. *Completion rate (coverage of the catch-up campaign): ([3]/[1]) #Completion rate (coverage of PCV, assuming [2] completed a designated schedule): (([2]+[3])/(1))

Figure 3.

Pneumococcal carriage prevalence and vaccine type proportion of carriage in trial arms across carriage surveys Panel A shows the prevalence of carriage and panel B shows the proportion of carriage, by carriage survey (6 carriage surveys conducted between 2016 October to 2020 October), trial arm, age group, and vaccine type definition.

Figure 4.

Non-inferiority analysis 1p+1 and 0p+1 arms versus 2p+1 and 3p+0 arms The figure shows the non-inferiority of reduced dose schedules (panel A: 1p+1) and (panel B: 0p+1) versus standard dose schedules (2p+1 and 3p+0) by age group (infants: 4-11 months, toddlers: 14-24 months) by mean (point) and 95% confidence intervals (CI) (line) of the difference in absolute vaccine-type prevalence in the final carriage survey in October 2020 for PCV10 and PCV10 + serotype 6A. Red line and shaded area indicate the 5% non-inferiority margin; estimates with 95% CIs overlapping the 5% margin indicate inferiority.