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.

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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.

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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