Elsevier

Vaccine

Volume 29, Issue 52, 6 December 2011, Pages 9711-9721
Vaccine

Comparing pneumococcal conjugate vaccine schedules based on 3 and 2 primary doses: Systematic review and meta-analysis

https://doi.org/10.1016/j.vaccine.2011.07.042Get rights and content

Abstract

Background

Pneumococcal conjugate vaccines (PCV) were first licensed for use with 3 primary doses in infancy and a booster dose. The evidence for the effects of different schedules was examined in this systematic review and meta-analysis.

Methods

We searched 12 databases and trial registers up to March 2010. We selected randomised controlled trials (RCTs), cohort and case–control studies making direct comparisons between PCV schedules with (2p) or (3p) primary doses, with (+1) or without (+0) a booster dose. We extracted data on clinical, nasopharyngeal carriage and immunological outcomes and used meta-analysis to combine results where appropriate.

Results

Seropositivity levels (antibody concentration ≥0.35 μg/ml) following 3p and 2p PCV schedules were high for most serotypes (5 RCTs). Differences between schedules were generally small and tended to favour 3p schedules, particularly for serotypes 6B and 23F; between-study heterogeneity was high. Seropositivity levels following 3p+1 and 2p+1 schedules were similar but small differences favouring 3p+1 schedules were seen for serotypes 6B and 23F. We did not identify any RCTs reporting clinical outcomes for these comparisons. In 2 RCTs there was weak evidence of a reduction in carriage of S. pneumoniae serotypes included in the vaccine when 3p+0 schedules were compared to 2p+0 at 6 months of age.

Conclusions

Most data about the relative effects of different PCV schedules relate to immunological outcomes. Both 3p and 2p schedules result in high levels of seropositivity. The clinical relevance of differences in immunological outcomes between schedules is not known. There is an absence of clinical outcome data from RCTs with direct comparisons of any 2p with any 3p PCV schedule.

Introduction

Streptococcus pneumoniae is estimated to cause over 500,000 deaths in children under 5 years every year and a further 13 million cases of severe disease, including meningitis, septicaemia, and pneumonia [1]. There are more than 90 identified serotypes of S. pneumoniae, but only 10 account for most paediatric infections [2]. The existing 23-valent pneumococcal polysaccharide vaccine (PPV), is not licensed for children under 2 years old and its efficacy against invasive pneumococcal disease (IPD) remains controversial [3], [4].

Pneumococcal conjugate vaccines (PCVs) are based on the conjugation of selected capsular polysaccharides to a protein carrier. Unlike PPV, they elicit T-cell dependent antibody responses, which make them immunogenic in infants [5]. The first of these vaccines was licensed in the US in 2000 and contains polysaccharide from 7 serotypes conjugated to a mutant diphtheria protein, CRM197 [6]. Since introduction, this vaccine has reduced the burden of invasive disease in young children in the US and offers indirect protection against disease in adults [7]. The licensure application for this vaccine included 2 randomised controlled trials (RCT) that assessed clinical outcomes. Both used a vaccination schedule of 3 primary doses before 7 months of age and a fourth dose at 12–15 months (schedule abbreviated as 3p+1) [8], [9]. Since then, vaccines containing 10 and 13 serotypes have been licensed, based mainly on immunological non-inferiority to the 7-valent vaccine and safety data [10], [11], [12].

The majority of high income countries have now implemented a variety of PCV schedules into their childhood vaccination programmes. The World Health Organization (WHO) recommends a schedule of 3 primary doses without a booster (3p+0) [13] based on the results of RCTs in South Africa and the Gambia [14], [15]. However, since PCVs induce immunological memory, it has been suggested that a schedule of 2 primary doses with a third dose in the second year of life (2p+1) might improve the duration of the immune response and ensure a strong herd effect [16]. This schedule has been introduced in several countries including the United Kingdom (UK) and France [17].

Schedules with fewer doses would be preferred, particularly in resource poor settings and countries where the routine immunisation schedule does not include a visit in the second year of life. Many middle and low income countries are currently in the process of making decisions about which PCV and which schedule to use and additional research about the use of alternative PCV schedules has been recommended [13]. We systematically reviewed data from studies that compared schedules containing 3 primary doses (with or without a booster) with 2 primary doses (with or without a booster).

Section snippets

Materials and methods

We followed a study protocol, which was developed with advice from an international expert group (available at http://www.ispm.ch/journal-downloads).

Results

Initial database searches yielded 3121 items and another 96 came from reference lists, experts, or repeat database searches, giving a total of 3217 unique items. Of these, 3188 items were excluded (Fig. 1). The remaining 29 items referred to 8 trials, 1 cohort study and 1 case–control study reporting on eligible comparisons and outcomes. Eight trials and the cohort study contributed to immunological outcome comparisons and 2 trials to nasopharyngeal carriage comparisons. Only the case–control

Discussion

In this systematic review of immunisation schedules for PCV, immunological data showed that 3p schedules might result in slightly higher antibody levels than 2p schedules both before and after a booster dose, particularly for serotypes 6B and 23F. Results of OPA assessments were generally similar to those of seropositivity assessed by ELISA. There is an absence of clinical outcome data and limited data about nasopharyngeal carriage from direct comparisons of any 2p to any 3p schedule.

Conclusion

The introduction of PCV into routine childhood vaccination programmes in high income countries has reduced the incidence of IPD across all age groups. However, the progress of introducing PCV into several low income countries remains slow. The varying country specific burden of diseases as well as varying health infrastructures and resources add to the complexities in the decision making process in determining optimal vaccination programmes. Thus, information on the benefits on different

Contributors

PS and NL designed the study, PS, AR, LB, NR, SS and TL extracted data, PS and TL analysed data, PS, AR, LB, NR, SS, TL, ME and NL interpreted data, drafted or revised the article. All authors approved the final version.

Funding

This project received funding from the World Health Organization.

Disclaimer

The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

Acknowledgements

We thank the members of the WHO ad hoc working group on PCV for their contributions to the development of the protocol and interpretation of the results: Dr. Steve Black, Prof. Ron Dagan, Prof. Paul Fine, Mr. Nigel Gay, Prof. David Goldblatt, Prof. Keith Klugman, Dr. Shabir Madhi, Dr. Alessia Melegaro, Prof. Kim Mulholland, Dr. Judith Müller, Dr. Cynthia Whitney. We also thank Dr. Shelagh Redmond for her help with the preparation of the review.

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