Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: A postlicensure indirect cohort study

Nicholas Andrews, Pauline A. Waight, Polly Burbidge, Emma Pearce, Lucy Roalfe, Marta Zancolli, Mary Slack, Shamez Ladhani, Elizbeth Miller, David Goldblatt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

399 Citations (Scopus)


Background: Efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) was inferred before licensure from an aggregate correlate of protection established for the seven-valent vaccine (PCV7). We did a postlicensure assessment of serotype-specific vaccine effectiveness and immunogenicity in England, Wales, and Northern Ireland to derive the correlates of protection for individual serotypes. Methods: We assessed vaccine effectiveness against invasive pneumococcal disease using the indirect cohort method. We measured serotype-specific IgG concentration in infants after they were given two priming doses of PCV7 (n=126) or PCV13 (n=237) and opsonophagocytic antibody titre from a subset of these infants (n=100). We derived correlates of protection by relating percentage protection to a threshold antibody concentration achieved by an equivalent percentage of infants. We used multivariable logistic regression to estimate vaccine effectiveness and reverse cumulative distribution curves to estimate correlates of protection. Findings: For the 706 cases of invasive pneumococcal disease included in the study, PCV13 vaccine effectiveness after two doses before age 12 months or one dose from 12 months was 75% (95% CI 58-84). Vaccine effectiveness was 90% (34-98) for the PCV7 serotypes and 73% (55-84) for the six additional serotypes included in PCV13. Protection was shown for four of the six additional PCV13 serotypes (vaccine effectiveness for serotype 3 was not significant and no cases of serotype 5 infection occurred during the observation period). The vaccine effectiveness for PCV13 and PCV7 was lower than predicted by the aggregate correlate of protection of 0·35 μg/mL used during licensing. Calculated serotype-specific correlates of protection were higher than 0·35 μg/mL for serotypes 1, 3, 7F, 19A, 19F, and lower than 0·35 μg/mL for serotypes 6A, 6B, 18C, and 23F. Opsonophagocytic antibody titres of 1 in 8 or higher did not predict protection. Interpretation: PCV13 provides significant protection for most of the vaccine serotypes. Although use of the aggregate correlate of protection of 0·35 μg/mL has enabled the licensing of effective new PCVs, serotype-specific correlates of protection vary widely. The relation between IgG concentration after priming and long-term protection needs to be better understood.

Original languageEnglish
Pages (from-to)839-846
Number of pages8
JournalThe Lancet Infectious Diseases
Issue number9
Publication statusPublished - Sept 2014

Bibliographical note

Funding Information:
DG and MS have served on ad-hoc advisory boards for Pfizer, GlaxoSmithKline, and Merck, and the University College London Institute of Child Health laboratory (London, UK; employer of DG, PB, EP, LR, and MZ) receives contract research funding from Pfizer, GlaxoSmithKline, and Merck. The Public Health England Respiratory and Vaccine Preventable Bacteria Reference Unit, Colindale, London, UK (employer of MS), has received research funding from Pfizer and GlaxoSmithKline. SNL has worked on clinical trials on behalf of St George's University of London (London, UK) for vaccine manufacturers including GlaxoSmithKline and Pfizer, but has received no personal remuneration. EM, PAW, and NJA declare no competing interests.

Funding Information:
The national surveillance of invasive pneumococcal disease is funded by Public Health England. The field and laboratory work for the immunogenicity study were supported by a grant from the UK Department of Health Research and Development Directorate ( grant number 039/0031 ). The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health. Public Health England has approval under PIAG Section 60 of the Health and Social Act 2001 (which has been subsumed into the National Information Governance Board for Health and Social Care with Section 60—now Section 251 of the NHS Act 2006) to process confidential information from patients for the purposes of monitoring the efficacy and safety of vaccination programmes. We thank the many general practitioners, hospital doctors, and laboratory staff in England and Wales who provided information about their patients. We also thank the administrative staff of the Public Health England Immunisation Department for their assistance in the follow-up of invasive pneumococcal disease cases and in the running of the clinical trials, the vaccine research nurses in Hertfordshire and Gloucestershire who recruited, bled, and vaccinated the individuals included in the study, and the technical staff in the Public Health England Respiratory and Vaccine Preventable Bacteria Reference Unit for serotyping the pneumococcal isolates. We also thank staff at the John Radcliffe Hospital Oxford (Oxford, UK) for reporting invasive pneumococcal disease cases in southern England serotyped by their laboratory.

Copyright 2014 Elsevier B.V., All rights reserved.


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