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de Waure C, Specchia ML, Capizzi S, Aljicevic M, Dujovic M, Malaj A, Ricciardi W. Effectiveness of 7-valent pneumococcal conjugate vaccine: A meta-analysis of post-marketing studies. World J Meta-Anal 2015; 3:151-162. [DOI: 10.13105/wjma.v3.i3.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 01/10/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the 7-valent pneumococcal conjugate vaccine (PCV7) effectiveness.
METHODS: A systematic literature review of studies which evaluated the effectiveness of PCV7 vaccine was performed searching the keyword “heptavalent pneumococcal conjugate vaccine” in PubMed and Scopus until March 16, 2013. The selection of potential eligible articles was done by two researchers independently on the basis of abstract and title and only post-marketing studies were included in the systematic review. Data extraction was carried out by two researchers with respect to invasive pneumococcal diseases due to both all and vaccine serotypes in pre-vaccine and post-vaccine periods in children less than 5 years. Results of studies which were considered suitable for meta-analysis were combined by means of relative risk (RR) with 95%CI. Vaccine effectiveness was calculated as (1-RR) × 100. Heterogeneity was assessed by I2 and a random effects model was used to combine data in the case of heterogeneity. RevMan 5 was used to pool data.
RESULTS: On the whole, 757 eligible papers were identified from the literature search in PubMed and Scopus. Of them, 62 were finally considered in the systematic review and 38 were included in the meta-analysis. In all post-marketing studies included in the systematic review the incidence of invasive pneumococcal diseases due to vaccine serotypes declined significantly with the exception of few studies showing stability or a slight, but not significant, increase. Furthermore most of studies highlighted also a reduction in the incidence of invasive pneumococcal diseases due to all serotypes. With regards to meta-analysis, a random effects model was used to combine data because of the high heterogeneity. Data combination showed that the effectiveness of PCV7 in reducing invasive pneumococcal diseases due to vaccine serotypes and to all serotypes was 84% (95%CI: 74%-90%) and 53% (95%CI: 46%-59%) respectively. These results are confirmatory with respect to the efficacy of PCV7 against invasive pneumococcal diseases due to vaccine serotypes.
CONCLUSION: PCV7 implementation determines a significant decrease of invasive pneumococcal diseases.
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Grando IM, Moraes CD, Flannery B, Ramalho WM, Horta MAP, Pinho DLM, Nascimento GL. Impact of 10-valent pneumococcal conjugate vaccine on pneumococcal meningitis in children up to two years of age in Brazil. CAD SAUDE PUBLICA 2015; 31:276-84. [DOI: 10.1590/0102-311x00169913] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 08/18/2014] [Indexed: 11/22/2022] Open
Abstract
The objective of this study was to analyze the impact of vaccination against Streptococcus pneumoniae on the morbidity and mortality from pneumococcal meningitis in children ≤ 2 years in Brazil, from 2007 to 2012. This is a descriptive study and ecological analysis using data from the Information System on Notifiable Diseases. Pre-vaccination (2007-2009) and post-vaccination (2011-2012) periods were defined to compare incidence rates and mortality. A total of 1,311 cases and 430 deaths were reported during the study period. Incidence decreased from 3.70/100,000 in 2007 to 1.84/100,000 in 2012, and mortality decreased from 1.30/100,000 to 0.40/100,000, or 50% and 69% respectively, with the greatest impact in the 6-11 month age group. This decrease in Pneumococcal meningitis morbidity and mortality rates two years after introduction of the 10-valent pneumococcal conjugate vaccine suggests its effectiveness.
