A systematic review of invasive pneumococcal disease vaccine failures and breakthrough with higher-valency pneumococcal conjugate vaccines in children

ABSTRACT

Introduction

The pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV/PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) protect against vaccine-serotype invasive pneumococcal disease (VT IPD). However, VT IPD can still occur in fully or partially vaccinated children (vaccine failure or breakthrough). We performed a systematic review of vaccine failures and breakthrough IPD with PCV10 and PCV13 in ≤5-year-olds.

Areas covered

We searched Scopus/Medline/EMBASE to retrieve articles/abstracts published between 1/2008-7/2019. We excluded reports only including data from ≥6-year-olds, exclusively assessing PCV7-vaccinated children or children with comorbidities. Twenty-six reports (20 PCV13, 1 PCV10, 5 both), covering studies with various designs in six continents, using different schedules, were included. Collectively, they reported 469 VT IPD cases classified as vaccine failures and 403 as breakthrough. Vaccine failure and breakthrough rates were low: 8.4% and 9.3%, respectively, of all IPD in vaccinated children, consistent with the vaccines’ high effectiveness. The main serotypes associated with vaccine failure/breakthrough were 19A, 3 and 19F for PCV13 and 14, 6B and vaccine-related 19A and 6A for PCV10.

Expert opinion

As we move to vaccines with more serotypes, it is not only important to consider which serotypes are added, but also monitor and address incomplete protection against specific serotypes.

PLAIN LANGUAGE SUMMARY

What is the context?

• Pneumococcal conjugate vaccines have been given to children for over 20 years to prevent infections caused by the bacterium Streptococcus pneumoniae (such as pneumonia, meningitis and sepsis).

• At least 100 different types of S. pneumoniae, so called serotypes, exist, but a relatively small number causes most disease.

• Two current vaccines (Synflorix, GSK and Prevnar 13, Pfizer) protect against 10 to 13 serotypes and have significantly reduced pneumococcal disease caused by these serotypes.

• A rise in serotypes not targeted by these vaccines has lessened the vaccines’ expected impact.

• As no vaccine is 100% protective, some serotypes targeted by the current vaccines continue to circulate.

What is new?

• We performed a systematic literature review to evaluate which serotypes are most often associated with invasive disease occurring after receives all planned pneumococcal vaccine doses (vaccine failure) or after a child receives part of the planned vaccine doses (breakthrough).

• We found that vaccine failures and breakthrough disease were uncommon with both vaccines, irrespective of the administered schedule.

• A small number of serotypes were responsible for most vaccine failures and breakthrough disease with both vaccines.

What is the impact?

• The low rate of vaccine failures and breakthrough disease observed with the current vaccines confirms their high effectiveness in preventing pneumococcal disease.

• The primary consideration in developing pneumococcal conjugate vaccines that include more than 13 serotypes will be how additional protection they can provide.

• Reduced protection against individual serotypes remains a risk.

• The evaluation of current vaccines demonstrates that incomplete protection against specific serotypes should also be addressed.

KEYWORDS:

• Breakthrough disease
• children
• higher-valency
• invasive pneumococcal disease
• pneumococcal conjugate vaccine
• vaccine failure
• PCV10
• PCV13
• PHiD-CV

Abbreviations

CPS, capsular polysaccharides; IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PHiD-CV/PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine; PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses; ROBINS-I, Risk Of Bias In Non-randomized Studies - of Interventions; VT, vaccine serotype.

Article highlights

• Although PCV10 and PCV13 are highly effective against vaccine-serotype invasive pneumococcal disease (VT IPD), fully or partially vaccinated children can still develop VT IPD (i.e. vaccine failure or breakthrough, respectively).

• We performed a systematic review of vaccine failures and breakthrough IPD in children ≤5 years old after PCV10 or PCV13 vaccination.

• Vaccine failure and breakthrough were uncommon with both vaccines (each <10% of all IPD in vaccinated children), confirming the vaccines’ high effectiveness.

• The main serotypes associated with vaccine failure or breakthrough were 19A, 3 and 19F in PCV13 studies and 14, 6B and vaccine-related 19A and 6A in PCV10 studies.

Acknowledgments

The authors thank Modis Life Sciences, Belgium, for editorial assistance and manuscript coordination, on behalf of GSK: Natalie Denef provided writing support and Stéphanie Deroo provided support with extraction of data, verification of extracted data and manuscript coordination. The authors also thank Nicolas Lecrenier (NL) for his contributions to the early stages of the systematic literature search, data extraction and analysis. Preliminary results of our analysis were presented at the 11th International Symposium on Pneumococci & Pneumococcal Diseases (ISPPD-11), 15–19 April 2018, Melbourne, Australia.

Author contributions

All authors contributed to the conception and design of the analyses. Bruce A. Mungall and Javier Nieto Guevara performed the systematic review. All authors contributed to the interpretation of the results and helped draft or revised the manuscript. All authors have reviewed and approved the final article.

Trademarks

Synflorix is a trademark of the GSK group of companies. Prevnar/Prevenar and Prevnar 13/Prevenar 13 are trademarks of Pfizer Inc.

Declaration of interests

Javier Nieto Guevara and Lamine Soumahoro are, and Bruce A. Mungall and Bernard Hoet were employed by the GSK group of companies and declare financial and non-financial relationships and activities. All authors hold shares in the GSK group of companies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

A reviewer on this manuscript has disclosed a current research grant to their institution from Pfizer. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by GlaxoSmithKline Biologicals SA, which was involved in all stages of the work and paid for all costs associated with the development and publication of this manuscript.