Title: The HVTN Experience with Modified Vaccinia Ankara
1The HVTN Experience with Modified Vaccinia Ankara
- Marnie L. Elizaga, MD
- Senior Clinical Trials Physician
- HVTN Core Operations Center
- Fred Hutchinson Cancer Research Center
2Poxviridae, 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.
3MVA 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
4HVTN 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
5HVTN 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
6HVTN 065 Geovax DNA and MVA
DNA clade B Gag, PR, RT, Env, Tat, Rev, Vpu MVA
clade B Gag, Pol, Env
7Compare / 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)
8Immunogenicity 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.
9ICS CD8 response rates at a glance(to any
antigen)
10MVA trend for CD4 CD8 responses(ICS assay)
11HVTN 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
12HVTN 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
13HVTN 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
14HVTN 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
15HVTN 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
16HVTN 065 CD8 Response rates maintained 15 weeks
after vaccination
Geovax DNA and MVA
17IFN? ELISpot in 055 shows trend towards gag
env responses
18Gagenv not seen in ICS CD8 except for DNA/MVA
HVTN 065
19MVA alone has strong Env antibody responses while
MVA/FP shows the opposite trend
20055 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
21055 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
22065 ELISA P55 Alpha after 4th vaccine
23HVTN 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
24HVTN 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)
25055 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
26HVTN 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
27Cardiac 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.
28MVAing 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.
29HVTN 205 Schema (Fall, 2008)
Geovax JS7 DNA clade B Gag, PR, RT, Env, Tat,
Rev, Vpu Geovax MVA clade B Gag, Pol, Env
30Proposed JS2/MVA Schema (2009)
Geovax JS2 DNA clade B Gag, PR, RT, Env, Tat,
Rev, Vpu Geovax MVA clade B Gag, Pol, Env
31Summary
- 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
32Teamwork
- 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