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González Martínez F, Navarro Gómez ML, Saavedra Lozano J, Santos Sebastián MM, Rodríguez Fernández R, González Sanchéz M, Cercenado Mansilla E, Hernández-Sampelayo Matos T. [Emergence of invasive pneumococcal disease caused by non-vaccine serotypes in the era of the 7-valent conjugate vaccine]. An Pediatr (Barc) 2013; 80:173-80. [PMID: 23796611 DOI: 10.1016/j.anpedi.2013.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 04/25/2013] [Accepted: 05/04/2013] [Indexed: 10/26/2022] Open
Abstract
INTRODUCTION There has been an increased incidence in invasive pneumococcal disease (IPD) produced by non-vaccine serotype (NVS) of Streptococcus pneumoniae after the introduction of PCV7. Our objective was to describe the epidemiological, clinical and microbiological characteristics of IPD caused by NVS in a tertiary hospital in Madrid. PATIENTS AND METHODS Retrospective (1998-2004) and prospective (2005-2009) study evaluating IPD caused by NVS in children. The study was divided into three periods: P1 (1998-2001) when PCV7 was not commercialized; P2 (2002-2005) with 40% vaccine coverage among children; and P3 (2006-2009) when the vaccine was added to the Childhood Immunization Schedule in Madrid. RESULTS We analyzed 155 cases of IPD. One hundred and fifty of these isolates were serotyped (100 were NVS). There was an increase in the prevalence of IPD from P1 (31%) to P2 (54%) and P3 (91%). The most relevant emerging serotypes were 19A, 7F, 1, 5, 3 and 15C. The most significant clinical syndromes produced by some specific serotypes were as follows: lower respiratory tract infection (LRTI) by serotypes 1, 3, 5 and 15C; LRTI, primary bacteremia and meningitis by serotype 19A; and primary bacteremia by serotype 7F (66%). The large majority (83.8%) of NVS were sensitive to penicillin. CONCLUSIONS There has been an increased prevalence of IPD caused by NVS since the introduction of PCV7. These changes should prompt the introduction of new pneumococcal vaccines, which include most of the NVS, in the childhood immunization calendar to prevent IPD in children.
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Affiliation(s)
- F González Martínez
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España.
| | - M L Navarro Gómez
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - J Saavedra Lozano
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - M M Santos Sebastián
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - R Rodríguez Fernández
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - M González Sanchéz
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - E Cercenado Mansilla
- Servicio de Microbiología, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
| | - T Hernández-Sampelayo Matos
- Departamento de Pediatría, Sección de Infectología Pediátrica, Hospital Infantil Universitario Gregorio Marañón, Madrid, España
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Impact of introduction of conjugate vaccines in the vaccination schedule on the incidence of pediatric invasive pneumococcal disease requiring hospitalization in Madrid 2007 to 2011. Pediatr Infect Dis J 2013; 32:656-61. [PMID: 23249906 DOI: 10.1097/inf.0b013e31827e8594] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Differences in invasive pneumococcal disease (IPD) in children are expected after a change from 7-valent pneumococcal conjugate vaccine (PCV7) to 13-valent pneumococcal conjugate vaccine (PCV13). Universal vaccination with PCV7 started in Madrid in November 2006, and it switched to PCV13 in June 2010. METHODS A prospective, laboratory-confirmed (by culture or polymerase chain reaction), clinical surveillance including all pediatric IPD requiring hospitalization in Madrid was performed in all hospitals with a pediatric department and included four 1-year periods from May 2007 to April 2011. Incidence rate (IR) was calculated as number cases per 100,000 inhabitants using children population data. RESULTS Six hundred fourteen IPDs were identified: 209 parapneumonic pneumococcal empyema, 191 bacteremic pneumonia, 75 primary bacteremia, 72 meningitis, 38 IPDs secondary to otic foci and 29 others. The incidence of IPD remained unchanged during 2007-2010 (IR=≈17.0), with a marked decrease in 2010-2011 (IR=11.34; P<0.05) attributable to reduction in children younger than 24 months (50.19 in 2008-2009 compared with 24.92 in 2010-2011; P<0.005). The incidence of bacteremic pneumonia (R²=0.966; β=1.132; P=0.017) and meningitis (R²=0.898; β=0.505; P=0.052) showed decreasing linear trends over time. The incidence of parapneumonic pneumococcal empyema increased in 2009-2010 but decreased in 2010-2011 (6.73 vs. 4.14; P=0.019). The incidence of IPDs by PCV13 serotypes was significantly (P≤0.004) lower in 2010-2011 (8.78) than in previous periods (IR=≈13.5). CONCLUSIONS Early data regarding changing from PCV7 to PCV13 use in the childhood vaccination calendar indicate that reductions in IR of bacteremic pneumonia and meningitis after PCV7 introduction (by reduction of cases by serotypes 1 and 19A) further decreased and there was a reversion of the increase in IR of parapneumonic pneumococcal empyema from 2010-2011, mainly because of reduction in serotype 1 and 19A cases.
