Pneumococcal Vaccine Effectiveness. Steven Black, MD Center for Global Health Cincinnati Children s s Hospital Cincinnati, Ohio USA

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1 Pneumococcal Vaccine Effectiveness Steven Black, MD Center for Global Health Cincinnati Children s s Hospital Cincinnati, Ohio USA

2 Overview Possible effectiveness outcomes for pneumococcal vaccines Pre-licensure assessment of conjugate vaccine efficacy Post licensure assessment of effectiveness

3 Streptococcus pneumoniae Associated Disease in U.S. Pre PCV7 Clinical Presentation Cases Per Year All ages Children <5yo Clinical features in children Meningitis 3,000 1,400 Neurological sequelae, hearing loss in up to 50% of cases, 10% mortality Bacteremia 61,000 16, % is occult Pneumonia 500,000 71,000 ~4%are bacteremic Otitis Media 7,000,000 5,100,000 Hearing Loss, Antibiotic use, PE tubes NOTE: ~127 deaths in children total per year in a cohort of ~ 20 million children < 5 yo Versus > 1.2 million deaths from pneumonia alone in the developing world each year.

4 Possible Effectiveness Outcomes for Pneumococcal Vaccines Immunologic outcomes Carriage Otitis Media Pneumonia Invasive Disease Health Economic Outcomes

5 Immunologic Endpoints Induction of an immune response is the mechanism for vaccine action The extent of and the duration of the immune response correlate with clinical effects Defining a strict correlate of protection is problematic ELISA OPA

6 PCV-10/NTHi Immunogenicity Data

7 Pre-licensure Trial Results in the Developed World Trial Outcome Result (95% confidence interval) Black et al IPD per protocol 97.4% ( 82.7, 99.9%) OM per protocol 7% ( 4.1, 9.7%) Pneumonia first episode 30.3% (10.7, 45.7%) Eskola et al OM 6% (- 4, 9.7%) O Brien et al IPD 76.8% ( 9.4, 95.1%) Black et al PIDJ 2000; 19:3// Hansen et al PIDJ :9 /// Eskola et al NEJM 344:403-9 /// O Brien et al Lancet 362:

8 Pre-licensure Trial Results in the Developing World Trial Outcome Result (95% confidence interval) Madhi et al IPD per protocol 83% ( 39-97) South Africa IPD in HIV infected Pneumonia first episode 65% ( 24-86) 20% (2-35) Cutts et al Gambia IPD 77% (51-90) Pneumonia 37% ( 27-45) Mortality 16% ( 3-28) REF:

9 Invasive Disease The most severe outcome is meningitis These outcomes are rare and account for only a small proportion of the total disease burden Attractive for licensure trials because Etiology can be documented by culture Serotype information is available

10 Otitis Media The most common pneumococcal manifestation in the developed world Direct determination of etiology is possible but logistically difficult Serotype information available if tympanocentesis performed

11 Pneumonia In developing countries this is the outcome which accounts for the majority of morbidity and mortality Uniform diagnosis of cases if difficult even with WHO training for reading of x-rays Etiologic diagnosis not usually available in children for vast majority of cases Serotype information also not available.

12 Carriage Easiest outcome to assess Assumption: Lack of reduction of vaccine serotypes for conjugate vaccines would predict for lack of indirect effect Appropriate interpretation of protein vaccine impact on carriage is not clear

13 Post Licensure Effectiveness Requires comprehensive data on a defined population Analysis of trends requires availability of baseline data Secular or other trends can interfere Watchful waiting and otitis Long term cyclic trends in serotype epidemiology

14 Post Licensure Effectiveness Invasive Disease Vaccine Serotypes Replacement Net effect Indirect Effects US experience UK experience Uncertainty regarding developing world Cost effectiveness

15 Analytic Frameworks Disease surveillance in a defined population Requires ascertainment of all cases and a defined denominator Sentinel surveillance May lead to bias in case ascertainment or serotype distribution Case control studies Dr. Kim Mulholland to discuss further

16 Active Bacterial Core Surveillance (ABCs) Emerging Infections Program Network Areas OR (3 counties) CA (1 county) MN (7 counties) GA (20 counties) MD (6 counties) CT (entire state) NY (7 counties) TN (10 counties) CO (8 counties) NM (entire state) Slide courtesy of Cyndie Whitney, CDC

17 Vaccine-Type Invasive Disease in Children <5 Years ABCs Cases per 100, % reduction / CDC unpublished data Slide courtesy of Cyndie Whitney, CDC

18 Rates of IPD among children aged <5 years, 1998/ Overall PCV7 type Serotype 19A Cases per 100, PCV7 introduction Slide courtesy of Cyndie Whitney, CDC Year

19 Replacement Emergence of non-vaccine serotypes following reduction of vaccine serotypes Causality may be multifactorial and vaccine may not play the major role Antibiotic usage Secular trends

20 Long Term Trends Serotype Epidemiology in Spain Courtesy of A Fennol

21 Rates of serotype 19A IPD among children aged <5 years, by penicillin susceptibility, Cases per 100, PEN-S 19A PEN-I 19A PEN-R 19A ABCs, Unpublished Year Slide courtesy of Cyndie Whitney, CDC

22 Is the Rise in 19A Related to Vaccine Use? Rises in serotypes 1, 7, and 19A observed in the UK prior to use of vaccine Rises in 19A observed in Korea and Israel without vaccine use. In Israel, Ron Dagan has shown that rises in 19A are related to use of Azithromycin. In the US in the Kaiser and Navajo populations, 19A has NOT increased. Antibiotic use controls are in place in both of these populations.

23 Indirect or Herd Effects

24 Rates of IPD among adults aged >18 years, 1998/ PCV7 serotypes Cases per 100, vs. baseline >80: -90% (-93,-86) 65-79: -88% (-91,-83) 50-64: -84% (-87,-79) 18-49: -88% (-91,-86) Pilishvili, IDSA 2007 Year S l Slide courtesy of Cyndie Whitney, CDC

25 Herd Effect in Adults 65+ Years PCV7 types vs. nonvaccine types ABCs 1998/99 average vs Serotype Cases/100,000 pop Percent 95% CI Baseline 2006 change Vaccine , -86 Nonvaccine , +41 Lexau et al. JAMA 2005 and unpublished data Slide courtesy of Cyndie Whitney, CDC

26 Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes NOT IN PCV-7 7 in Children aged < 2 Years in England and Wales by Epidemiological Year: July-June June ( ) 2009)

27 Cost Effectiveness of PCV-7 in the USA G Tom Ray et al PIDJ June 2006

28 Assessment of Effectiveness will Depend on the Primary Outcome Chosen In the US, invasive disease was the primary clinical driver for vaccination In cost effectiveness modeling two factors predominate OM Indirect effects in adults In the developing world, pneumonia and ALRI mortality are the primary concern An estimated 1.2 million pneumococcal pneumonia deaths in children annually Nature of indirect effects, if any, are not known.

29 Conclusion Assessment of the effectiveness of pneumococcal conjugate vaccination programs is complex Assessments vary between countries and regions. Our lack of understanding of the factors determining serotype epidemiology and the dynamics of indirect effects in different populations hampers generalizing from existing results.