1. DECADES OF VACCINES Vaccine trials: some highs and lows INTERVENTION RESEARCH TO IMPROVE HEALTH IN DEVELOPING COUNTRIES: PROGRESS AND FUTURE CHALLENGES Celebrating 40 years of the MRC Tropical Epidemiology Group 29-30 March 2012 Peter Smith

2. DTP3 COVERAGE 1980- 2008 GAVI 2011

3. MRC TEG: INVOLVEMENT IN VACCINE TRIALS DENGUE HAEMOPHILUS INFLUENZA HEPATITIS B HIV HPV HOOKWORK HSV2 LEISHMANIASIS LEPROSY MALARIA PNEUMOCOCCAL DISEASE ROTAVIRUS SCHISTOSOMIASIS (BOVINE) TUBERCULOSIS

4. MRC TEG: INVOLVEMENT IN VACCINE TRIALS DENGUE HAEMOPHILUS INFLUENZA  HEPATITIS B HIV HPV HOOKWORK HSV2  LEISHMANIASIS  LEPROSY MALARIA  PNEUMOCOCCAL DISEASE ROTAVIRUS SCHISTOSOMIASIS (BOVINE) TUBERCULOSIS

5. LEPROSY VACCINE TRIALS Vaccine trials Venezuela Malawi South India Nine-banded armadillo

6. STUDY YEAR Latitude 0 Relative risk 1 RR (95% CI) STUDIES OF THE PROTECTIVE EFFECT OF BCG VACCINATION AGAINST LEPROSY Merle, Cunha & Rodrigues, 2010

7. TRIAL OF LEPROSY VACCINE IN VENEZUELA Conducted in 29,000 close contacts of leprosy cases in 3 States of Venezuela Individually randomised to BCG or BCG+M.leprae (double-blind) Followed for 5 years post-vaccination, with yearly examination for disease 150,000 person-years-at-risk – 59 post vaccination cases by July 1991 BCG aloneBCG + M. leprae Cases of leprosy 3128 Cases with onset >1 y post vaccination and M. leprae soluble antigen skin test negative 119 Convit et al 1992

8. RISK OF LEPROSY ACCORDING TO NUMBER OF BCG SCARS AT ENTRY TO THE TRIAL No. of BCG scarsNo. of contactsCases of leprosyCases/1000Relative risk 0 10890343.121.0 1-2 11450171.480.47 3-4 443361.350.43 5+ 227520.880.28 Convit et al 1992

9. TRIAL OF LEPROSY VACCINE IN MALAWI Conducted in 121,000 residents of Karonga District, Malawi Individually randomised to BCG or BCG+M.leprae or Placebo (depending on BCG status) Followed for 5 -9 years post-vaccination, with enhanced passive case detection of cases of leprosy and tuberculosis BCG Scar +veBCG Scar -veBCG Scar –ve and +ve Randomised group No. of persons BCG 23,456 Placebo 23,307 RRBCG+ KML 38,251 BCG 27,904 RRBCG+ KML (Hi dose) 30,262 BCG 31,971 RR Cases of leprosy16290.54*54371.0930 1.05 Karonga Prevention Trial Group 1996

10. TRIAL OF LEPROSY VACCINE IN MALAWI Conducted in 121,000 residents of Karonga District, Malawi Individually randomised to BCG or BCG+M.leprae or Placebo (depending on BCG status) Followed for 5 -9 years post-vaccination, with enhanced passive case detection of cases of leprosy and tuberculosis BCG Scar +veBCG Scar -veBCG Scar –ve and +ve Randomised group No. of persons BCG 23,456 Placebo 23,307 RRBCG+ KML 38,251 BCG 27,904 RRBCG+ KML (Hi dose) 30,262 BCG 31,971 RR Cases of leprosy16290.54*54371.0930 1.05 Cases of TB65621.041621011.21108921.25 Karonga Prevention Trial Group 1996

11. TRIAL OF LEPROSY VACCINES IN SOUTH INDIA Conducted in 171,000 residents of Chingleput District, Tamilnadu Individually randomised to BCG or BCG+KML or ICRC or Myco.W or Placebo (5-arm trial) Initially followed for 5-6 years post-vaccination with two surveys for leprosy cases Incidence of leprosy in trial much lower than expected Protective efficacy in 2 nd resurvey – 5-6 years post vaccination Gupte et al 1998

12. Trial of single dose of autoclave-killed Leishmania major + BCG against cutaneous leishmaniasis in Bam, Iran 3600 school children (6- 15y), LST-ve, randomised to BCG or BCG+ALM Followed for lesions 2y post-vaccination BCGBCG+ALM Cases of leishmaniasis 6353

13. Efficacy of killed whole parasite vaccines against leishmaniasis Noazin et al, 2009 Iran

14. GLOBAL BURDEN OF PNEUMOCOCCAL DISEASE

15. Cutts et al, 2005 Endpoint Vaccine (n=8189)Placebo (n=8151) Vaccine efficacy (95%CI) NumberRate/1000 yearsNumberRate/1000 years Radiographic pneumonia 20722.132335.1 37 (25 – 48) Deaths33025.238930.1 16 (3 – 28) Hospital admissions 106589.41216104.7 15 (7 – 21) Clinical pneumonia 2172231.52284248.5 7 (1 – 12)

16. ....987654321....987654321 Vaccination team 123 Time since start of programme (years) Usual EPI vaccines given plus HBV Usual EPI vaccines given 45 Introduction of Hepatitis B vaccine in The Gambia (Stepped-wedge design)

17. Introduction of Hepatitis B vaccine in The Gambia (Stepped-wedge design) 1986-1990: 60,000 infants received EPI vaccines, 60,000 received EPI vaccines + HBV vaccine Long term aim (40 years+) is to compare incidence of liver cancer and liver diseases in the two groups Sample of study population examined at age 15 years to assess long-term protective effect of vaccination against HB carrier state.

18. Protective effect of infant HBV vaccination against HBV chronic carriage at age 15 years UnvaccinatedFully vaccinatedPartially vaccinated Chronic carriers/ No. examined 51/4202/4921/84 Vaccine efficacy (95%CI) 96.6% (91.5-99.9)90.1% (69.9 – 99.9) Van de Sande et al, 2007

19. Thank you