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The HVTN Experience with Modified Vaccinia Ankara

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Title: The HVTN Experience with Modified Vaccinia Ankara


1
The HVTN Experience with Modified Vaccinia Ankara
  • Marnie L. Elizaga, MD
  • Senior Clinical Trials Physician
  • HVTN Core Operations Center
  • Fred Hutchinson Cancer Research Center

2
Poxviridae, subfamily Chordopoxvirinae
Refs MicrobiologyBytes.com. Sharon Frey and Bob
Belshe, NEJM, 350324-327, 2004. EM photo CDC,
Cynthia Goldsmith, 2002.
Members of subfamily Entomopoxvirinae infect
arthropods.
3
MVA background
  • Modified Vaccinia Ankara is a highly attenuated
    vaccinia
  • Serial passages of smallpox vaccine from Ankara,
    Turkey (chorioallantois vaccinia Ankara) in chick
    embryo fibroblasts resulted in loss around 10 of
    vaccinia genome
  • MVA used as smallpox vaccine in Germany in over
    100,000 people
  • Host-range restricted, and cannot replicate in
    humans due to multiple genomic deletions
  • Can be grown using cell culture (chick embryo
    fibroblasts)
  • As with other poxviruses, MVA has the capacity to
    accommodate and express a large amount of foreign
    DNA
  • Investigational vaccine vector for multiple
    applications other than smallpox HIV, malaria,
    tuberculosis, SARS, other infections, and
    immunotherapy for melanoma and colorectal cancer
  • A safe vaccine for use even in immunosuppressed
    persons investigational MVA vectors have been
    given to people with HIV infection

4
HVTN Phase I trials
  • HVTN 055 (Therion Biologics)
  • Fowlpox HIV vaccine (FPV) alone, 109 pfu
  • MVA HIV vaccine alone, 109 pfu
  • MVA in escalating doses of 107, 108, 109 pfu as a
    prime for FPV
  • HVTN 065 (GeoVax)
  • DNA prime, MVA boost, two dose levels, 107 TCID50
    and 108 TCID50
  • Part B three dose regimens D-M-M or M-M-M
  • HVTN 067 (Pharmexa-Epimmune and Bavarian Nordic)
  • DNA prime, MVA boost 108 TCID50

5
HVTN 055 Therion Fowlpox and MVA
Fowlpox and MVA (two vectors each) clade B Env,
Gag Tat, Rev, Nef, Pol, from vertically
transmitted isolate. 1095x108 pfu Env, Gag
vector 5x108 pfu Tat, Rev, Nef, Pol vector
6
HVTN 065 Geovax DNA and MVA
DNA clade B Gag, PR, RT, Env, Tat, Rev, Vpu MVA
clade B Gag, Pol, Env
7
Compare / contrast protocol features
  • All participants were vaccinia-naive (40)
  • All screened for history of cardiac problems,
    cardiac risk factors, and had screening ECG
  • Standard HVTN criteria
  • MVAs from different MVA passages and
    manufacturers
  • Different insertsgenes, HIV sequences,
    polyepitopes (067)

8
Immunogenicity testing
  • ELISpot analysis performed for HVTN 055 at Duke
    (using consensus peptides) and in Seattle (using
    global PTE peptides) at different timepoints.
    ELISpot for HVTN 065 only performed for a small
    low dose group.
  • 8-color Intracellular Cytokine Staining (ICS) was
    performed in the HVTN laboratory in Seattle
  • Assessed at one or more time points after
    vaccination
  • Pools of global Potential T Cell Epitope (PTE)
    peptides used for in vitro stimulation (6 hours
    for ICS, overnight for ELISpot). PTE peptides are
    not matched to the vaccine inserts.
  • These studies have not been designed to compare
    responses across trials.

