Safety and Immunogenicity of a multigene multiclade HIV-1 ... · 1. Safety and Immunogenicity of a...
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Safety and Immunogenicity of a multigene multiclade HIV-1 DNA plasmid vaccine boosted with
heterologous HIV-1 MVA among healthy volunteers in Dar es Salaam,
Tanzania
Presentation to the 5th EDCTP forum, AICC, Arusha, Tanzania, 12th – 14th October 2009
M Bakari1, F Mhalu1, S Aboud1*, C Nilsson2, J Francis1, M Janabi1, E Lyamuya1*, EA Aris1, J Mbwana1*, D Buma1, L Mwanyika3, B Hejdeman4, A Bråve2, M Robb5, M Marovich5, N Michael5, P Earl6, B Moss6, R Stout7, B
Wahren2, G Biberfeld2, K Pallangyo1, E Sandström4, for the HIVIS study group.1Muhimbili University of Health and Allied Sciences and Muhimbili National Hospital, Departments of Internal Medicine, and 1*Microbiology and Immunology, Dar es Salaam, Tanzania; 2Swedish Institute for Infectious Disease Control (SMI) and Karolinska Institute (KI), Stockholm, Sweden; 3Tanzania Police Force; 4Venhälsan, Karolinska University Hospital, Department of Infectious Diseases, Stockholm, Sweden; 5US Military HIV Research Program, Rockville, MD, 6National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), Bethesda, MD and 7Bioject, Portland, Oregon, USA.
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Objectives
To assess the safety and immunogenicity of a plasmid DNA-MVA prime boost HIV-1 vaccine candidate*
To build expertise and capacity in evaluating HIV vaccine candidates in Tanzania.
*Previously tested in Sweden with excellent results. Sandstrom et al, J Infect Dis 2008 November; 198(10):1482-1490
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ORI
CMV
Kanr
poly A
gene
7 plasmid HIV-1 DNA multigene/multiclade vaccine Inserted
pKCMV
gp160 env B
gp160 env A
gp160 env C
V1 – V5 A
V1 – V5 C
R511SA512M
rev B
p37 gag B
p37 gag A p24 Gag Ap17 Gag B
RTmut B
D185LD186L
Developed by B Wahren, Dept. of virology, SMI, Karolinska InstituteProduced by Vecura
gp120 gp41
LEFT ARM
RIGHT ARM
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MVA* / CMDR boostDeveloped by P Earl and B Moss, Laboratory of Viral Diseases, NIAID, NIHProduced by Walter Reed Army Institute of Research
Deletion IIIDeletion II
MVAgag protease / RTgp150 env
Subtype ECM235
Subtype ACM240
mH5 mH5
*Modified Vaccinia Ankara
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Inclusion Criteria
• Voluntary Informed Consent• Age <40 years• HIV negative by Antigen-Antibody ELISAs• Healthy by clinical and laboratory
assessment
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Study DesignRandomized, Double Blind, Placebo controlledArm Number DNA immunization MVA boost
I 20 DNA 3.8mg IM by Biojector MVA 108 pfu IM
II 20 DNA 1 mg ID by Biojector MVA 108 pfu IM
IIIa 10 Saline IM by Biojector Saline IM
IIIb 10 Saline ID by Biojector Saline IM
HIV-1 DNA/placebo
1 2 3 4 5 6 7 8 90 10month
HIV-1 MVA/placebo
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Injections
Biojector
im
Left arm: Env/rev, 1 inj
Right arm: Gag/RT, 1 inj
id
Left arm: Env/rev, 3 inj
Right arm: Gag/RT, 2 inj
spacer
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Methods• IFN-γ ELISpot Assay
Baseline (visit 3)2 weeks after the last DNA vaccination (visit 9)2 weeks after the MVA boost (visit 12) 2 months after the MVA boost (visit 14); analysis ongoing6 months after the MVA boost (visit 15); analysis ongoing
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Methods• IFN-gamma ELISpot (Mabtech, Nacka,
Sweden) responses measured on freshcells (within 6 hours of collection)stimulated with peptide pools.
