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Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

ABSTRACT: Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005-2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard.

SUBMITTER: Jokinen J

PROVIDER: S-EPMC5982705 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

Jokinen Jukka J Snellman Marja M Palmu Arto A AA Saukkoriipi Annika A Verlant Vincent V Pascal Thierry T Devaster Jeanne-Marie JM Hausdorff William P WP Kilpi Terhi M TM

American journal of epidemiology 20180601 6

Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumo ...[more]

PMID: 29253067

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Project description:BACKGROUND: Pneumonia is the leading cause of child mortality worldwide. Streptococcus pneumoniae (SP) or pneumococcus is estimated to cause 821,000 child deaths each year. It has over 90 serotypes, of which 7 to 13 serotypes are included in current formulations of pneumococcal conjugate vaccines that are efficacious in young children. To further reduce the burden from SP pneumonia, a vaccine is required that could protect children from a greater diversity of serotypes. Two different types of vaccines against pneumococcal pneumonia are currently at varying stages of development: a multivalent pneumococcal conjugate vaccine covering additional SP serotypes; and a conserved common pneumococcal protein antigen (PPA) vaccine offering protection for all serotypes. METHODS: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging SP vaccines relevant to several criteria of interest: answerability; efficacy and effectiveness; cost of development, production and implementation; deliverability, affordability and sustainability; maximum potential for disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to sensitive nature of their involvement in such exercises. They answered questions from CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%. RESULTS: The experts expressed very high level of optimism (over 80%) that low-cost polysaccharide conjugate SP vaccines would satisfy each of the 9 relevant CHNRI criteria. The median potential effectiveness of conjugate SP vaccines in reduction of overall childhood pneumonia mortality was predicted to be about 25% (interquartile range 20-38%, min. 15%, max 45%). For low cost, cross-protective common protein vaccines for SP the experts expressed concerns over answerability (72%) and the level of development costs (50%), while the scores for all other criteria were over 80%. The median potential effectiveness of common protein vaccines in reduction of overall childhood pneumonia mortality was predicted to be about 30% (interquartile range 26-40%, min. 20%, max 45%). CONCLUSIONS: Improved SP vaccines are a very promising investment that could substantially contribute to reduction of child mortality world-wide.

Project description:BackgroundPeople with chronic obstructive pulmonary disease (COPD) are at increased risk of pneumococcal disease, especially pneumonia, as well as acute exacerbations with associated morbidity and healthcare costs.ObjectivesTo determine the efficacy of injectable pneumococcal vaccination for preventing pneumonia in persons with COPD.Search methodsWe searched the Cochrane Airways COPD Trials Register and the databases CENTRAL, MEDLINE and Embase, using prespecified terms. Searches are current to November 2016.Selection criteriaWe included randomised controlled trials (RCT) comparing injectable pneumococcal polysaccharide vaccine (PPV) or pneumococcal conjugated vaccine (PCV) versus a control or alternative vaccine type in people with COPD.Data collection and analysisWe used standard Cochrane methodological procedures. For meta-analyses, we subgrouped studies by vaccine type.Main resultsFor this update, we added five studies (606 participants), meaning that the review now includes a total of 12 RCTs involving 2171 participants with COPD. Average age of participants was 66 years, male participants accounted for 67% and mean forced expiratory volume in one second (FEV1) was 1.2 L (five studies), 54% predicted (four studies). We assessed risks of selection, attrition and reporting bias as low, and risks of performance and detection bias as moderate.Compared with control, the vaccine group had a lower likelihood of developing community-acquired pneumonia (CAP) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.43 to 0.89; six studies, n = 1372; GRADE: moderate), but findings did not differ specifically for pneumococcal pneumonia (Peto OR 0.26, 95% CI 0.05 to 1.31; three studies, n = 1158; GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) (preventing one episode of CAP) was 21 (95% CI 15 to 74). Mortality from cardiorespiratory causes did not differ between vaccine and control groups (OR 1.07, 95% CI 0.69 to 1.66; three studies, n = 888; GRADE: moderate), nor did all-cause mortality differ (OR 1.00, 95% CI 0.72 to 1.40; five studies, n = 1053; GRADE: moderate). The likelihood of hospital admission for any cause, or for cardiorespiratory causes, did not differ between vaccine and control groups. Vaccination significantly reduced the likelihood of a COPD exacerbation (OR 0.60, 95% CI 0.39 to 0.93; four studies, n = 446; GRADE: moderate). The NNTB to prevent a patient from experiencing an acute exacerbation was 8 (95% CI 5 to 58). Only one study (n = 181) compared the efficacy of different vaccine types - 23-valent PPV versus 7-valent PCV - and reported no differences for CAP, all-cause mortality, hospital admission or likelihood of a COPD exacerbation, but investigators described a greater likelihood of some mild adverse effects of vaccination with PPV-23.Authors' conclusionsInjectable polyvalent pneumococcal vaccination provides significant protection against community-acquired pneumonia, although no evidence indicates that vaccination reduced the risk of confirmed pneumococcal pneumonia, which was a relatively rare event. Vaccination reduced the likelihood of a COPD exacerbation, and moderate-quality evidence suggests the benefits of pneumococcal vaccination in people with COPD. Evidence was insufficient for comparison of different pneumococcal vaccine types.

Project description:INTRODUCTION:Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019. METHODS AND ANALYSIS:Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of Streptococcus pneumoniae carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the ?2 test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION:This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER:CRD42019130976.

Dataset Information

Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

Publications

Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

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