Articles
Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study

https://doi.org/10.1016/S1473-3099(20)30173-0Get rights and content

Summary

Background

Ten-valent and 13-valent pneumococcal conjugate vaccines (PCVs) have shown important benefits by decreasing invasive pneumococcal disease caused by vaccine serotypes. Belgium had an uncommon situation with sequential use of PCV7, PCV13, and PCV10 in the childhood vaccination programmes between 2007 and 2018. We aimed to analyse the changes in incidence of invasive pneumococcal disease and serotype distribution in children throughout this period.

Methods

Streptococcus pneumoniae isolates were obtained from patients with invasive pneumococcal disease in Belgium between 2007 and 2018 by the national laboratory-based surveillance. Paediatric invasive pneumococcal disease incidence, serotype distribution, and antimicrobial susceptibility were analysed in periods during which PCV7 (2009–10), PCV13 (2013–14), both PCV13 and PCV10 (2015–16), and PCV10 (2017–18) were used. Incidence rates and trends were compared. Vaccination status was collected. For a subset of serotype 19A isolates, multilocus sequence type was identified.

Findings

After a decrease in PCV7 serotype invasive pneumococcal disease was observed during the PCV7 period, total paediatric invasive pneumococcal disease incidence significantly declined during the PCV13 period (−2·6% monthly, p<0·0001). During the PCV13–PCV10 period (2015–16), the lowest mean in paediatric invasive pneumococcal disease incidence was achieved, but the incidence increased again during the PCV10 period (2017–18), especially in children younger than 2 years (+1·7% monthly; p=0·028). This increase was mainly due to a significant rise in serotype 19A invasive pneumococcal disease incidence in the PCV10 period compared with the PCV13 period (p<0·0001), making serotype 19A the predominant serotype in paediatric invasive pneumococcal disease in the PCV10 period. Genetic diversity within the 2017–18 serotype 19A collection was seen, with two predominant clones, ST416 and ST994, that were infrequently observed before PCV10 introduction. In 2018, among children younger than 5 years with invasive pneumococcal disease who were correctly vaccinated, 37% (37 of 100) had PCV13 serotype invasive pneumococcal disease, all caused by serotype 19A and serotype 3.

Interpretation

After a significant decrease during the PCV13 period, paediatric invasive pneumococcal disease incidence increased again during the PCV10 period. This observation mainly resulted from a significant increase of serotype 19A cases. During the PCV10 period, dominant serotype 19A clones differed from those detected during previous vaccine periods. Whether changes in epidemiology resulted from the vaccine switch or also from natural evolution remains to be further elucidated.

Funding

The Belgian National Reference is funded by the Belgian National Institute for Health and Disability Insurance and the whole genome sequencing by an investigator-initiated research grant from Pfizer.

Introduction

Both the ten-valent pneumococcal conjugate vaccine (PCV10) and the 13-valent pneumococcal conjugate vaccine (PCV13) have shown substantial effects and vaccine effectiveness against vaccine serotype and overall incidence of invasive pneumococcal disease in multiple studies.1, 2, 3 The effectiveness and impact of PCV13 on serotype 19A paediatric invasive pneumococcal disease is well described.2, 4, 5 Also vaccine effectiveness of PCV10 against serotype 19A invasive pneumococcal disease is reported.1, 2, 6, 7 Studies of short-term outcomes have shown evidence for the cross-protection of PCV10 against serotype 19A invasive pneumococcal disease,6, 7 but some studies published between 2017 and 2019 evaluating the impact of PCV10 for at least 3 years were not able to support this effect.1, 3, 8, 9 An increase in invasive pneumococcal disease caused by non-vaccine serotypes has been reported because of a serotype replacement phenomenon.3

In Belgium, seven-valent pneumococcal conjugate vaccine (PCV7) became available on the market in October, 2004 (estimated vaccine uptake of 42% in 2006).10 It was in 2007 that PCV7 was included in the nation's childhood vaccination programmes in a 2 + 1 schedule, rapidly achieving a coverage of more than 90%. The effect of the PCV7 introduction on the invasive pneumococcal disease epidemiology in Belgium has previously been described in detail.10 From 2011, PCV13 was used but replaced by PCV10 in July, 2015 (in Flanders), and May, 2016 (in Wallonia).