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The impact of 7-valent pneumococcal conjugate vaccine on invasive pneumococcal disease: a literature review. Adv Ther 2013; 30:127-51. [PMID: 23397399 DOI: 10.1007/s12325-013-0007-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Streptococcus pneumoniae can cause invasive pneumococcal diseases (IPD), such as bacteremic pneumonia, bacteremia, meningitis, and sepsis, and non-IPDs, such as otitis media, nonbacteremic pneumonia, and upper respiratory tract infections. It was estimated in 2000 that, worldwide, S. pneumoniae was responsible for 826,000 deaths annually in children aged between 1 month and 5 years. A 7-valent pneumococcal conjugate vaccine (PCV7) was licensed in 2000 in the USA and in 2001 in Europe. METHODS A literature search was performed in PubMed to identify studies assessing the impact of routine childhood PCV7 vaccination on pneumococcal morbidity and mortality. Here, the impact on IPD is reported. RESULTS A total of 37 articles reporting impact data on IPD were included in this review: four from Australia, 17 from western Europe, and 16 from North America. In vaccine-eligible children in the postvaccination period, a reduction ranging from 39.9% in Spain to 99.1% in the USA in vaccine-type (VT) IPD incidence, compared with the prevaccination period, was reported in 18 studies. All but one of the 30 studies assessing the impact of PCV7 on all-type IPD reported a reduction ranging from 1.7% in Spain to 76.3% in Australia. In addition, the majority of studies reported reductions in VT and all-type IPD incidence in age groups that were not vaccine eligible. CONCLUSIONS The results from this review illustrate that PCV7 has had a significant impact on IPD across all ages through its use in pediatric immunization programs. With the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) further reductions in the incidence of IPD due to the six additional serotypes included, as well as continued protection against IPD due to PCV7 serotypes may be expected. Robust surveillance systems are essential for the evaluation of the impact of PCV13 on all-type IPD and for monitoring the evolution of non-VT IPD.
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Vila-Corcoles A, Ochoa-Gondar O, Guzman-Avalos A, Gomez-Bertomeu F, Figuerola-Massana E, Raga-Luria X, de Diego-Cabanes C, Gutierrez-Perez A, Vila-Rovira A, Rodriguez-Fernandez M. Incidence of pneumococcal infections among children under 15 years in southern Catalonia throughout the heptavalent conjugate vaccine era, 2002–2009. Infection 2012; 41:439-46. [DOI: 10.1007/s15010-012-0345-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Accepted: 09/17/2012] [Indexed: 10/27/2022]
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García-Vera C, Ruiz Andrés MÁ, Arana Navarro T, Moneo Hernández I, Castillo Laita JA, Macipe Costa R, Revillo Pinilla MJ. [Nasopharyngeal carriage of pneumococcal serotypes in healthy pre-school aged children after 7-valent pneumococcal vaccine]. Med Clin (Barc) 2011; 137:1-7. [PMID: 21514939 DOI: 10.1016/j.medcli.2010.09.051] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 09/24/2010] [Accepted: 09/28/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVE To determine the characteristics influencing pneumococcal serotype colonization in healthy pre-school aged children, the distribution of serotypes and their antimicrobial susceptibility, after the introduction of pneumococcal 7-valent conjugate vaccine (VNC-7 v). SUJETOS AND METHODS: Nasopharyngeal samples were collected from children under 6 years of age attending well-child examinations in the province of Zaragoza (Spain). Logistic regression was used to study different variables related to the status of the carriers. RESULTS Of the 371 children studied 30.7% were found to be carriers. With a vaccine coverage rate of 66%, factors related with presence of pneumococcal carriage were found to be the number of siblings (OR 1.44; CI 95% 1.05-1.97 for each sibling), attending a school or child day care centre (OR 3.99; CI 95% 2.00-7.96) and suffering from a minor upper respiratory tract infection (URTI) (OR 1.72; CI 95% 1.02-2.90). Only 8.7% corresponded to VNC-7 v serotypes. The most common non VNC-7 v serotypes isolated were 19A, 6A, 15B, 11, and 15A. Significantly greater resistance was detected among VNC-7 v serotypes. CONCLUSION Children in the setting of this study carried pneumococci more commonly when they have siblings, attend school or day care, or suffer from minor URTI. In the VNC-7 v vaccine era, VNC-7 v serotypes have become rare occurrences (8.7%) and emerging serotypes present better susceptibility to antibiotics.
