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

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Summary

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.

Funding

Public Health England and UK Department of Health Research and Development Directorate.

Introduction

Since 2010, the seven-valent pneumococcal conjugate vaccine (PCV7) has been replaced in many countries by higher valency vaccines containing ten (PCV10, GlaxoSmithKline, Brentford, UK) or 13 (PCV13, Pfizer, New York, NY, USA) serotypes. This change in vaccine became necessary as a result of the change in serotypes causing invasive pneumococcal disease, partly driven by the use of PCV7. The high effectiveness of PCV7 at reducing vaccine-type invasive pneumococcal disease1 has been partly offset by an increase in invasive pneumococcal disease caused by non-vaccine serotypes.2, 3 The serotypes that emerged as major causes of invasive pneumococcal disease after the widespread use of PCV7 include many of the additional serotypes in PCV10 and PCV13.

Assessment of vaccine effectiveness for the newer, extended-valency PCVs is of particular interest because, unlike PCV7, PCV10, and PCV13 were licensed on the basis of immunogenicity data alone. Head-to-head studies of PCV7 and the new vaccines with immunogenicity endpoints were deemed acceptable for licensing the new conjugates,4 largely because of the existence of a correlate of protection for PCV7. An anticapsular polysaccharide antibody concentration of 0·35 μg/mL measured by ELISA aggregated across all the seven serotypes in PCV7 is regarded as predictive of protection against invasive pneumococcal disease.5 This correlate was derived from three randomised trials of PCV7 or an experimental nine-valent conjugate (Wyeth, Collegeville, PA, USA) done in California, USA,6 in an Indigenous American population,7 and in South Africa,8 by correlation of post-primary IgG concentrations aggregated across the three studies with aggregate efficacy against invasive pneumococcal disease.5

Individual serotype-specific correlates could not be derived from the efficacy trials because even the largest PCV7 trial showed significant serotype-specific efficacy for only three of the seven serotypes, with wide CIs because of small numbers of cases of invasive pneumococcal disease.9 Researchers therefore derived an aggregate estimate, although serotype-specific differences in the amount of antibody needed to protect against invasive pneumococcal disease and otitis media are now recognised.10, 11 Pooled data from the heterogeneous populations investigated in the efficacy trials6, 7, 8 were used to narrow the confidence limits around the point estimate of efficacy, despite different levels of protection seen in these three populations. With effectiveness estimates for the additional serotypes in the extended-valency conjugates now available, the possibility exists to derive serotype-specific correlates of protection. More precise estimates will both aid decision making relevant to vaccine schedules and inform the licensure of next-generation extended-valency conjugates.

PCV13 replaced PCV7 in the UK on April 1, 2010. For both vaccines, a 2 + 1 schedule was used (at 2, 4, and 12 months). We previously reported on the effectiveness of PCV13 against vaccine-type invasive pneumococcal disease in the first 15 months after introduction in a case-control (indirect cohort) study.12 Here, we extend the estimates of effectiveness to 3·5 years after introduction. Additionally, using data from immunogenicity studies of PCV13 and PCV7 in infants in the UK and previously published data for the effectiveness of PCV7,13 we aimed to derive individual serotype-specific estimates of correlates of protection for the vaccine serotypes and to calculate the first serotype-specific functional correlates of protection based on opsonophagocytic killing.

Section snippets

Setting

We did a postlicensure indirect cohort study to investigate the serotype-specific effectiveness and correlates of protection for PCV13. We used cases of invasive pneumococcal disease (diagnosed in infants by culture of Streptococcus pneumoniae from a normally sterile site or by DNA detection in pleural fluid or cerebrospinal fluid) for which a serotype was identified. Cases were reported during a sufficiently long surveillance period (3·5 years and about 700 cases) to produce serotype-specific

Results

Of 716 serotyped cases of invasive pneumococcal disease, eight were assigned a serogroup only (serogroup 7) and were therefore excluded, and two other individuals had an unknown vaccination status. The remaining 706 cases included 30 PCV7 serotypes, 292 with the additional six PCV13 serotypes or 6C, and 414 with non-PCV13 serotypes. The serotype distribution varied by age, because of vaccine effects and possible natural differences in serotype distribution by age (table 1, appendix p 1). As

Discussion

The findings of our postlicensure indirect cohort study of the use of PCV13 over 3·5 years in England, Wales, and Northern Ireland show generally good vaccine effectiveness for four of the six new serotypes in PCV13 and high vaccine effectiveness against the PCV7 serotypes (panel). Of particular importance is evidence of significant protection against serotypes 7F and 19A, which have been major causes of replacement disease,2, 3 and protection against serotype 1, which is an important cause of

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