Preparing for tuberculosis vaccine
efficacy trials: baseline epidemiology,
improved diagnosis, markers of
protection and phase I/II trials
(Tb Trials: 2008-2012)
Global Health and vaccination program: RCN 179342
Tb Trials: 2008-2012
• Epidemiologic Studies to Prepare for
TB Vaccine Trials
• Correlates of immunity to TB
• Genotyping of mycobacterial infection
• Clinical novel TB vaccine phase 1 trials
• Contribute to bilateral (multi) capacity
Parameter
Data
Total
Population
~450,000 (~800 villages / 3
towns)
Public Health
services
13 Primary Health Centres
2 sub district hospitals
CAPACITY BUILDING FOR TB TRIALS
Personnel
TRAINING
200 field staff
7 students
Immumology Lab
TB lab
Ancillary Lab
Biorepository
1000 community
facilitators
QC / QA
Audits
Data Management
GIS mapping
Clinical Ward
Clinical Diagnostics
EPIDEMIOLOGICAL STUDIES
• Infant cohort
• Adolescent cohort
•Household Contact Study
TB Vaccine
Trials
SSI/GSK: Denmark
PI – Norway
(Univ of Bergen)
PI – India
Univ of Oslo
Aeras Global TB Vaccine Foundation
SUN-south Africa
Admin Staff
LUMC, Netherlands
Admin. Manager
Op-Manager
Co-Inv
(lab)
QA Manager
& QA team
CRM
Local Admin
Staff
Ancillary
e.g. drivers
PDP Manager
Data manager
Syst.
Admin
IPHCR Lab
Manager
MO
Study
Coordinators
HQ Field Supv.
Lab Manager
Nursing Coordinator
Sen. Lab Supv.
Staff Nurses
Clerical
Assistant
Sen. Lab tech
Field Supv.
Nursing assistants
Jun Lab Tech
Ward Orderlies
Outreach workers
CRM = Clinical Research Manager
Op-Manager = Operations Manager
PDP = Professional Development Programme
Epidemiologic Studies to Prepare for
TB Vaccine Trials
• A prospective cohort study of 6435 adolescents
to measure the incidence of MTB infection and
TB disease among 12-18 year olds
• A prospective cohort study of 4,382 newborns to
measure the incidence of MTB infection and TB
disease among infants
• A prospective household contact study of 200
households to measure the incidence of MTB
infection and TB disease in a highly-exposed
population
Neonatal cohort study
4382
recruited at birth
Active
Surveillance
Passive
Surveillance
• Accurate incidence of TB in this
target age group is the primary
objective of the study to allow for
the design of future vaccine trials
• Status completed
Case verification wrd
Self referral
Diagnostic work up
2 year follow-up
Age distribution of tuberculosis in India
WHO-Country profile - SEARO
Neonatal cohort study
Diagnosis of childhood TB remains a challenge
Tuberculin skin test (TST) is widely used in the diagnosis of TB infection.
Validity of interferon gamma release assays have been examined in adults
Children with failure to thrive: reduced odds of being
TST positive (OR 0.14 [95% CI 0.07; 0.26], p= <0.01; QFT
positivity was unaffected.
(J Nelson, D Mahelai et al and the TB Trials Study group 41st UNION conference; Berlin 2010)
• Genotyping of mycobacterial isolates
• Biomarker discovery: ongoing
A Phase I Study in India of a Recombinant Adenovirus-35 Vectored
Vaccine
(AERAS-402) to Prevent Tuberculosis
(R Walker, HMS Grewal, J Kenneth, TM Doherty, M Douoguih, M Vaz,
and the TB Trials Study Group)
Clinical Trial of TB Vaccine Candidate Starts in
India
Phase I trial of AERAS-402/Crucell Ad35 in
Bangalore
This trial, conducted by the TB trials study group represents the first trial
of a novel recomombinant new TB vaccine in the Asian subcontinent.
