Articles
Comparison of two schedules of two-dose priming with the ten-valent pneumococcal conjugate vaccine in Nepalese children: an open-label, randomised non-inferiority controlled trial

https://doi.org/10.1016/S1473-3099(18)30568-1Get rights and content

Summary

Background

Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval.

Methods

We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40–60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 μg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513.

Findings

Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI −9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [−2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [−7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference −4·92% [−9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference −3·39% [95% CI −13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference −10·23% [−21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference −10·41% [−20·65 to −0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference −4·91% [−15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference −15·31% [−25·78 to −4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference −2·01% [−12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 μg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6  +  14 group.

Interpretation

The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection.

Funding

Gavi, the Vaccine Alliance.

Introduction

Streptococcus pneumoniae is the leading cause of bacterial pneumonia, meningitis, and septicaemia in children worldwide, and disproportionately affects children from low-income and middle-income countries.1 Pneumococcal conjugate vaccines (PCVs) reduce pneumococcal disease burden by direct protection and by reducing nasopharyngeal carriage, thereby preventing transmission and inducing herd protection.2, 3

Research in context

Evidence before this study

We searched PubMed on May 1, 2018, for studies comparing the immunogenicity of different pneumococcal conjugate vaccine (PCV) schedules in children using the search terms “immunogenicity” AND “children” AND “PCV” AND “clinical trial” [publication type]. The search was unrestricted by language or publication date. Using this search strategy, we identified one systematic review, which had meta-analysed studies reporting immunogenicity data up until 2011, and two further randomised controlled trials (RCTs) making a head-to-head comparison of PCV schedules, since the systematic review. The previous systematic review examining the effect that timing of seven-valent pneumococcal conjugate vaccine (PCV7) priming schedules had on immunogenicity found that schedules with 2 month intervals between priming doses had improved immunogenicity for three of the PCV7 serotypes before boosting when compared with those with a 1 month interval. Notably there were no RCTs that assessed the interval of PCV priming in a head-to-head design included in this review, with comparisons of intervals made across studies done in different settings. As such, the role of covariates, which have been shown to affect immunogenicity, should be considered. A study completed since this review, compared four 13-valent pneumococcal conjugate vaccine (PCV13) infant schedules (2, 4, and 6 months; 2, 3, and 4 months; 2 and 4 months; or 3 and 5 months) in a head-to-head design among healthy Dutch children, and showed that PCV13 priming schedules with 2 month intervals had improved immunogenicity post-priming when compared with 1 month intervals (2, 4, and 6 months superior for 11 serotypes compared with 2, 3, and 4 months). However, the differences between the schedules diminished with time, with few differences detected after boosting at 11·5 months of age (2, 4, and 6 months superior for two serotypes compared with 2, 3, and 4 months). Of note, this study was designed in such a way that it could not completely differentiate the interplay between age of initial vaccination and interval of dosing. Another study compared PCV13 administered in three doses at 1 month intervals (2, 3, and 4 months) with 2 month intervals (2, 4, and 6 months) among premature infants in the UK, and showed significantly higher immunogenicity for seven serotypes after the priming series in the children who received PCV13 with 2 month intervals. Children in this study then received a booster at 12 months of age with those children who had PCV13 at 1 month intervals having better immunogenicity for three of the PCV13 serotypes. It should be noted that the findings from this study of premature infants should be translated to healthy infants with caution. It is also difficult to generalise the findings of both of these head-to-head studies, done in European children, which used 11·5–12 months of age boosters, to resource-limited settings where 9-month boosters are used.

Added value of this study

Our study is the first randomised trial to make a head-to-head comparison of a 1 month interval with a 2 month interval PCV priming schedule followed by a 9 month booster. In this trial improved immunogenicity is conferred by a 2 month PCV priming interval; however, the differences between the two schedules lessened over time, particularly after the booster dose.

Implications of all the available evidence

A 2 month interval between priming doses is the preferred strategy for PCV delivery in infants. However, a WHO review, which includes the consideration of data from this trial, indicates that an accelerated priming schedule with a 1 month PCV priming interval might be used where programmatic reasons dictate, since there is little difference between groups post-boosting and there is still a substantial effect expected on invasive disease in resource-limited settings.