• The criteria for positive ELISpotresponses were >55 spots/106 PBMCsand 4 times the medium background andthe baseline value.
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Methods
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Peptide pools used
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Methods
• T-lymphocyte proliferative (TLP) responses to AT-2 inactivated HIV-1 antigen were tested by a standard 3H-thymidine uptake assay
• TLP was reported as stimulation index (SI) and SI above 6 was considered positive based on mean reactivity at baseline in 40 volunteers
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Results, Safety*
• Safety profile has been good to date– Most adverse events were of Grade I
and II severity– There were eleven (11) Grade 3, Severe
Adverse Events, none of which was related to vaccination
*Oral presentation on safety profile
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HIV-specific IFN-γ ELISpotResponses
• 21/38 (55%) vaccinees had a positive IFN-γELISpot response after the third HIV- DNA vaccination.
• 35/35 (100%) had a positive IFN-γ ELISpot response after the HIV-MVA boost.
• All 15 placebo recipients were negative
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Gag
IG
ag II
Gag
WR
Env
IEn
v II
Env
IIIEn
v W
RPo
l WR
1
10
100
1000
Peptide pool
SFC
/mill
ion
PBM
Cs
Gag
IG
ag II
Gag
WR
Env
IEn
v II
Env
IIIEn
v W
RPo
l WR
1
10
100
1000
Peptide pool
SFC
/mill
ion
PBM
Cs
IFN-γ ELISpot reactivity inresponders 2 weeks after 3 x HIV-DNA and
responders 2 weeks after HIV-MVA
2 weeks after 3 x HIV-DNA 2 weeks after 1 x HIV-MVA
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IFN-γ ELISpot reactivity to peptide pools in 35 responders 2 weeks after
HIV-1 MVA boost
• Any Gag 35 (100%) • Any Env 31 (89%)• Gag and Env 31 (89%)• Gag or Env 35 (100%)
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CD8+ and CD4+ T-cell IFN-γ ELISpot reactivity two weeks after HIV-MVA boost
in 13 tested vaccinees*
Responses to Gag
CD8+ CD4+9/13 13/13
Responses to Env
CD8+ CD4+3/11 11/11
* Determined by IFN-γ ELISpot testing before and after CD8 T-cell depletion
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HIV-specific TLP Responses
• 24/52 (46%) individuals had positive TLP responses after the third HIV-DNA/placebo vaccination.Excluding 1/3 placebo 69%
• 35/48 (73%) had positive TLP responses after the HIV-MVA/placebo boost. Excluding 1/3 placebo 100%
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Discussion• In comparison to the completed phase I
HIVIS trial conducted among 38 volunteers in Stockholm, Sweden:– After receipt of the DNA priming vaccine,
11 (30%) of 37 vaccinees had HIV-specific IFN-γ ELISpot responses
– After receipt of the MVA boosting vaccine, 34 (92%) of 37 vaccinees had HIV-specific IFN-γ ELISpot responses
– 35 (92%) of 38 had a positive LPA response
• Immunogenicity relatively higher in HIVIS03
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Conclusions• The high immunogenicity of
HIVIS03 DNA-MVA vaccine is consistent with the previous phase I study in Sweden
• Capacity built through HIVIS03 paved the way for EDCTP-funded TaMoVaC01 Project aimed at optimizing DNA vaccine delivery
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Acknowledgements• Police volunteers• EU and Sida• Swedish Embassy, Tanzania• WHO and AAVP• EDCTP• Investigators, collaborators and support staff
in:–Tanzania; at MUHAS, MNH, Tanzania Police Force–Sweden; at Karolinska Institute, Swedish Institute for Infectious Disease Control, Southern Hospital–United States of America; at WRAIR and LVD/NIH
• Tanzania Government, in particular the MoH & SW through NACP