Carlos G. Grijalva, MD MPH Department of Preventive Medicine Vanderbilt University School of Medicine Nashville, Tennessee

 Pneumococcal diseases  Importance of pneumonia  PCV7 efficacy against pneumonia  Study design considerations  PCV7 uptake & secular trends  Population-based changes after PCV7 introduction

Study focus InvasivePneumococcal Disease (IPD) Meningitis Bacteremia Pneumonia Otitis media/Sinusitis More severe More common

Property Polysaccharide Conjugate Immunogenicity children <2 years NO YES B cell dependent immune responseYES YES T cell dependent immune response NO YES Immune memory NO YES Booster effect NO YES Long term protection NO YES Reduction of carriage NO YES Herd immunity NO YES Adapted from Granoff DM. Vaccines. 2004

Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network, Streptococcus pneumoniae, , Centers for Disease Control and Prevention. Accessed Sep 16th, PCV7

Bryce J, et al. Lancet. 2005;365: Pneumonia 19% Injuries 3% Other 10% Neonatal 37% HIV/AIDS 3% Diarrhea 17% Measles 4% Malaria 8% Preterm 28% Congenital 8% Asphyxia 23% Sepsis or pneumonia 26% Diarrhea 3% Tetanus 7% Other 7% Causes of neonatal deaths Pneumonia is the leading killer of children

 Leading infectious cause of death  3% to 18% of all childhood hospitalizations  Streptococcus pneumoniae is the leading bacterial cause of pneumonia  17–44% pneumonia admissions in children  13–34% pneumonia admissions in adults Marston BJ, et al. Arch Intern Med. 1997;157: Farha T, Thomson AH. Paediatr Respir Rev. 2005;6:76-82 Michelow I, et al. Pediatrics. 2004;113: Drummond P, et al. Arch Dis Child. 2000; 83: The British Thoracic Society and the Public Health Laboratory Service. Q J Med. 1987; 62:

 Black et al. PIDJ. 2002;21:810–15  Hansen et al. PIDJ. 2006;25:779–81 Control Rate / 1000 PCV7 Rate / 1000 Vaccine Efficacy (%) 95% CI Clinical pneumonia –3.5 to 11.5 Chest X-ray obtained to 18.5 Positive chest X-ray to 34.0 WHO consolidation to 45.7

 To estimate the impact of PCV7  Pneumonia hospitalization rates in children aged <2 years (target population)  To evaluate indirect effects

CDC. Biosurveillance 2000–2005 and National Immunization Survey Grijalva CG, et al. Expert Rev Vaccines. 2008;7:83–95

 HCUP: Nationwide Inpatient Sample  Sponsored by AHRQ  Largest inpatient database publicly available  ~20% of US hospital discharges  Discharge level information  De-identified data, diagnoses, procedures, no lab, no chest x- rays  Complex sampling design

 Monthly hospitalization rates (annualized):  All-cause pneumonia  Pneumococcal pneumonia  Dehydration (control condition)  Segmented regression analysis: ITS  Log-transformed rates as outcomes  Quantified vaccine effect by end of 2004 Grijalva CG, et al. Lancet. 2007;369:1179–1186

 Quasi-experimental design Wagner AK, et al. J Clin Pharm Therap. 2002;27:299–309

 Evaluate longitudinal effects of time- delimited interventions  Account for seasonal and secular trends  With a control group can assess non- specific changes

Intervention (2000)

Intervention (2000) Overestimation of Effect

Intervention (2000)

Intervention (2000) Underestimation of Effect

Grijalva CG, et al. Lancet. 2007;369:1179–1186

< > Percent (%) change Grijalva CG, et al. Expert Rev Vaccines Feb;7(1):83-95

20 < > Percent (%) change Grijalva CG, et al. Expert Rev Vaccines Feb;7(1):83-95

Age group Rate difference per 100,000 US population Annual pneumonia admissions prevented <2 years – million 41,287 18–39 years – million 24,743 Grijalva CG, et al. Lancet. 2007;369:1179–1186

Zhou F, et al. Arch Pediatr Adolesc Med. 2007;161:1162–1168

Grijalva et al, 2009 MMWR 58(1): 1-4 ↓22 % NC

Grijalva et al. Clin Infect Dis. 2010; 50(6):805-13

♦Major declines in all-cause and pneumococcal pneumonia after PCV7 program introduction ♦Sustained declines consistently observed in different studies/settings ♦Large national database (HCUP NIS) allowed detection and monitoring of direct and indirect effects

♦Marie R. Griffin, MD MPH ♦Professor of Medicine and Preventive Medicine. VUMC ♦J. Pekka Nuorti, MD DSc ♦Epidemiologist, CDC