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Thoughts about Development of HIV and
HCV Gene-Based Vaccines
• Britta Wahren• Karolinska Institutet
• St Petersburg April 2012
DNA vaccines, and electroporation
Licenced, no electroportion• West Nile virus for horses• Hematopoietic necrosis (rhabdovirus) for salmon• Melanoma (tyrosine kinase) for dogs, humans?• Growth factor pigs (gene therapy)
Clinical small trials, electroporation• HCV for chronic disease, Sällberg et al SE• Prostate heterologous antigen Pisa et al at SE• CEA heterologous and homologous antigen for gi cancer
Mellstedt et al SE• HIV for healthy individuals, Ho et al US and CH• HIV for healthy individuals, Wahren et al SE
CC
BB
EE
BBCC
BB
BB
BB AA
BBAA
AA
DD
OtherOther
BB AA
OtherOther
AA
BB
CC
Others 5%(F, G, H, J, NT)
DD5.3%
CC
47.2%
E E 3.2%
B B 12.3%
AA 27%
Geographical distribution of 35 million HIV-1
genetic subtypes UNAIDS 2005-2012
HIV vaccines for humans Vaxgen phase III
Sanofi-Thailand
Gp160 protein B
Alvac boost B
HIV proph
HIV proph
Immunogenic,
No protection
Moderate
NIH, VRC I DNA ABC high dose and adeno
HIV proph High response
similar to HIVIS
Merck I, II
Phambili
Adenovector, clade B
HIV proph Over 70% resp
No protection
Geovax DNA B followed by poxvirus B
HIV proph Protection in macaques
Eurovacc DNA+Nyvac C HIV proph High env response
KI/SMI-HIVIS DNA ABC high dose, MVA boosts
A, B, C, (D), E
HIV proph High (100%) broad immunogenicity
Concepts for HIVIS vaccine
Containing DNA genes and a vaccinia virus vectorWhole genes to cover polymorphic MHC in humansAll genes to cover structural and regulatory genesSeveral subtypes to cover virus variability and polymorphic MHC in humans
Small total vector sizeEffective delivery, divided delivery
General: whole genes representing several proteinsFor antibody surface antigens, for cmi interior, less variable antigens (genes, VLP, proteins, vectorized genes)
Vaccine DNA clinical studies …-2005-2012
Prophylactic vaccinationPhase 1 SE done HIVIS-EU, SIDA, KI, WR Phase 1 TZ done, HIVIS-EU, SIDA, WR Phase 2a TZ and Mocambique TaMoVac 1, SIDA, EDCTP and Gates Phase 2a TC and MC with EDCTP TaMoVac 2 (electroporation)Phase 1 SE, electroporation-Cellectis, id-ZetajetPhase 1 SE 3rd gen. DNA-MVA-protein gp140
Therapeutic vaccinationPhase 1 mab antibody repeatedly SEPhase 3 high dose anti-HIV at birth, UgandaPhases 1/pilot studies, early antigens nef, rev, tat SEPhase 1 therapeutic SE AVIP, Dermavir Phase 1 therapeutic in children, IT
A clade B clade C clade D clade E clade
HIV genetic vaccine
gag
RT
R
The HIVIS plasmids. Subtypes
p37 gag B
p37 gag A gp160 env A
gp160 env B
gp160 env C
rev B
RTmut B
Gp41, gp120 additional subtypes
Traps
• Too little protein for antibody
• Delivery not optimal (intracellular)
• Too few immunizations
• Autoimmunity, carcinogenesis
• Failed innate activation
• Incorrect or not optimal cytokines
• Must be delivered with drugs???
Injections
Biojector
im
Left arm: Env/rev, 1 inj +/- GMCSF im
Right arm: Gag/RT, 1 inj
id
Left arm: Env/rev, 3 inj +/- GMCSF sc (needle)
Right arm: Gag/RT, 2 inj
spacer
HIVIS – The Biojector
Does needle free intradermal delivery of vaccine plasmids induce potent responses against vaccine antigens?
In vivo electroporation
Total length of pulse-train: 0,27 seconds
Cellectis
Time
Vo
ltage
2x450V
8x110V
The HIVIS DNA vaccine, represents subtypes A, B,
C Vial 1
Envelope and rev plasmids
Vial 2
gag and RT plasmids
Vaccine intramuscularly deliveredVial 1 in the left arm, Vial 2 in the right
0 1Months 3 9
Swedish HIV DNA vaccine
US poxvirus based HIV vaccine
HIV-genes
Vaccination schedule
Karolinska Institutet, Smittskyddsinstitutet, Södersjukhuset, US Army, Muhimbili University, SIDA, EU
Late boost
IFN-g ELISpot reactivityim/id
* *
Many responses, ID more responders than IM
Bakari et al 2011
Broad persistent immune responses
HIVIS03, Tanzania
2 weeks after HIV-MVA/placebo 2 months after HIV-MVA/placebo 6 months after HIV-MVA/placebo
Broad responses to several subtypes Bakari et al 2011
3 years broad memory response after 1 or 2 HIV-MVA (n=42)
Two weeks after the 1st HIV-MVA vaccination (n=30)
Two weeks after the 2nd HIV-MVA vaccination (n=27)
30/40 reactive 27/38 reactive
Tcell reactivity best after 1st boost Bakari et al 2011
p = <0.0001
p = <0.0001
Antibody to env
Antibody best after 2nd boost
p = <0.0001
p = <0.0001
Antibody to gag
p = 0.0149
p = 0.9103
Antibody to RT
Build on previous knowledge in clinical trials
1-Prime DNA only, cellmediated reponseABC: Gp150env A, B, C, Gag A, B, RTdelPRi
2-Boost vectors and/or peptide/proteins,antibody and cellmediated reponsesA_E: MVA-CMDR env E gagRT AA, E:