1. No category

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 Reither
Swiss Tropical and Public Health Institute
AIDS 2014 - Melbourne - 21.07.2014
On behalf of the Aurum102/THYB05 team
Background
Urgent need to develop safe and effective TB
vaccines to accelerate progress towards TB
elimination.
Essential to evaluate the safety and immunogenicity of TB vaccines in HIV-infected persons.
Abu Raddad et al, PNAS 2009
Tuberculosis: 8.6 million new active TB cases and
1.3 million TB deaths in 2012 (WHO).
Background
The H1/IC31 vaccine:
recombinant fusion protein Ag85B-ESAT-6
TB vaccine [Hybrid (H1)] , adjuvanted with IC31®
H1/IC31
trials
Phase Ia
n=36
Phase Ib
n=20
Phase Ic
n=39
Phase IIa
n=240
First trial in
HIV-infected
individuals
Phase IIa
n=48
Background
Primary
objective
To evaluate the H1/IC31 TB vaccine in HIVinfected 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
Randomisation
Inclusion criteria (summary)
H1/IC31 vaccine or placebo was randomly
allocated in a 5:1 ratio.

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
evaluation
the
safety
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.
Trial design
Schedule of events (summary)
Study day
Visit number
SCREEN
1
2
0
3
14
54
56
59
70
182
3
4
5
6
7
8
9
10
X
X
X
X
X
X
X
X
X
X
X
X
Vaccination
Safety
Solicited local/systemic AEs
Unsolicited AEs
X
QuantiFERON
X
Haematology, Serum chemistry
X
Urinalysis
X
X
CD4+ count, HIV-1 viral load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity
WBA ICS
Primary immunogenicity endpoint
Consort diagram
Screened (n=167)
Randomised
(n=48)
Excluded (n=119)
- Screening failure (n=109)
- Withdrawn consent (n=1)
- Sleep apnoea, persistent
shortness of breath (n=1)
- Enrolment closed (n=8)
Placebo arm (n=8)
H1/IC31 arm (n=40)
Received 1st vaccination (n=8)
Received 1st vaccination (n=40)
Received 2nd vaccination (n=8)
Received 2nd vaccination (n=39)
Did not receive 2nd vaccination
(n=1), because of pregnancy
Lost to follow-up (2nd vaccination
Lost to follow-up (2nd vaccination
and end of study) (n=0)
and end of study) (n=1)
Safety
analysis (n=8)
Safety
analysis (n=40)
Immunogenicity
analysis (n=4)
Immunogenicity
analysis (n=20)
Samples from
Tembisa Site did not
meet internal quality
control standards
Demographic and baseline characteristics
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)
Safety
Adverse events
Placebo (n=8)
H1/IC31 (n=40)
All grades
Grade ≥3
All grades
Grade ≥3
1
0
62
0
17
0
84
0
Unsolicited AEs
46
0
251
2
Total
64
0
397
2
Solicited
local AEs
pain, tenderness, erythema,
induration, nodules
Solicited
systemic AEs
malaise, myalgia, headache,
nausea, vomiting, athralgia,
fatigue, chills, fever
• 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
Immunogenicity - whole blood intracellular cytokine assay
H1/IC31 vaccination
group (n=20):
IFN-γ, TNF-α, IL-2 and
IL-17 expressing CD4+
T cells after stimulation
with H1
Data not shown
Durable immune
response:
CD4+ T cell
expressing IFN-γ,
IL-2 or TNF-α
Response
independent of
CD4 count or
QFT status.
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
Data not shown
Predominately
IFN-γ/TNF-α/IL-2
or
TNF-α and IL-2
Poor CD8+ T
cells responses.
No humoral
responses.
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
Acknowledgment
Sponsor: SSI
Peter
Andersen
PI: Gavin J
Churchyard
Lynn
Katsoulis
Khadija Said
Elirehema
Mfinanga
Claudia
Daubenberger
Benjamin M
Kagina
Katherine L
Fielding
Nicole Lenz
Elisabeth J
Hughes
Hannah
Jeffery
Christian
Pohl
Willem A
Hanekom
Søren T Hoff
Peter Bang
Trevor
Beattie
Ingrid
Kromann
Nicolene
Gardiner
Thomas J
Scriba
Funded by the European Developing Countries Clinical Trials Partnership (EDCTP)