9
ICS CD8 response rates at a glance(to any
antigen)
10
MVA trend for CD4 CD8 responses(ICS assay)
11
HVTN 055 IFN-? ELISpot Responses to any Env
Peptides
2 weeks post VAC4, FHCRC Lab
0/31
9/26
4/28
0/26
IFN-? SFC/106 PBMC
Placebo
FP
MVA at 109
MVA at 109 FP
12
HVTN 055 IFN-? ELISpot Responses to any Gag
Peptides
2 weeks post VAC4, FHCRC Lab
0/22
2/31
15/26
11/28
IFN-? SFC/106 PBMC
Placebo
FP
MVA at 109
MVA at 109 FP
13
HVTN 055 ICS magnitude of responses to Env
CD8 T cells, 2 weeks post VAC4
0/22
1/31
8/28
4/28
T Cells Producing IFN-? or IL-2
Placebo
FP
MVA at 109
MVA at 109 FP
14
HVTN 055 ICS magnitude of responses to Gag
CD8 T cells, 2 weeks post VAC4
7/28
0/22
0/31
1/28
T Cells Producing IFN-? or IL-2
Placebo
FP
MVA at 109
MVA at 109 FP
15
HVTN 065 HIV specific CD8 preserved 15 weeks
since last vaccination
CD8 T cells, Treatment 3mg DNA 1.108 MVA
0.8
0.4
0.2
T Cells Producing IFN-? or IL-2
0.1
0.05
0.025
Placebo or Day 0
2 weeks post- vac3
2 weeks post- vac4
15 weeks post- vac4
2 weeks post- vac3
2 weeks post- vac4
15 weeks post- vac4
2 weeks post- vac3
2 weeks post- vac4
15 weeks post- vac4
16
HVTN 065 CD8 Response rates maintained 15 weeks
after vaccination
Geovax DNA and MVA
17
IFN? ELISpot in 055 shows trend towards gag
env responses
18
Gagenv not seen in ICS CD8 except for DNA/MVA
HVTN 065
19
MVA alone has strong Env antibody responses while
MVA/FP shows the opposite trend
20
055 ELISA PS-gp120 after 3rd vaccine
0/173
1/9
0/28
20/30
5/30
Background subtracted OD
MVA at 109
MVA at 109 FP
Placebo or Day 0
FP
Positive response
Negative response
21
055 ELISA Mp24 after 3rd vaccine
11/30
6/30
8/173
1/9
1/9
4/28
Background subtracted OD
MVA at 109 FP
Placebo or Day 0
FP
MVA at 109
Positive response
Negative response
22
065 ELISA P55 Alpha after 4th vaccine
23
HVTN 055 ICS Polyfunctionality of all positive
responses for any antigens (Env, Gag, Pol, Nef)
CD8 T Cells
3
3
3
3
3
1
1
1
1
1
2 weeks post-vac 3
2
2
2
2
2
n1
n2
n4
n10
n4
3
3
3
3
3
1
1
1
1
1
2 weeks post-vac 4
2
2
2
2
2
n1
n5
n6
n19
n7
FP
MVA at 109
MVA at 107 FP
MVA at 108 FP
MVA at 109 FP
n Number of positive responses
Data as of 5/13/08
24
HVTN 065 Polyfunctionality of CD8 T cells in
vaccinee positive responders (any pool)
Any Gag
Any Env
Any Pol
3mg 1.108
3mg 1.108
3mg 1.108
0.3mg 1.107
0.3mg 1.107
2 weeks post Vac3 (4/25)
2 weeks post Vac4 (11/26)
15 weeks post Vac4 (6/19)
25
055 Neutralizing Antibody Assay Day 98 Isolate MN
1/33
1/32
1/33
0/24
0/9
2/9
1/33
Antibody Titer
Placebo
FP
MVA at 109
MVA at 109 FP
Positive response
Negative response
26
HVTN 055 End of study testing for
vaccine-induced positive HIV tests
  • Abbott kit positive at the end of study visit
    for
  • 33-62 of participants in MVAFPV arms
  • 86 of participants in the MVA alone arm
  • 3 of FPV alone participants

27
Cardiac Safety
  • Well tolerated with no myo/pericarditis detected
    in healthy volunteer trials (around 230 MVA
    recipients)
  • Healthy participants during the protocol may turn
    up with
  • Unreported preexisting arrhythmias such as SVT
  • QT prolongation due to concomitant medication
  • Minimal troponin increases (due to endurance
    sports)
  • All of which necessitate spending time and money
    to rule out actual cardiac adverse events.

