Vaccine Efficacy IPD and Pneumonia

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2 Vaccine Efficacy IPD and Pneumonia Hanna Nohynek, MD PhD National Public Health Institute Helsinki, Finland for 3rd Regional Pneumococcal Symposium Istanbul, Turkey February 13-14, 2008

3 Vaccine efficacy (VE) VE = 100 x (1 RR) = 100 x (1 AR v / AR UV )

4 Composition of Pneumococcal Conjugate Vaccines in trials Capsular polysaccharide of 7-13 pneumococcal serotypes, conjugated to Carrier protein CRM 197 PD (D-protein of Haemophilus influenzae) OMPC D or T

5 Invasive Pneumococcal Disease

6 Randomized controlled trials of PCV against IPD PCV-7 4, 6B, 9V, 14, 18C, 19F, 23F PCV-9 + 1, 5 N =

7 Incidence of IPD / PY in children < 2 year of age in trial sites HIVseveral fold higher in HIV+

8 Efficacy of PCV against vaccine type (VT) IPD is established for PncCRM NCKP ZA HIV (-) 84.6 Gambia 77.0 Native Am 76.8 ZA HIV (+) PCV-7; PCV Vaccine Efficacy (PP, 95%CI)

9 References NCKP / California, the US Black S, Shinefield H, et al. PIDJ 2000; 19 (3): South Africa HIV(-) and HIV(+) Klugman KP, Madhi SA, et al. NEJM 2003; 349 (14): Lucero MG, Dulalia VE, et al. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD DOI: / CD The Gambia Cutts FT, Zaman SMA, et al. Lancet 2005; 365: American Indian, the US O Brien KL, Moulton LH, et al. Lancet 2003; 362:

10 N = 54 in vaccinees N = 180 in controls Meta analysis of the efficacy of conjugate vaccines against invasive pneumococcal disease Klugman KP, Cutts F, Adegbola RA, Black S, Madhi SA, O Brien KL, Santosham M, Shinefield H, Sterne JAC In Press

11 Meta-analysis main message: PCV efficacious (VE ITT) against vaccine-serotype specific IPD in Randomized Controlled (RC) Trials 7v vaccine type IPD in HIV negative Study NCKP (2000) Native American (2003) South Africa HIV - (2007) The Gambia (2005) M-H Overall (p = 0.251) D+L Overall RR (95% CI) 0.06 (0.02, 0.20) 0.17 (0.04, 0.78) 0.23 (0.07, 0.81) 0.24 (0.11, 0.51) 0.15 (0.09, 0.25) 0.16 (0.08, 0.31) Vaccine efficacy (%) 94 (80, 98) 83 (22, 96) 77 (19, 93) 77 (49, 89) 85 (75, 91) 84 (69, 92) Risk ratio

12 Meta-analysis PCV efficacy against individual vaccineserotype specific IPD in RCTrials Serotype Events Vaccinees N = Events Controls N = Vaccine Efficacy (95%CI) (-65 to 93) 6B ( 47 to 90) 9V (-23 to 80) (59 to 91) 18C ( 3 to 89) 19F (13 to 82) 23F ( 3 to 78)

13 Meta-analysis PCV efficacy against individual vaccineserotype specific IPD in RCTrials Serotype Events Vaccinees N= Events Control N= Vaccine Efficacy (95%CI) (-120 to 76) N= N= (-65 to 93) (26 to 96) N= N= B ( 47 to 90) 9V (-23 to 80) (59 to 91) 18C ( 3 to 89) 19F (13 to 82) 23F ( 3 to 78) 6A (12 to 79)

14 Meta-analysis PCV not efficacious against non-vaccine serotypes (excluding ST 6A) IPD in RCTrials Non-vaccine types excluding 6A Study RR (95% CI) Vaccine efficacy (%) NCKP (2000) Native American (2003) South Africa HIV - (2007) South Africa HIV + (2007) The Gambia (2005) Overall 0.60 (0.14, 2.51) 1.36 (0.52, 3.56) 3.50 (0.73, 16.84) 0.87 (0.43, 1.78) 1.00 (0.57, 1.74) 1.06 (0.74, 1.54) 40 (-151, 86) -36 (-256, 48) -250 (-900, 27) 13 (-78, 57) 0.0 (-74, 43) -6 (-54, 26) Risk ratio

15 Meta-analysis PCV not efficacious against serotype 19A IPD in RCTrials Serotype 19A, Study RR (95% CI) Vaccine efficacy (%) NCKP (2000) Native American (2003) South Africa HIV - (2007) South Africa HIV + (2007) The Gambia (2005) Overall (I-squared = 0.0%, p = 0.620) 0.33 (0.01, 8.19) 2.85 (0.12, 69.91) 3.00 (0.31, 28.83) 0.50 (0.13, 1.99) 0.86 (0.29, 2.55) 0.87 (0.43, 1.79) 66.6 (-718.7, 98.6) (-899.9, 88.4) (-899.9, 68.8) 50.0 (-99.2, 87.5) 14.3 (-154.9, 71.2) 12.8 (-78.5, 57.5) Risk ratio

16 Randomized controlled trials of PCV against pneumonia PCV-11 PCV-7 PCV-9 N =

17 What kind of pneumonia? WHO Pneumonia Vaccine Trial Investigators Group. Standardization of interpretation of chest radiographs for the diagnosis of pneumonia in children. WHO/V&B/01.35, Geneva 2001.

18 Diagnosing pneumococcal pneumonia Sensitivity Clinical criteria Modified criteria Any X-ray abnormality Alveolar consolidation Lung aspirate culture Blood culture Specificity

19 PCV efficacy is higher with a more specific diagnosis of pneumococcal pneumonia Specificity of pneumococcal pneumonia diagnosis High Low Clinical pneumonia Xray-confirmed pneumonia WHO-defined severe pneumonia Vaccine serotype-confirmed pneumonia Low PCV Efficacy High

20 PCV efficacy against pneumonia in RCTrials % VE USA NCKP 20 ZA HIV- 15 Gambia 10 Philippines 5 0 Xray+ Severe Clinical Pneumonia

21 PCV efficacious in reducing Xray confirmed pneumonia Trial PCV valency Incidence* Vaccinees Incidence* Controls Efficacy (95%CI) VPD** USA NCKP PCV-7 (5; 29) USA Native Am NA NA NA NA PCV-7 SA HIV Neg PCV-9 (3, 35) SA HIV Pos PCV-9 (-7, 28) The Gambia PCV-9 (25, 48) Philippines PCV-11 (-1, 41) *Per 1000 child years **Vaccine Preventable Disease Black S et al. PIDJ 2001/ Hansen PIDJ 2007; Klugman KP et al. NEJM 2003; Cutts F et al. Lancet 2005, O Brien, Lucero pers comm

22 The complicated relationship of observed vs. true efficacy of PCV against pneumococcal pneumonia # Cases Preventable Xray confirmed pneumonia 100 Pneumococcal Vaccine Serotype 50-70%? 50-70% Efficacy 50-70% Expected Effect Still cases of Xray confirmed pneumonia

23 Summary points PCV has - high efficacy against IPD - good efficacy against Xray confirmed pneumonia In addition, PCV has been found to reduce all-cause child mortality in a low-income country setting

24 Thank you to ARIVAC consortium GAVI ADIP Pneumo Thomas Cherian Terhi Kilpi Keith Klugman Shabir Madhi