Effectiveness of Heptavalent Pneumoccal Conjugate Vaccine in Young Children
Effectiveness of Heptavalent Pneumoccal Conjugate Vaccine in Young Children
Background: A World Health Organization (WHO) working group in 2001 developed a method for standardizing interpretation of chest radiographs in children for epidemiologic purposes. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method.
Methods: Seven-valent pneumococcal conjugate vaccine was evaluated in a randomized, controlled study including 37,868 infants. Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading. There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers (A and B); discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists.
Results: Of the 2841 radiographs, 2446 were available for scanning and were reviewed using WHO-defined descriptive categories. Two hundred fifty of the 2446 radiographs were read as positive by both readers. An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the reviewers. The concordance rate between the 2 reviewers was 250 of 521 (48%). Of the 271 discordant radiographs, 45 of 129 (34.9%) of reader A and 66 of 142 (46.5%) for reader B were finalized as positive by the adjudicating panel. Overall, 361 radiographs were finalized as positive (12.7%). With these 361 images as the standard, the sensitivity and specificity of reader A were 82% and 97%, respectively, and for reader B, 88% and 97%, respectively. Kappa between the 2 readers was 0.58. Of 25 control radiographs read as positive by both A and B, 80% were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel. Using original readings by point-of-care radiologists, efficacy against first episode of radiograph confirmed pneumonia was 17.7% (95% confidence interval [CI] = 4.8-28.9%) in intent-to-treat and 20.5% (95% CI = 4.4-34%) in per protocol. Using the WHO method, the efficacy against first episode of radiograph confirmed pneumonia adjusting for age, gender and year of vaccination of 25.5% (95% CI = 6.5-40.7%, P = 0.011) for intent-to-treat and 30.3% (95% CI = 10.7-45.7%, P = 0.0043) for per protocol.
Conclusion: Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity.
Between October 1995 and August 1998, Northern California Kaiser Permanente (NCKP) conducted a trial that evaluated the efficacy, safety and immunogenicity of the heptavalent pneumococcal conjugate vaccine (Prevnar; Wyeth, Philadelphia, PA). In this randomized, double-blind trial, there were 37,868 children at 23 medical clinics in California who received either the CRM197 pneumococcal conjugate vaccine (vaccine group) or the meningococcal type C CRM197 conjugate vaccine (control group). In per-protocol cases, this trial showed 97.4% efficacy (95% confidence interval [CI] = 82.7-99.9%) against invasive disease caused by vaccine serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. In the intent-to-treat analysis for the same, there was an efficacy of 93.9% (95% CI = 79.6-98.5%). In this trial, it was also shown that there was a statistically significant decrease in otitis media severe enough to require tympanostomy tubes.
In September 2002, the pneumococcal conjugate vaccine was found to be effective in this same trial for reducing the risk of pneumonia in young children. Children with clinical diagnoses of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified and the original reading of their radiographs by the radiologist was obtained from the automated databases. Rates were compared between vaccinated and control groups for the following: clinically diagnosed pneumonia, pneumonia with a radiograph obtained regardless of result, pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and pneumonia with only perihilar infiltrates. Because the trial involved a large number of subjects in a large HMO, there were several hundred radiologists interpreting the radiographs.
In 2001, the World Health Organization (WHO) convened a working group, the World Health Organizations Pneumonia Vaccine Trial Investigators' Group, which developed a document entitled Standardization of Interpretation of Chest Radiographs for the Diagnosis of Pneumonia in Children. The process defined in this working group and described in this document is intended to help standardize radiologic diagnosis of pneumonia in children for epidemiologic purposes, particularly with regard to evaluating the impact of interventions such as pneumococcal conjugate vaccine in a large patient population.
Background: A World Health Organization (WHO) working group in 2001 developed a method for standardizing interpretation of chest radiographs in children for epidemiologic purposes. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method.
Methods: Seven-valent pneumococcal conjugate vaccine was evaluated in a randomized, controlled study including 37,868 infants. Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading. There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers (A and B); discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists.
Results: Of the 2841 radiographs, 2446 were available for scanning and were reviewed using WHO-defined descriptive categories. Two hundred fifty of the 2446 radiographs were read as positive by both readers. An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the reviewers. The concordance rate between the 2 reviewers was 250 of 521 (48%). Of the 271 discordant radiographs, 45 of 129 (34.9%) of reader A and 66 of 142 (46.5%) for reader B were finalized as positive by the adjudicating panel. Overall, 361 radiographs were finalized as positive (12.7%). With these 361 images as the standard, the sensitivity and specificity of reader A were 82% and 97%, respectively, and for reader B, 88% and 97%, respectively. Kappa between the 2 readers was 0.58. Of 25 control radiographs read as positive by both A and B, 80% were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel. Using original readings by point-of-care radiologists, efficacy against first episode of radiograph confirmed pneumonia was 17.7% (95% confidence interval [CI] = 4.8-28.9%) in intent-to-treat and 20.5% (95% CI = 4.4-34%) in per protocol. Using the WHO method, the efficacy against first episode of radiograph confirmed pneumonia adjusting for age, gender and year of vaccination of 25.5% (95% CI = 6.5-40.7%, P = 0.011) for intent-to-treat and 30.3% (95% CI = 10.7-45.7%, P = 0.0043) for per protocol.
Conclusion: Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity.
Between October 1995 and August 1998, Northern California Kaiser Permanente (NCKP) conducted a trial that evaluated the efficacy, safety and immunogenicity of the heptavalent pneumococcal conjugate vaccine (Prevnar; Wyeth, Philadelphia, PA). In this randomized, double-blind trial, there were 37,868 children at 23 medical clinics in California who received either the CRM197 pneumococcal conjugate vaccine (vaccine group) or the meningococcal type C CRM197 conjugate vaccine (control group). In per-protocol cases, this trial showed 97.4% efficacy (95% confidence interval [CI] = 82.7-99.9%) against invasive disease caused by vaccine serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. In the intent-to-treat analysis for the same, there was an efficacy of 93.9% (95% CI = 79.6-98.5%). In this trial, it was also shown that there was a statistically significant decrease in otitis media severe enough to require tympanostomy tubes.
In September 2002, the pneumococcal conjugate vaccine was found to be effective in this same trial for reducing the risk of pneumonia in young children. Children with clinical diagnoses of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified and the original reading of their radiographs by the radiologist was obtained from the automated databases. Rates were compared between vaccinated and control groups for the following: clinically diagnosed pneumonia, pneumonia with a radiograph obtained regardless of result, pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and pneumonia with only perihilar infiltrates. Because the trial involved a large number of subjects in a large HMO, there were several hundred radiologists interpreting the radiographs.
In 2001, the World Health Organization (WHO) convened a working group, the World Health Organizations Pneumonia Vaccine Trial Investigators' Group, which developed a document entitled Standardization of Interpretation of Chest Radiographs for the Diagnosis of Pneumonia in Children. The process defined in this working group and described in this document is intended to help standardize radiologic diagnosis of pneumonia in children for epidemiologic purposes, particularly with regard to evaluating the impact of interventions such as pneumococcal conjugate vaccine in a large patient population.