(Initiated March 2011. Status: completed)
Adolescent cohort study
6435
12 to 18 years
Active
Surveillance
Passive
Surveillance
Home visits 1/3 mo
Blood draw 1/6 mo
TST 1/12 mo
Self referral
Diagnostic work up
2 year follow-up
• Accurate incidence of TB in this
target age group is the primary
objective of the study to allow for
the design of future vaccine trials
• Status completed
Household Contact Study
200 new S+
index cases
Household
members
1 Year Follow –up
Serial clinical assessment
Blood sampling
Incident TB infection and
disease
• Study: ongoing (will be completed
in September 2012)
The knowledge gap: issues raised during TB
education programmes at the vaccine trial site
Community
School
Parents
Total
No of education programmes
140
30
25
195
Queries related to the proposed
Research Study
28
12
18
58
Extent of the TB problem
2
0
0
2
Causes of TB
23
0
0
23
Symptoms of TB
30
5
0
35
Spread of TB
38
8
1
47
Treatment of TB
16
6
5
27
Outcomes of TB
9
2
0
11
Diagnosis of TB
4
0
0
4
TB/HIV co-infection
1
0
0
1
General Health questions
0
6
0
6
Others
4
1
0
5
The education gap: Preparing field staff for future
vaccine trials
LONG-TERM
RETENTION OF
KNOWLEDGE
Level 1 (6 MONTHS)
Level
2
Clinical Staff
Laboratory
Staff
Field Staff
Post graduate
Or higher
Clinical
Infectious Disease
(CID)
Category of Staff*
College
Degree
Field Staff
Clinical Research Practice
(CRP) Clinical Staff
Higher
secondary or
postgraduate
Diploma
Lab Staff
Total Number of
Total
Difference between infectious and non infectious
assessments
disease, Types of microbes, Types of transmission,
Defenses against infection
156
Explain GCP, GLP, Types of Clinical Research,
Define protocol, Protection
of human volunteers,
49
Rules for informed consent
22
Others
passed
Routes of transmission for TB, HIV, Malaria, disease
cycles, Active and PassivePercentage
immunity, Need for new
Tb vaccines, Public health measures to control HIV,
TB and Malaria
129
48
22
83
Basic guidelines of GCP, GCP related to QA, QC,
adverse event reporting, time, specimen
and
98
document management, Role of Community
100Trials
Advisory Boards, Phases of clinical
Others
Clinical Research
Organization and
Type
of Module
High
School
Management
(CROM)
32research, Clinical Research and25 Research budget, Trial implementation
78 process,
Life cycle of clinical
other research, Clinical Research team: roles and
Regulatory processes, Management systems, Study
responsibilities
close out
EpidemiologyCID-1
and Biostatistics
67Basic terms, Differentiate 65 Sources of bias, active and passive
97surveillance,
Define epidemiology,
between types of studies, Advantages of a
Sample size, Goals of an epidemiological study
59
55
93
randomized controlled Width
trial reflects number of people
or below
CRP-1
CROM-1
Good Laboratory
Practice
(GLP)
E&B-1
Define GLP, Areas 50
of clinical research governed by 40
GLP, Responsibilities related to GLP, Define SOP,
47
41
Purpose of QA and QC
80
87
CID-2
23
17
74
CRP-2
13
6
46
Evaluating ethical issues at the vaccine trial site in
a poorly educated, largely rural community
Improving vital event registration: an exploratory
intervention at the vaccine trial site
100
90
80
70
60
Pre
Post
50
40
30
20
10
0
Birth registration
Death registration
TB Trials study group
Norway : University of Bergen (PI: HMS Grewal), Bernt lindtjørn
University of Oslo (Frode Jahnsen)
Denmark: Statens serum Institute/GSK: Mark Doherty (Co-PI)
India: St John’s Research Institute, Bangalore (PI: Mario Vaz, John
Kenneth, Anura Kurpad)
USA: : Aeras Global TB Vaccine Foundation (Robert Walker, Tom
Evans)
South Africa: Stellenbosch University (Anneke Hesseling, Gerhard
Walzl)
Netherlands: LUMC, Leiden (Marielle Haks and Tom Ottenhoff)