decades of vaccines vaccine trials: some highs and lows intervention research to improve health in...
TRANSCRIPT
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 TRIALS
Vaccine 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)
.
.
.
.987654321
Vaccinationteam
1 2 3
Time 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