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Phase 2b placebo-controlled trial of M72/AS01E
candidate vaccine to prevent active tuberculosis
in adults
Olivier Van Der Meeren, MD,* Mark Hatherill, MD, FCPaed,* Videlis Nduba, MBChB, MPH, Robert J
Wilkinson, F Med Sci, Monde Muyoyeta, MBChB, PhD, Elana Van Brakel, MBChB, MSc, Helen M Ayles,
MBBS, PhD, German Henostroza, MD,§ Friedrich Thienemann, MD, Thomas J. Scriba, PhD, Andreas
Diacon, MD, PhD, Gretta L. Blatner, MS, MPH, Marie-Ange Demoitié, MSc, Michele Tameris, MBChB,
Mookho Malahleha, MD, MPH, James C. Innes, MBChB, MSc, Elizabeth Hellstrom, MBChB, MPhil, Neil
Martinson, MBChB, MPH, Tina Singh, MD, Elaine Jacqueline Akite, MSc, Aisha Khatoon, MBBS, Anne
Bollaerts, MSc, Ann M. Ginsberg, MD, PhD, Thomas G. Evans, MD,† Paul Gillard, MD,** and Dereck R.
Tait, MBChB, FRCPath**al
N Engl J Med. 2018 Sep 25
Hintergrund
Mycobacterium tuberculosis
• Leading infectious cause of death worldwide
• 2017: 10.000.000 fell ill, 1.600.000 died; estimated 558.000 MDR
• WHO aim: Reduce deaths by 95%, reduce new cases by 90%
until 2035
• Only licensed TB vaccine: BCG (bacille Calmette-Guérin)
Study
• M72/AS01E: recombinant fusion protein (Mtb32A + Mtb39A) +
Adjuvant (System AS01 Mosquirix, Shingrix)
• Prevention of acive pulmonary TB in HIV-negative adults with
latent TB (pos. IGRA)
• GlaxoSmithKline Biologicals
Study design / Methods
Multi-center, double-blind, randomized (1:1), placebo-controlled
• Kenya, South Africa, Zambia – 11 study sites
Follow up: for 3a
• Pre-specified primary analysis after 2 years
• Final analysis after 3 years planned.
Study design – Inclusion / Exclusion
Inclusion:
• Adults (18-50a), non-pregnant; pos. QFT
• Healthy/stable med. cond., HIV-neg.
• No TB-symptoms,, neg. sputum PCR (GeneXpert)
Vaccination:
• 2 doses of M72/AS01E or placebo deltoid, 1 month apart
Exclusion:
• >14d immunosuppressants/immune-modifying drugs within last 6 months (z.B.
≥20mg Prednison/d)
• Immunodeficient disorder; autoimmune disease
• Administration of Ig / Blood products within 3 months
Efficacy endpoints
Primary objective (primary endpoint)
• Vaccine efficacy* to prevent active pulmonary TB (case def. 1)
Secondary objectives (secondary endpoints)
• VE (additional case definitions: 2-5)
• Immunogenicity + safety of the vaccine.
• Immunogenicity (CMI response, humorale immune response
assessed in subgroup (300 Patients)
*VE = Vaccine efficiacy
Case definitions
Evaluation for TB
TB Surveillance
• Active (visits, calls, text) + passive (self reporting)
• Suspicion : 3x sputum over 1 week; PCR + culture (Case def. 3-5: up
to 4 weeks after start treatment)
• Diagnostic/treatment decisions by non-study physicians
• HIV-retest and screening for diabetes in all confirmed TB-cases
Evaluation for safety / Immunogenicity
Evaluation of safety
Whole cohort:
• Serious adverse events, potential immune-mediated diseases: recorded until
6 months after 2. dose
Related to study product: until end of study
• Unsolicited AE: until 30d after each dose
Sub-cohort (N=299)
• Solicited AE until 7d after each dose.
• Laboratory (Chem./hemat.): days 0, 7, 30, 37
Evaluation of immunogenicity of the subgroup
• Anti-M72IgG (ELISA) before dose 1 + 1 month post dose 2 + annually until
year 3
• M72-specific CD4+/CD8+ T-cells
Screening and Randomization 1/2
1/3/2019 Präsentationstitel in der Fusszeile des Folienmasters definieren10
Results – Primary analysis (after mean follow up 2.3y) - According-
to-protocol analysis (Start 30d after 2. dose)
N = 1623 N = 1660
N = 1785 N = 1783
Kaplan–Meier Estimate of Definite Pulmonary Tuberculosis (First Case
Definition) – According-to-protocol efficacy cohort
Vaccine Efficacy (Case Definition 1: Covariate)
Solicited:
(most frequently)
M72/ASO1E N=148 Placebo N = 151
Pain (81%) (34.4%)
Fatigue/malaise/
myalgia
(58.1-68.9%) (26.5-47%)
Fever (>38°C)
Fever (>39.5°C)
(18.9%)
(4.1%)
(6.6%)
(1.3%)
Immunogenicity: 100% seroconversion at month 2,
99% at month 12)
Discussion
Significant lower incidence of pulmonary Tb in M.
tuberculosis infected ,HIV-neg., healthy BCG-vacc. adults
Limitations:
• Possible active Tb while inclusion
• Only open pulmonary Tb for primary case definition
Differences in age and gender?
• Hypothesis : Less recent infection / infection under control
• Not enough power to detect differences between
subgroups
Vielen Dank für die Aufmerksamkeit!
Präsentationstitel in der Fusszeile des Folienmasters definieren