Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study
TL;DR: Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups.
Abstract: Summary Background The seven-valent pneumococcal conjugate vaccine (PCV7) has reduced vaccine-type (VT) invasive pneumococcal disease but increases in non-vaccine-type (NVT) disease have varied between countries. We assess the effect of the PCV7 vaccination on VT and NVT disease in England and Wales. Methods The study cohort was the population of England and Wales from July, 2000, to June, 2010. We calculated incidence rate ratios (IRRs) to compare incidences of VT and NVT disease before (2000–06) and after (2009–10) the introduction of PCV7. We used data from the national surveillance database. Cases included in our analysis were restricted to those confirmed by culture linked with isolates referred for serotyping at the national reference centre by laboratories in England and Wales. We adjusted for potential bias from missing data (serotype and age of patient) and changes in case ascertainment rates during the study period. Findings 5809 cases of invasive pneumococcal disease were reported in 2009–10, giving an incidence of 10·6 per 100 000 population in 2009–10, which, when compared with the adjusted average annual incidence of 16·1 in 2000–06, gives an overall reduction of 34% (95% CI 28–39). VT disease decreased in all age groups, with reductions of 98% in individuals younger than 2 years and 81% in those aged 65 years or older. NVT disease increased by 68% in individuals younger than 2 years and 48% in those aged 65 years or older, giving an overall reduction in invasive pneumococcal disease of 56% in those younger than 2 years and 19% in those aged 65 years or older. After vaccine introduction, more NVT serotypes increased in frequency than decreased, which is consistent with vaccine-induced replacement. Key serotypes showing replacement were 7F, 19A, and 22F. Increases in NVT invasive pneumococcal disease were not associated with antimicrobial resistance. Interpretation Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups. Further reductions should be achievable by use of higher valency vaccines. Robust surveillance data are needed to properly assess the epidemiological effect of multivalent pneumococcal disease vaccines. Funding Health Protection Agency.
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National Center for Immunization and Respiratory Diseases1, Vanderbilt University2, University of Rochester3, New York State Department of Health4, Johns Hopkins University5, University of California, Berkeley6, Colorado Department of Public Health and Environment7, University of New Mexico8, Veterans Health Administration9, Emory University10, University of Texas Health Science Center at San Antonio11
TL;DR: PCV13 reduced IPD across all age groups when used routinely in children in the USA, providing reassurance that, similar to PCV7, PCVs with additional serotypes can also prevent transmission to unvaccinated populations.
Abstract: Summary Background In 2000, seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the USA and resulted in dramatic reductions in invasive pneumococcal disease (IPD) and moderate increases in non-PCV7 type IPD. In 2010, PCV13 replaced PCV7 in the US immunisation schedule. We aimed to assess the effect of use of PCV13 in children on IPD in children and adults in the USA. Methods We used laboratory-based and population-based data on incidence of IPD from the Active Bacterial Core surveillance (part of the Centers for Disease Control and Prevention's Emerging Infections Program) in a time-series model to compare rates of IPD before and after the introduction of PCV13. Cases of IPD between July 1, 2004, and June 30, 2013, were classified as being caused by the PCV13 serotypes against which PCV7 has no effect (PCV13 minus PCV7). In a time-series model, we used an expected outcomes approach to compare the reported incidence of IPD to that which would have been expected if PCV13 had not replaced PCV7. Findings Compared with incidence expected among children younger than 5 years if PCV7 alone had been continued, incidence of IPD overall declined by 64% (95% interval estimate [95% IE] 59–68) and IPD caused by PCV13 minus PCV7 serotypes declined by 93% (91–94), by July, 2012, to June, 2013. Among adults, incidence of IPD overall also declined by 12–32% and IPD caused by PCV13 minus PCV7 type IPD declined by 58–72%, depending on age. We estimated that over 30 000 cases of IPD and 3000 deaths were averted in the first 3 years after the introduction of PCV13. Interpretation PCV13 reduced IPD across all age groups when used routinely in children in the USA. These findings provide reassurance that, similar to PCV7, PCVs with additional serotypes can also prevent transmission to unvaccinated populations. Funding Centers for Disease Control and Prevention.
620 citations
TL;DR: The herd protection induced byPCV7 is continuing, and similar indirect protection is occurring from the additional serotypes covered by PCV13, but there is, however, evidence of increasing invasive pneumococcal disease due to non-PCV13 serotypes, particularly in children younger than 5 years in 2014.