Research in context

Evidence before this study

We searched PubMed for articles in English on invasive pneumococcal disease using the terms “pneumococcal conjugate vaccine”, “impact”, “pneumococcal disease”, or “serotype replacement”. We searched for population-based studies published between Jan 1, 2000, and Sept 1, 2019, that studied the effect of both ten-valent and 13-valent pneumococcal conjugate vaccine (PCV) on serotype distribution and incidence. These vaccines are used worldwide and have shown substantial benefit in reducing the Streptococcus pneumoniae paediatric burden, especially by decreasing the incidence of invasive pneumococcal disease related to vaccine serotypes. For each country, the choice of using PCV10 or PCV13 depends on the targeted infections (invasive or non-invasive) and the expected effect on the S pneumoniae burden. In addition to immunogenicity studies, prediction of vaccine effects is based on careful assessment and follow-up of local S pneumoniae epidemiology and on experiences from other countries. The current literature mainly describes results from implementing a single PCV, but apart from one published study comparing the use of PCV13 and PCV10 among Swedish counties, there is no report of long-term follow-up after consecutive use of both PCV13 and PCV10 on a national scale.

Added value of this study

Our study describes the evolution of paediatric invasive pneumococcal disease epidemiology with the sequential use of the three conjugate vaccines PCV7, PCV13, and PCV10 in Belgium from 2007 to 2018. The significant decrease in paediatric invasive pneumococcal disease incidence that was observed during the PCV13 period was followed by an increase during the PCV10 period. This rise in invasive pneumococcal disease cases was significant already 2 years after the vaccine switch and mainly due to serotype 19A. Moreover, we observed a high genetic diversity among the serotype 19A circulating clones involved in invasive pneumococcal disease during the PCV10 period.

Implications of all the available evidence

This Article delivers the real word experience of a country with high vaccine coverage that switched from a higher-valent pneumococcal vaccine (PCV13) to a lower-valent pneumococcal vaccine (PCV10), and underlines the importance of a long-term follow-up of S pneumoniae dynamics to assess vaccine effects. This observation is important because it could guide policy makers when introducing either PCV13 or PCV10 in childhood vaccination programmes, while each country's own epidemiology and expectations also needs to be taken into account.

In general, in addition to financial requirements, the choice between vaccines depends on objectives (decrease of invasive or noninvasive diseases, such as acute otitis media), targeted groups (eg, children, older adults) and local epidemiology. Moreover, decision making is complicated by uncertainties about serotype cross-protection, serotype replacement phenomenon, interaction with other bacteria in the nasopharynx, and indirect effects.11 The switch from PCV13 to PCV10 in Belgium was decided following the equally effective rating of PCV10 and PCV13 published by the Belgian Superior Health Council in 2015.12

Thanks to the Belgian national prospective surveillance network, the epidemiology of invasive pneumococcal disease is monitored closely. Passive laboratory surveillance has been done for more than 20 years at the National Reference Centre for Streptococcus pneumoniae (NRC). A mean of 1632 invasive pneumococcal disease strains from 95 laboratories are sent yearly (appendix 3 p 2), making the surveillance representative for the roughly 11 million inhabitants. Based on the surveillance, changes in the incidence of paediatric invasive pneumococcal disease and serotype distribution were already observed in 2017, and it has been hypothesised that these changes resulted from the switch in vaccine schedule.13 The aim of the present study was to deeply assess the Belgian epidemiology of paediatric invasive pneumococcal disease before and after the switch in PCV. The vaccine coverage of more than 93% (2 + 1 schedule) and the easy access to health-care systems in Belgium provide an interesting model to examine the epidemiology of invasive pneumococcal disease.14, 15

Section snippets

Study design and participants

This retrospective observational study was based on the Belgian laboratory-based surveillance of invasive pneumococcal disease. All Streptococcus pneumoniae isolates sent to the NRC from Jan 1, 2007, to Dec 31, 2018, that were collected from a normally sterile site from children younger than 16 years were included in the study.

This study was approved by the ethics committee research UZ/KU Leuven. No written informed consent was collected.

Data collection

Data collection was part of routine invasive pneumococcal

Results

3384 isolates of paediatric invasive pneumococcal disease were sent to the NRC over the 11-year surveillance period (2007–18). Based on the proportion of reimbursements of blood cultures, the overall NRC coverage per year ranged from 87% to 93% (appendix 3 p 2). In 2018, 92 laboratories participated in the surveillance of invasive pneumococcal disease and represented 88% of the total paediatric beds available in the whole country.

Figure 1, Figure 2 illustrate the evolution of the total

Discussion

Belgium has an uncommon situation with a switch from PCV13 to PCV10 in the childhood vaccination programmes in 2015 after the sequential use of PCV7 (2007–10) and PCV13 (2011–16). On the basis of the Belgian national surveillance of invasive pneumococcal disease, a fast resurgence of PCV13-only serotype invasive pneumococcal disease, which was mainly related to serotype 19A, could be documented already 2 years after the switch from PCV13 to PCV10. The ten times increase in serotype 19A invasive

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