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Rodrigo Gonzalo de Liria C. [Pneumococcus and the theatre of classic Greece]. Med Clin (Barc) 2011; 137:17-9. [PMID: 21513960 DOI: 10.1016/j.medcli.2011.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 02/17/2011] [Indexed: 11/27/2022]
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Relationship between serotypes, age, and clinical presentation of invasive pneumococcal disease in Madrid, Spain, after introduction of the 7-valent pneumococcal conjugate vaccine into the vaccination calendar. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2010; 18:89-94. [PMID: 21047996 DOI: 10.1128/cvi.00317-10] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
To assess invasive pneumococcal disease (IPD) clinical presentations and relationships with age and serotype in hospitalized children (<15 years) after PCV7 implementation in Madrid, Spain, a prospective 2-year (May 2007 to April 2009) laboratory-confirmed (culture and/or PCR) IPD surveillance study was performed (22 hospitals). All isolates (for serotyping) and culture-negative pleural/cerebrospinal fluids were sent to the reference laboratory for pneumolysin (ply) and autolysin (lyt) gene PCR analysis. A total of 330 IPDs were identified: 263 (79.7%) confirmed by culture and 67 (20.3%) confirmed by PCR. IPD distribution by age (months) was as follows: 23.6% (<12), 15.8% (12 to 23), 15.5% (24 to 35), 22.4% (36 to 59), and 22.7% (>59). Distribution by clinical presentation was as follows: 34.5% bacteremic pneumonia, 30.3% pediatric parapneumonic empyema (PPE), 13.6% meningitis, 13.3% primary bacteremia, and 8.2% others. Meningitis and primary bacteremia were the most frequent IPDs in children <12 months old, and bacteremic pneumonia and PPE were most frequent in those >36 months old. Frequencies of IPD-associated serotypes were as follows: 1, 26.1%; 19A, 18.8%; 5, 15.5%; 7F, 8.5%; 3, 3.9%; nontypeable/other 30 serotypes, 27.3%. Serotype 1 was linked to respiratory-associated IPD (38.6% in bacteremic pneumonia and 38.0% in PPE) and children of >36 months (51.4% for 36 to 59 months and 40.0% for >59 months), while serotype 19A was linked to nonrespiratory IPDs (31.1% in meningitis, 27.3% in primary bacteremia, and 51.9% in others) and children of <24 months (35.9% for children of <12 months and 36.5% for those 12 to 23 months old), with high nonsusceptibility rates for penicillin, cefotaxime, and erythromycin. After PCV7 implementation, non-PCV7 serotypes caused 95.5% of IPDs. The new 13-valent conjugate vaccine would provide 79.1% coverage of serotypes responsible for IPDs in this series.
