DECADES OF VACCINESVaccine trials: some highs and

lows

INTERVENTION RESEARCH TO IMPROVE HEALTH IN DEVELOPING COUNTRIES: PROGRESS AND FUTURE CHALLENGESCelebrating 40 years of the MRC Tropical Epidemiology Group29-30 March 2012

Peter Smith

DTP3 COVERAGE 1980- 2008

GAVI 2011

MRC TEG: INVOLVEMENT IN VACCINE TRIALS

• DENGUE• HAEMOPHILUS INFLUENZA• HEPATITIS B• HIV• HPV• HOOKWORK• HSV2• LEISHMANIASIS• LEPROSY• MALARIA• PNEUMOCOCCAL DISEASE• ROTAVIRUS• SCHISTOSOMIASIS (BOVINE)• TUBERCULOSIS

MRC TEG: INVOLVEMENT IN VACCINE TRIALS

• DENGUE• HAEMOPHILUS INFLUENZA HEPATITIS B• HIV• HPV• HOOKWORK• HSV2 LEISHMANIASIS LEPROSY• MALARIA PNEUMOCOCCAL DISEASE• ROTAVIRUS• SCHISTOSOMIASIS (BOVINE)• TUBERCULOSIS

LEPROSY VACCINE TRIALSVaccine trials• Venezuela• Malawi • South India

Nine-banded armadillo

STUDY YEAR Latitude 0 Relative risk 1 RR (95% CI)

STUDIES OF THE PROTECTIVE EFFECT OF BCG VACCINATION AGAINST LEPROSYMerle, Cunha & Rodrigues, 2010

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 alone BCG + M. leprae

Cases of leprosy 31 28Cases with onset >1 y post vaccination and M. leprae soluble antigen skin test negative

11 9

Convit et al 1992

RISK OF LEPROSY ACCORDING TO NUMBER OF BCG SCARS AT ENTRY TO THE TRIAL

No. of BCG scars No. of contacts Cases of leprosy Cases/1000 Relative risk

0 10890 34 3.12 1.0

1-2 11450 17 1.48 0.47

3-4 4433 6 1.35 0.43

5+ 2275 2 0.88 0.28

Convit et al 1992

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 +ve BCG Scar -ve BCG Scar –ve and +veRandomised group

No. of persons

BCG

23,456

Placebo

23,307

RR BCG+KML

38,251

BCG

27,904

RR BCG+KML (Hi

dose)30,262

BCG

31,971

RR

Cases of leprosy 16 29 0.54* 54 37 1.09 30 30 1.05

Karonga Prevention Trial Group 1996

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 +ve BCG Scar -ve BCG Scar –ve and +veRandomised group

No. of persons

BCG

23,456

Placebo

23,307

RR BCG+KML

38,251

BCG

27,904

RR BCG+KML (Hi

dose)30,262

BCG

31,971

RR

Cases of leprosy 16 29 0.54* 54 37 1.09 30 30 1.05

Cases of TB 65 62 1.04 162 101 1.21 108 92 1.25

Karonga Prevention Trial Group 1996

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 2nd resurvey – 5-6 years post vaccination

BCG Myco.W BCG+KML ICRC0

10

20

30

40

50

60

70

80

90

Gupte et al 1998

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

BCG BCG+ALM

Cases of leishmaniasis

63 53

Efficacy of killed whole parasite vaccines against leishmaniasis

Noazin et al, 2009

Iran

GLOBAL BURDEN OF PNEUMOCOCCAL DISEASE

Cutts et al, 2005

EndpointVaccine (n=8189) Placebo (n=8151)

Vaccine efficacy (95%CI)Number Rate/1000 years Number Rate/1000 years

Radiographic pneumonia 207 22.1 323 35.1 37 (25 – 48)

Deaths 330 25.2 389 30.1 16 (3 – 28)

Hospital admissions 1065 89.4 1216 104.7 15 (7 – 21)

Clinical pneumonia 2172 231.5 2284 248.5 7 (1 – 12)

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.987654321

Vaccinationteam

1 2 3Time since start of programme (years)

Usual EPI vaccinesgiven plus HBV

Usual EPIvaccines given

4 5

Introduction of Hepatitis B vaccine in The Gambia

(Stepped-wedge design)

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.

Protective effect of infant HBV vaccination against HBV chronic carriage at age 15 years

Unvaccinated Fully vaccinated Partially vaccinated

Chronic carriers/ No. examined

51/420 2/492 1/84

Vaccine efficacy (95%CI)

96.6% (91.5-99.9) 90.1% (69.9 – 99.9)

Van de Sande et al, 2007

Thank you