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Safety and immunogenicity of H1/IC31 ® , an adjuvanted TB subunit vaccine , in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm 3 : a phase II, multi-centre , double-blind , randomized , placebo-controlled trial. Dr. Klaus Reither - PowerPoint PPT Presentation
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Safety and immunogenicity of H1/IC31®, an adjuvanted TB
subunit vaccine, in HIV-infected adults with CD4+ lymphocyte
counts greater than 350 cells/mm3: a phase II, multi-centre,
double-blind, randomized, placebo-controlled trial
Dr. Klaus ReitherSwiss Tropical and Public Health Institute
AIDS 2014 - Melbourne - 21.07.2014On behalf of the Aurum102/THYB05 team
Background
Tuberculosis: 8.6 million new active TB cases and 1.3 million TB deaths in 2012 (WHO).
Urgent need to develop safe and effective TB vaccines to accelerate progress towards TB elimination.
Essential to evaluate the safety and immuno-genicity of TB vaccines in HIV-infected persons.
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Background
The H1/IC31 vaccine:
recombinant fusion protein Ag85B-ESAT-6
TB vaccine [Hybrid (H1)] , adjuvanted with IC31®
H1/IC31trialsPhase Ian=36
Phase Ibn=20
Phase Icn=39
Phase IIa n=240
First trial in HIV-infectedindividuals
Phase IIan=48
Background
Primary objective
To evaluate the H1/IC31 TB vaccine in HIV-infected adults for: Safety Induction of cellular and humoral immunity
Secondary objective
To describe the effect of the H1/IC31 TB vaccine in HIV-infected adults on: CD4+ lymphocyte counts HIV viral loads
Trial sites
Ifakara Health Institute: Bagamoyo, TZ
Aurum Institute: Tembisa, SA
Trial design
Inclusion criteria (summary)
Healthy (no evidence of active TB)
18 - 55 years of age
HIV infection CD4 > 350/mm3
Naïve to antiretroviral therapy
Women of child bearing potential
must not be pregnant and agree to
avoid pregnancy
No medical history on conditions
that compromise the safety
evaluation
Randomisation
H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio.
Blinding
The investigators, study monitors and participants were blinded.
The study pharmacists prepared the investigational product.
Syringes were masked in order to conceal a slight difference in the appearance of the H1/IC31 and placebo.
Primary immunogenicity endpoint
Trial design
Study day SCREEN 0 3 14 54 56 59 70 182
Visit number 1 2 3 4 5 6 7 8 9 10
Vaccination
Safety
Solicited local/systemic AEs X X X X X X
Unsolicited AEs X X X X X X X X X
QuantiFERON X X
Haematology, Serum chemistry X X X X X
Urinalysis X X X X X X X X X
CD4+ count, HIV-1 viral load X X X X X X X
Immunogenicity
WBA ICS X X X X X
Schedule of events (summary)
Excluded (n=119) - Screening failure (n=109)- Withdrawn consent (n=1)- Sleep apnoea, persistent shortness of breath (n=1)- Enrolment closed (n=8)
Randomised (n=48)
H1/IC31 arm (n=40)Received 1st vaccination (n=40)
Placebo arm (n=8)Received 1st vaccination (n=8)
Received 2nd vaccination (n=39)
Did not receive 2nd vaccination
(n=1), because of pregnancy
Received 2nd vaccination (n=8)
Lost to follow-up (2nd vaccination
and end of study) (n=1)
Lost to follow-up (2nd vaccination
and end of study) (n=0)
Safety analysis (n=8)
Screened (n=167)
Immunogenicityanalysis (n=4)
Immunogenicityanalysis (n=20)
Consort diagram
Safety analysis (n=40) Samples from
Tembisa Site did not meet internal quality control standards
Variable Placebo (n=8) H1/IC31 (n=40)
Age Mean (SD) 34 (11.0) 35.6 (8.0)
Gender Female n (%) 6 (75.0) 21 (52.5)
Ethnic group Black n (%) 8 (100) 40 (100)
Body Mass Index Mean (SD) 23.5 (4.2) 26.4 (7.4)
BCG vaccination (self-report) Yes n (%) 6 (75.0) 33 (82.5)
CD4 (cells/uL) Mean (SD) 590.1 (155.5) 652.9 (258.4)
Viral load (cp/mL) Median (IQR) 17887 (544, 43297) 16968 (2228, 52547)
Demographic and baseline characteristics
Safety
Adverse events Placebo (n=8) H1/IC31 (n=40)
All grades Grade ≥3 All grades Grade ≥3
Solicited local AEs
pain, tenderness, erythema, induration, nodules 1 0 62 0
Solicited systemic AEs
malaise, myalgia, headache, nausea, vomiting, athralgia, fatigue, chills, fever
17 0 84 0
Unsolicited AEs 46 0 251 2
Total 64 0 397 2
• Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p=0.015)
• 3 serious adverse events (malaria, perianal abscess and pregnancy with death of premature child): not related to the investigational product
• No effect on CD4+ T cell count and HIV viral load
H1/IC31 vaccination group (n=20): IFN-γ, TNF-α, IL-2 and IL-17 expressing CD4+ T cells after stimulation with H1
Durable immuneresponse:CD4+ T cell expressing IFN-γ, IL-2 or TNF-α
Response independent of CD4 count or QFT status.
Dat
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wn
Immunogenicity - whole blood intracellular cytokine assay
H1/IC31 vaccination group (n=20): H1 specific CD4+ T cells expressing any combination of IFN-, TNF- and IL-2
PredominatelyIFN-γ/TNF-α/IL-2or TNF-α and IL-2
Poor CD8+ T cells responses. No humoral responses.
Dat
a no
t sho
wn
Immunogenicity - whole blood intracellular cytokine assay
Conclusions
Safety
H1/IC31 was well tolerated and safe in HIV-infected adults, with CD4+ lymphocyte counts greater than 350 cells/mm3, from TB endemic areas. Similar to safety profiles of previous trials in HIV-uninfected TB-uninfected, BCG vaccinated or latently TB-infected participants.
Immunogenicity
H1/IC31 induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells and polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells.
Future clinical TB vaccine development
Multistage vaccine H56/IC31 will continue in clinical development,might prevent acute TB disease as well as re-activation of LTBI.H1/IC31 data has been and will be used as supportive data. Aagaard C et al., Nat Med. 2011
PI: Gavin J Churchyard
Lynn Katsoulis
Trevor Beattie
Nicolene Gardiner
Sponsor: SSI
Peter Andersen
Søren T Hoff
Peter Bang
Ingrid Kromann
Khadija Said
Elirehema Mfinanga
Claudia Dauben-berger
Nicole Lenz
Christian Pohl
Benjamin M Kagina
Elisabeth J Hughes
Willem A Hanekom
Thomas J Scriba
Katherine L Fielding
Hannah Jeffery
Funded by the European Developing Countries Clinical Trials Partnership (EDCTP)
Acknowledgment