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. 2013;10(9):e1001517.
doi: 10.1371/journal.pmed.1001517. Epub 2013 Sep 24.

Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites

Daniel R Feikin  1 , Eunice W Kagucia, Jennifer D Loo, Ruth Link-Gelles, Milo A Puhan, Thomas Cherian, Orin S Levine, Cynthia G Whitney, Katherine L O'Brien, Matthew R Moore; Serotype Replacement Study Group
Collaborators, Affiliations

Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites

Daniel R Feikin et al. PLoS Med. 2013.

Abstract

Background: Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.

Methods and findings: Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥ 2 years before and ≥ 1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0.55, 95% CI 0.46-0.65) and remained relatively stable through year 7 (RR 0.49, 95% CI 0.35-0.68). Point estimates for VT IPD decreased annually through year 7 (RR 0.03, 95% CI 0.01-0.10), while NVT IPD increased (year 7 RR 2.81, 95% CI 2.12-3.71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18-49 year-olds [RR 0.52, 95% CI 0.29-0.91], 50-64 year-olds [RR 0.84, 95% CI 0.77-0.93], and ≥ 65 year-olds [RR 0.74, 95% CI 0.58-0.95]).

Conclusions: Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used. Please see later in the article for the Editors' Summary.

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Conflict of interest statement

The manuscript coauthors and members of the Serotype Replacement Study Group have the following conflicts: RD has, in the last five years, received grants/research support from Berna/Crucell, Wyeth/Pfizer, MSD and Protea; he has been a scientific consultant for Berna/Crucell, GlaxoSmithKline, Norvatis, Wyeth/Pfizer, Protea, MSD; he has been a speaker for Berna/Crucell, GlaxoSmithKline, and Wyeth/Pfizer; he is a shareholder of Protea/NASVAX. PDW has received research grants, honoraria, and travel expense reimbursements from vaccine manufacturers including Glaxo SmithKline, Norvatis, Sanofi Pasteur, Merck, and Wyeth, as well as from governmental agencies including the Quebec Ministry of Health and Social Services, Health Canada, and the Public Health Agency of Canada. JE has served as a member of a data safety monitoring board (DSMB) for Novartis meningococcal and typhoid vaccines and participated in an advisory meeting of their pneumococcal protein vaccine in 2009. JE works at the National Institute for Health and Welfare (THL), Helsinki, Finland, which has a research contract with GSK on pneumococcal vaccines. MH is a lead investigator for the Switzerland IPD surveillance program, which is partly funded by an unrestricted grant from Pfizer. JDK and OV are lead investigators of the Calgary Streptococcus pneumoniae Epidemiology Research (CASPER) study which is sponsored in part by an unrestricted grant from Pfizer, Canada. NPK has received research support from Pfizer, GSK, Merck, Sanofi Pasteur, and Norvatis. ML has received consulting fees from Pfizer. KLO has had research grants from Pfizer and GSK in the past 5 years, and has served on expert panels for GSK, Merck, and Aventis. GJT has received research funding from Wyeth and Pfizer, and has also received funding from Wyeth and Pfizer for serving on Advisory boards and as a speaker in relation to pneumococcal disease. EV has received support for travel to meetings from Wyeth/Pfizer and has been a speaker for Pfizer. IV has received funding support from Pfizer. RvK and SW are investigators of the German pneumococcal surveillance project in children/ESPED study, which is sponsored by an unrestricted grant by Pfizer Germany.

Figures

Figure 1
Figure 1. Flow diagram of datasets included in the analysis.
Figure 2
Figure 2. Pre-PCV7 introduction average annual invasive pneumococcal disease rates and percent vaccine serotype isolates.
(A) IPD rates as cases per 100,000. (B) Percent VT isolates as a proportion of all pre-PCV7 introduction isolates. *Only children aged <5 years included. Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 3
Figure 3. Post-PCV7 introduction invasive pneumococcal disease summary rate ratios.
Summary RRs from random effects meta-analysis. Summary RRs estimated by dividing observed over expected rates and calculated for each age-serotype group. 95% confidence interval indicated by error bars. Y-Axis on log scale.
Figure 4
Figure 4. All serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for children aged <5 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 5
Figure 5. Vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for children aged <5 years.
Site abbreviations: ABCs (USA Active Bacterial Core Surveillance); AIP (USA Alaska); Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 6
Figure 6. Non-vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for children aged <5 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 7
Figure 7. Post-PCV7 introduction pneumococcal meningitis summary rate ratios.
Summary RRs from random effects meta-analysis. Summary RRs esimated by dividing observed by expected rates and calculated for each age-serotype group. 95% confidence interval indicated by error bars. Y-Axis on log scale.
Figure 8
Figure 8. All serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 18–49 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 9
Figure 9. Vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 18–49 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 10
Figure 10. Non-vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 18–49 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 11
Figure 11. All serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 50–64 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 12
Figure 12. Vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 50–64 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 13
Figure 13. Non-vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged 50–64 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 14
Figure 14. All serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged ≥65 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 15
Figure 15. Vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged ≥65 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
Figure 16
Figure 16. Non-vaccine serotype invasive pneumococcal disease summary rate ratio forest plots by post-introduction year from random effects meta-analysis for adults aged ≥65 years.
Site abbreviations: ABCs, USA Active Bacterial Core Surveillance; AIP, USA Alaska; AUSI, Australian Indigenous Northern Territory; AUSN, Australian Non-Indigenous; CAL, Canada Calgary; CHE, Switzerland; CZE, Czech Republic; DEN, Denmark; E&W, England and Wales; GRC, Greece; ISR, Israel; NAV, USA Navajo; NCK, USA Kaiser Permanente Northern California; NLD, The Netherlands; NOR, Norway; NZL, New Zealand; SCT, Scotland; URY, Uruguay; UTA, USA Utah.
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