28
MVAing along with Future TrialsHVTN 073 Schema
SAAVI DNA-C2 clade C Gag, RT, Tat, Nef clade C
gp150CT SAAVI MVA-C clade C Gag, RT, Tat, Nef,
gp150CT DNA and MVA by the University of Cape
Town for SAAVI, Medical Research Council, South
Africa. Immunogenicity assays will be done in
South Africa.
29
HVTN 205 Schema (Fall, 2008)
Geovax JS7 DNA clade B Gag, PR, RT, Env, Tat,
Rev, Vpu Geovax MVA clade B Gag, Pol, Env
30
Proposed JS2/MVA Schema (2009)
Geovax JS2 DNA clade B Gag, PR, RT, Env, Tat,
Rev, Vpu Geovax MVA clade B Gag, Pol, Env
31
Summary
  • MVAs produce multifunctional CD4 and CD8
    responses
  • Responses persist at least 3 months after
    vaccination
  • Differences in responses rates and responses to
    different HIV-1 proteins may be due to
    differences in vector insert design
  • MVAs potential should be explored with other
    products in heterologous prime-boost regimens
  • Develop vector immunity assays to supplement
    understanding of vaccine-induced responses
  • Evaluate breadth and phenotype of responses
  • So far MVAs are not an answer to the neutralizing
    antibody problem but do elicit binding antibody
    and lead to frequent vaccine-induced
    seropositivity.
  • Safe and overall well tolerated with no
    myo/pericarditis to date

32
Teamwork
  • Study participants and Unit PIs, Staff
  • SeattleJulie McElrath, 055
  • Saint LouisSharon Frey, 055, 065
  • BaltimoreBill Blattner, 065
  • RochesterMike Keefer, 055, 065
  • NashvilleSpyros Kalams, 055, 065
  • BirminghamPaul Goepfert, 055, 065
  • BostonLindsey Baden, 065
  • Rio de JaneiroMauro Schechter, Paulo Barroso,
    055
  • Sao PauloArtur Kalichman, 055
  • Protocol Leadership
  • 055 Mike Keefer, Sharon Frey, Massimo Cardinali,
    Barb Metch, Nina Russell
  • 065 Paul Goepfert, Mhorag Hay, Massimo
    Cardinali, Li Qin
  • Study Support, Data and Safety
  • SCHARP Gina Escamilla, Huguette Redinger, Diana
    Lynn, Ya-Lin Chiu, Alicia Sato, Allan deCamp,
    Donna Robinett, Molly Swenson
  • St. Louis ECG Core Laboratory Bernard Chaitman,
    Bandula Guruge, Karen Stocke
  • Laboratory Program
  • Duke Kent Weinhold, Guido Ferrari, David
    Montefiori, Georgia Tomaras
  • FHCRC Cristine Cooper, Stephen De Rosa, Don
    Carter, Susan Zimmermann, John Hural, Olivier
    DeFawe, Julie McElrath
  • Sponsor
  • DAIDS Michael Pensiero, Chris Butler, Alan Fix,
    Jorge Flores, Patricia DeSousa, Mary Anne Luzar,
    Michelle Conan-Cibotti, Scharla Estep
  • HVTN Core
  • Larry Corey, Ann Duerr, Larry Smith, Renee Holt,
    Carter Bentley
  • Developers
  • Geovax, Inc. (Atlanta, GA) Harriet Robinson, Don
    Hildebrand, Bernard Moss at NIAID
  • Therion Biologics, Inc. Dennis Panicali, Valerie
    Philipon, Mary Lou Horzempa, Gail Mazzara
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