Abstract: Summary Background The 13-valent pneumococcal conjugate vaccine (PCV13) protects against key serotypes that increased after routine immunisation with the seven-valent vaccine (PCV7), but its potential for herd protection and serotype replacement is uncertain. The aim of this study was to analyse the effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction. Methods We used a national dataset of electronically reported and serotyped invasive pneumococcal disease cases in England and Wales to estimate incidence rate ratios (IRRs) for vaccine and non-vaccine type invasive pneumococcal disease between July, 2013, and June, 2014, versus the pre-PCV13 and pre-PCV7 baseline. Incidence rates were corrected for missing serotype data and changes in surveillance sensitivity over time. An over-dispersed Poisson model was used to estimate IRRs and confidence intervals. Findings Incidence of invasive pneumococcal disease in the epidemiological year 2013/14 decreased by 32% compared with the pre-PCV13 baseline (incidence 10·14 per 100 000 in 2008–10 vs 6·85 per 100 000 in 2013/14; IRR 0·68, 95% CI 0·64–0·72). This was due to an 86% reduction of the serotypes covered by PCV7 (1·46 vs 0·20 per 100 000; IRR 0·14, 0·10–0·18) and a 69% reduction of the additional six serotypes covered by PCV13 (4·48 vs 1·40 per 100 000; IRR 0·31, 0·28–0·35). When compared with the pre-PCV7 baseline, there was a 56% overall reduction in invasive pneumococcal disease (15·63 vs 6·85 per 100 000; IRR 0·44, 95% CI 0·43–0·47). Compared with the pre-PCV13 baseline, the incidence of non-PCV13 serotypes increased (incidence all ages 4·19 vs 5·25 per 100 000; IRR 1·25, 95% CI 1·17–1·35) due to increases across a broad range of serotypes in children younger than 5 years and in people aged 45 years or more. In children younger than 5 years, incidence of non-PCV13 serotypes in 2013/14 was higher than in 2012/13 (age vs 10·83 per 100 000; age 2–4 years: 4·08 vs 3·63 per 100 000). Interpretation 8 years of PCV use in England and Wales has reduced the overall incidence of invasive pneumococcal disease by more than 50%. The herd protection induced by PCV7 is continuing, and similar indirect protection is occurring from the additional serotypes covered by PCV13. There is, however, evidence of increasing invasive pneumococcal disease due to non-PCV13 serotypes, particularly in children younger than 5 years in 2014. If this increase continues, the maximum benefit of the PCV13 programme in children might already have been achieved. Funding Public Health England funds national surveillance of invasive pneumococcal disease.
498 citations
TL;DR: 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, and serotype-specific correlates of protection vary widely.
Abstract: 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.
425 citations
TL;DR: In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococCal conjugate vaccine (PCV7) into national immunization programs.
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-vaccineserotype (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
411 citations
Cites background or methods from "Herd immunity and serotype replacem..."
...We assumed that overall IPD was a more stable indicator of pre-PCV7 trends than either VT or NVT, which could be affected by outbreaks of a single serotype [16]....
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...Because IPD rates were changing before PCV7 introduction in some sites, we used the pre-PCV7 IPD trends (excluding the year of introduction) to predict future years’ IPD rates, absent PCV7 use [15,16]....
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TL;DR: Both PCV7 and PCV13 have had a major effect in reducing the burden of invasive pneumococcal disease in England and Wales; however, rapid increases in some non-PCV13 serotypes are compromising the benefits of the programme.
Abstract: Summary Background Pneumococcal conjugate vaccines (PCVs) have substantially reduced the incidence of invasive pneumococcal disease caused by vaccine serotypes; however, replacement disease with non-PCV serotypes remains a concern. We describe the population effect of the seven-valent and 13-valent PCVs (PCV7 and PCV13) on invasive pneumococcal disease in England and Wales. Methods Using national invasive pneumococcal disease surveillance data for 2016/17, we compared incidence rate ratios (IRRs) against pre-PCV13 (2008/09–2009/10) and pre-PCV7 (2000/01–2005/06) baselines. We also estimated the number of invasive pneumococcal disease cases prevented since the introduction of PCVs. Findings In 2016/17, overall invasive pneumococcal disease incidence (9·87 cases per 100 000; 5450 cases) across all age groups was 37% lower (IRR 0·63, 95% CI 0·60–0·65) than pre-PCV7 incidence (14·79 per 100 000; 8167 cases) and 7% lower (0·93; 0·89–0·97) than pre-PCV13 incidence (10·13 per 100 000; 5595 cases). By 2016/17, PCV7-type invasive pneumococcal disease incidence across all age groups had decreased by 97% (0·24 per 100 000; 0·03, 0·02–0·04) compared with the pre-PCV7 period, whereas additional PCV13-type invasive pneumococcal disease decreased by 64% (1·66 per 100 000; 0·36, 0·32–0·40) since the introduction of PCV13. Invasive pneumococcal disease incidence due to non-PCV13 serotypes doubled (7·97 per 100 000; 1·97, 1·86–2·09) since the introduction of PCV7, and accelerated since 2013/14—especially serotypes 8, 12F, and 9N, which were responsible for more than 40% of invasive pneumococcal disease cases by 2016/17. Invasive pneumococcal disease incidence in children younger than 5 years remained stable since 2013/14, with nearly all replacement disease occurring in adults. We estimated 38 366 invasive pneumococcal disease cases were prevented in the 11 years since the introduction of PCV7. Interpretation Both PCV7 and PCV13 have had a major effect in reducing the burden of invasive pneumococcal disease in England and Wales; however, rapid increases in some non-PCV13 serotypes are compromising the benefits of the programme. Funding Public Health England.