In Nepal, invasive pneumococcal disease is responsible for a substantial disease burden in children.4, 5 Surveillance done since 2005 at Patan Hospital (Kathmandu, Nepal), indicates that the majority of invasive pneumococcal disease is due to serotypes 1, 5, and 14, and that the majority of invasive pneumococcal disease occurs in late infancy and toddlerhood.5, 6, 7 Ten-valent PCV (PCV10) was introduced into the routine infant immunisation schedule of Nepal during 2015.8

A randomised trial done at Patan Hospital, assessing the immunogenicity of PCV10, showed that a two-dose prime (at 6 and 14 weeks) with a 9 month booster was non-inferior for IgG concentrations at 18 weeks and 10 months and superior at 2–4 years of age to a conventional three-dose priming-only schedule (6, 10, and 14 weeks).6 This two-dose prime and boost schedule, with an 8 week interval between the priming doses, is endorsed by WHO and recommended in late 2014 by the Nepal Ministry of Health.9 WHO however, has also recommended introduction of a single inactivated poliomyelitis virus vaccine at 14 weeks of age to mitigate the risk of outbreaks from vaccine derived serotype 2 poliomyelitis virus, to protect against serotype 2 poliomyelitis virus once countries switch to bivalent oral polio vaccine (OPV; containing only serotypes 1 and 3 poliovirus) from trivalent OPV, and to enhance immunogenicity of OPV to serotypes 1 and 3 poliovirus strains.10 This approach has created a programmatic dilemma because it requires administering three injections at the 14 week visit (pentavalent vaccine [PCV5], PCV, and inactivated poliomyelitis virus vaccine). On the basis of concerns around public and provider acceptance, and feasibility, the Nepalese Ministry of Health opted to move the second PCV10 priming dose from 14 weeks to 10 weeks of age, creating a 4 week rather than 8 week interval between the two priming PCV doses.11 Given this decision, it is important to evaluate the immunogenicity of this accelerated 2 + 1 schedule (ie, with a 1 month interval between priming doses), comparing it with the standard 2 + 1 schedule (ie, with a 2 month interval between priming doses), which has been shown to provide a level of immunogenicity that would predict substantial programme effect on disease and colonisation. This immunogenicity is important because accelerated two-dose priming schedules have shown a reduction in immunogenicity in other settings.12, 13

Therefore, this study was done to evaluate the immunogenicity of a schedule of immunisation with PCV10 at 6 and 10 weeks, which is used in Nepal, compared with priming at 6 and 14 weeks of age in healthy Nepalese infants. In both groups a PCV10 booster was given at 9 months of age.

Section snippets

Study design and participants

We did a single-centre open-label, parallel group, randomised controlled trial, at Patan Hospital, Kathmandu, Nepal. Ethics approval was obtained from Oxford Tropical Research Ethics Committee (OXTREC 25-15) and the Nepal Health Research Ethics Committee (NHRC 90-2015). A copy of the study protocol can be obtained on request from the corresponding author and is also available online.

We recruited healthy Nepalese infants aged 40–60 days, who presented to the immunisation clinic at Patan

Results

Between Aug 21, 2015, and April 4, 2016, 850 children were screened and 304 enrolled (figure 1; appendix). 152 children each were randomly assigned to the 6 + 10 group, or the 6 + 14 group. Both groups received PCV10 at 9 months of age. The baseline characteristics of the study participants are shown in table 1.

At 9 months of age, the proportion of children achieving serotype-specific IgG greater than or equal to 0·35 μg/mL in the 6 + 10 group was non-inferior to the proportion of patients in

Discussion

This is the first trial to compare antibody responses in children who received two doses of PCV10 in early infancy with either a 1 month or 2 month interval between doses, followed by a booster at 9 months of age. Our results show that at 9 months of age, before the booster, the immunogenicity of the 6 + 10 schedule was non-inferior to the 6 + 14 group for four of the ten vaccine serotypes (serotypes 5, 9V, 14, and 19F). Non-inferiority was not shown for the other six serotypes (1, 4, 6B, 7F,

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