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Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease in children in the USA: a matched case-control study

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Summary

Background

In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was licensed and recommended in the USA for prevention of invasive pneumococcal disease in children. Licensure was based on immunogenicity data comparing PCV13 with the earlier seven-valent formulation. Because clinical endpoints were not assessed for the new antigens, we did a postlicensure matched case-control study to assess vaccine effectiveness.

Methods

Cases in children aged 2–59 months were identified through active surveillance in 13 sites. Controls were identified via birth registries and matched to cases by age and postal (zip) code. The primary objective was the vaccine effectiveness of at least one dose against the 13 serotypes included in PCV13. Secondary objectives included vaccine effectiveness against all-cause invasive pneumococcal disease, against antibiotic non-susceptible invasive pneumococcal disease, and among children with and without underlying conditions. Vaccine effectiveness was calculated as (1 – matched odds ratio) × 100%.

Findings

We enrolled 722 children with invasive pneumococcal disease and 2991 controls; PCV13 serotype cases (217 [30%]) included most commonly serotypes 19A (128 [18%]), 7F (32 [4%]), and 3 (43 [6%]). Vaccine effectiveness against PCV13 serotypes was 86·0% (95% CI 75·5 to 92·3), driven by serotypes 19A and 7F, for which vaccine effectiveness was 85·6% (95% CI 70·6 to 93·5) and 96·5% (82·7 to 100), respectively. We also identified statistically significant effectiveness against serotype 3 (79·5%, 95% CI 30·3 to 94·8) and against antibiotic non-susceptible invasive pneumococcal disease (65·6%, 44·9 to 78·7). Vaccine effectiveness against all-cause invasive pneumococcal disease was 60·2% (95% CI 46·8 to 70·3). Vaccine effectiveness was similar among children with (81·4%, 95% CI 45·4 to 93·6) and without (85·8%, 74·9 to 91·9) underlying conditions.

Interpretation

PCV13 appears highly effective against invasive pneumococcal disease among children in the USA in the context of routine and catch-up schedules, although some new vaccine antigens could not be assessed. PCV13 immunisation provides a robust strategy for combating pneumococcal antimicrobial resistance.

Funding

Centers for Disease Control and Prevention.

Introduction

Streptococcus pneumoniae, or pneumococcus, is a major cause of morbidity and mortality globally. In 2000, a seven-valent pneumococcal conjugate vaccine (PCV7 [Prevnar]; Wyeth, Collegeville, PA, USA) was introduced into the routine infant immunisation programme in the USA, using a schedule of doses at 2, 4, 6, and 12–15 months of age.1 Rates of invasive pneumococcal disease caused by PCV7 serotypes declined dramatically (>90% by 2007) after introduction.2, 3 After a few years, disease caused by serotype 19A, which was not included in PCV7, increased and became the most important cause of pneumococcal disease.2, 4 Invasive pneumococcal disease caused by other non-vaccine serotypes has increased in many countries. Although important, this phenomenon of serotype replacement has not overshadowed the overall benefits of conjugate vaccine introduction; rates of all invasive pneumococcal disease in the post-PCV7 period have remained well below pre-PCV7 rates in the USA.5

In 2010, a 13-valent conjugate vaccine (PCV13 [Prevnar-13]; Pfizer, New York, NY, USA) replaced PCV7 in the USA infant immunisation schedule. PCV13 included serotypes causing replacement disease in the USA and was licensed on the basis of a randomised trial with immunogenicity endpoints only.6 In addition to the routine schedule, children who started the schedule with PCV7 were recommended to complete the schedule with PCV13, and children aged up to 59 months inclusive who had completed the schedule with PCV7 were recommended to receive a single dose of PCV13.7 We used active, population-based surveillance for invasive pneumococcal disease in the USA to conduct a case-control study of PCV13 effectiveness.8 Our primary objective was to estimate the effectiveness of PCV13 in preventing invasive pneumococcal disease caused by any of the 13 serotypes included in the vaccine among children aged 2–59 months.9

Research in context

Evidence before this study

We searched PubMed using the search terms “13-valent pneumococcal conjugate vaccine”, “Prevnar 13”, and “pneumococcal vaccine effectiveness”, with no language restrictions for articles published between Jan 1, 2012 (2 years after PCV13 was licensed), and July 9, 2015. 237 papers were identified, most of which related to the safety, immunogenicity, or cost-effectiveness of PCV13. Only one paper, by Andrews and colleagues, described a postlicensure effectiveness study of PCV13 in children. They described an assessment of the effectiveness and immunogenicity of PCV13 in England, Wales, and Northern Ireland using the indirect cohort method and found the vaccine effectiveness against the six serotypes unique to PCV13 was 73% (95% CI 55–84) for two doses given before 12 months of age or one dose given after 12 months of age.

Added value of this study

This study provides the first postlicensure estimates of vaccine effectiveness from a case-control study in an active population-based surveillance system. PCV13 had strong effectiveness against serotypes 7F and 19A and provided evidence of some effectiveness against serotype 3, an area of concern during prelicensure assessments.

Implications of all available evidence

Taken together with existing evidence from the USA and other vaccine programmes, the effectiveness of PCV13 was confirmed in a real-world setting (as opposed to a prelicensure trial), which should encourage countries not yet using conjugate vaccines to introduce them into their routine immunisation schedule.

Section snippets

Study design and data collection

We did an individually matched case-control study of PCV13 effectiveness against invasive pneumococcal disease. Cases were defined as pneumococcus isolated from a normally sterile site (eg, blood, cerebrospinal fluid) in a child aged 2–59 months on the date of culture, had a serotype available (via PCR or standard Quellung reaction), and occurred among residents of one of ten active bacterial core surveillance (ABCs) sites or three additional sites added for the purpose of achieving an adequate

Results

From May 1, 2010, to May 31, 2014, we identified 1344 cases of invasive pneumococcal disease. Of these, 171 (13%) did not have a specimen available for serotyping, 15 (1%) were deemed to be recurrent, and four (<1%) were residents of long-term care facilities, leaving 1154 (86%) eligible for enrolment. Of the 1154 eligible cases, 722 (63%) were enrolled. Reasons for non-enrolment included refusal (211), inability to contact (212), no vaccine history available but parent did not report

Discussion

Our results show PCV13 had high effectiveness when given to young children in the USA in the context of the ACIP-recommended four-dose schedule for infants and catch-up doses for older children. The findings were driven largely by the effectiveness of PCV13 against serotypes 19A, 7F, and 3, serotypes that were responsible for 59% of invasive pneumococcal disease among children younger than 5 years during the 2 years before PCV13 introduction.13 Effectiveness was especially high for serotypes

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