361 citations
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TL;DR: The use of the pneumococcal conjugate vaccine is preventing disease in young children, for whom the vaccine is indicated, and may be reducing the rate of disease in adults.
Abstract: Background In early 2000, a protein–polysaccharide conjugate vaccine targeting seven pneumococcal serotypes was licensed in the United States for use in young children. Methods We examined population-based data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention to evaluate changes in the burden of invasive disease, defined by isolation of Streptococcus pneumoniae from a normally sterile site. Serotyping and susceptibility testing of isolates were performed. We assessed trends using data from seven geographic areas with continuous participation from 1998 through 2001 (population, 16 million). Results The rate of invasive disease dropped from an average of 24.3 cases per 100,000 persons in 1998 and 1999 to 17.3 per 100,000 in 2001. The largest decline was in children under two years of age. In this group, the rate of disease was 69 percent lower in 2001 than the base-line rate (59.0 cases per 100,000 vs. 188.0 per 100,000, P<0.001); the rate of disease caused by va...
2,135 citations
TL;DR: Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later, and IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV 7-type IPD.
Abstract: Background. Changes in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children. Methods. Laboratory-confirmed IPD cases were identified during 1998-2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998-1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations. Results. Overall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P<.01 for all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P<.01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P<.05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006-2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old. Conclusions. Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD.
1,238 citations
TL;DR: The magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and bias in the disease surveillance systems that could underestimate the true amount of replacement.
866 citations
TL;DR: There have been considerable changes to the format of the recommendations since the previous version (version 7); the majority of the footnotes to the tables have been removed and the notations added to the end column; it is hoped that this change will avoid confusion in interpretation.
Abstract: The changes that have been made to the previous version of the recommendations (version 6) are as follows: medium and incubation condition for testing Acinetobacter spp. (Tables 1 and 6); use of cefoxitin as an indicator antibiotic for detecting methicillin/oxacillin/cefoxitin resistance in coagulase-negative staphylococci (Tables 1, 6 and 11); MIC breakpoint for co-trimoxazole based on the trimethoprim concentration in a 1:19 combination with sulfamethoxazole (Tables 7, 10, 11, 12, 15, 16 and 19); advice on the use of azithromycin for the treatment of infections with Salmonella typhi (footnote to Table 7); amendment to the recommendation for cefuroxime for the treatment of infections with Proteus mirabilis (footnote Table 7); MIC and zone diameter breakpoints for Stenotrophomonas maltophilia only (Table 10); MIC breakpoints for daptomycin (Tables 11 and 15); clarification for staphylococci that the neomycin zone diameter breakpoints are for topical use only and differentiate the isolates outside the 'wild-type' population in Table 11; clarification for beta-haemolytic streptococci that the linezolid zone diameter breakpoints relate to an MIC breakpoint of 2 mg/L as no data for the intermediate category are currently available (Table 15); clarification that strains with reduced susceptibility to fluoroquinolones give no zone of inhibition with a 30 microg nalidixic acid disc (Tables 16 and 21); erythromycin is no longer used for therapy of Neisseria gonorrhoeae, but may be tested for epidemiological purposes (Table 17); clarification that the ciprofloxacin zone diameter breakpoint for Neisseria meningitidis relates to the MIC breakpoint of 0.03 mg/L as no data for the intermediate category are currently available; clarification that the ciprofloxacin zone diameter breakpoints for Campylobacter spp. relate to an MIC breakpoint of 0.5 mg/L as no data for the intermediate category are currently available; clarification that for ciprofloxacin and vancomycin zone diameter breakpoints for coryneform organisms relate to an MIC breakpoint of 0.5 and 4 mg/L, respectively, as no data for the intermediate category are currently available; MIC and zone diameter breakpoints for Gram-negative rods isolated from urinary tract infections have been expanded to include Klebsiella spp.; and a definition of coliforms is also included (Table 26).
744 citations