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Coste-utilidad de la incorporación de las nuevas vacunas antineumocócicas conjugadas al programa de vacunación de la comunidad de Madrid. Impacto sobre la enfermedad neumocócica invasora. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/s1576-9887(10)70021-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Salleras L, Domínguez A, Ciruela P, Izquierdo C, Navas E, Torner N, Borras E. Changes in serotypes causing invasive pneumococcal disease (2005–2007 vs. 1997–1999) in children under 2 years of age in a population with intermediate coverage of the 7-valent pneumococcal conjugated vaccine. Clin Microbiol Infect 2009; 15:997-1001. [DOI: 10.1111/j.1469-0691.2009.02938.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Guevara M, Barricarte A, Gil-Setas A, García-Irure JJ, Beristain X, Torroba L, Petit A, Polo Vigas ME, Aguinaga A, Castilla J. Changing epidemiology of invasive pneumococcal disease following increased coverage with the heptavalent conjugate vaccine in Navarre, Spain. Clin Microbiol Infect 2009; 15:1013-9. [PMID: 19673968 DOI: 10.1111/j.1469-0691.2009.02904.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The present study evaluated changes in the incidence of invasive pneumococcal disease (IPD) and the pattern of serotypes isolated in Navarre, Spain, after the introduction and increased coverage of the heptavalent pneumococcal conjugate vaccine (PCV7). All cases with isolation of pneumococcus from normally sterile bodily fluids were included. The incidence of IPD in children and adults was compared for the periods 2001-2002 and 2006-2007. By the end of 2002, only 11% of children aged <5 years had received any dose of PCV7, whereas, beginning in 2007, the proportion exceeded 50%. Among the cases of IPD aged <5 years, the percentage of those vaccinated increased from 7% during 2001-2002 to 53% during 2006-2007 (p <0.001). The incidence of IPD from PCV7-serotypes decreased by 85% in children <5 years (p <0.001), by 45% in the population aged 5-64 years (p 0.10) and by 68% in those >or=65 years (p 0.004). By contrast, the incidence of IPD from non-PCV7 serotypes increased by 40% overall (p 0.006). The incidence of IPD from all serotypes did not change significantly in children <5 years (from 83 to 72 per 100 000) or in the total population (from 15.8 to 16.3 per 100 000). The percentage of cases as a result of serotypes 7 and 19A increased significantly in both children and adults. No significant changes were seen in the clinical forms of IPD. The pattern of serotypes causing IPD has changed, in both children and adults, following the increased coverage of PCV7, although the incidence has been reduced only slightly.
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Affiliation(s)
- M Guevara
- Instituto de Salud Pública de Navarra, Navarre, Spain
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Salleras L, Domínguez À, Ciruela P, Izquierdo C, Borràs E. Impacto de la vacuna neumocócica conjugada heptavalente en una población con valores bajos-intermedios de vacunación. Enferm Infecc Microbiol Clin 2009; 27:275-7. [DOI: 10.1016/j.eimc.2008.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Accepted: 09/22/2008] [Indexed: 10/20/2022]
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Artiles F, Horcajada I, Cañas AM, Álamo I, Bordes A, González A, Santana M, Lafarga B. Aspectos epidemiológicos de la enfermedad neumocócica invasiva antes y después del uso de la vacuna neumocócica conjugada en Gran Canaria. Enferm Infecc Microbiol Clin 2009; 27:14-21. [DOI: 10.1016/j.eimc.2008.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Accepted: 03/27/2008] [Indexed: 12/01/2022]
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Gérvas J. La vacuna contra el virus del papiloma humano desde el punto de vista de la atención primaria en España. REVISTA BRASILEIRA DE EPIDEMIOLOGIA 2008. [DOI: 10.1590/s1415-790x2008000300017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Moore MR, Whitney CG. Emergence of Nonvaccine Serotypes following Introduction of Pneumococcal Conjugate Vaccine: Cause and Effect? Clin Infect Dis 2008; 46:183-5. [DOI: 10.1086/524661] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Bernaola E, Herranz M, Clerigue N, Gil F. Case-control studies to assess vaccine effectiveness? Yes, but not this way. Clin Infect Dis 2007; 45:1240-1; author reply 1242-3. [PMID: 17918091 DOI: 10.1086/522286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Barricarte A, Castilla J, Navarro-Alonso JA, Gil-Setas A, Torroba L. Reply to Bernaola et al. and Moore et al. Clin Infect Dis 2007. [DOI: 10.1086/522284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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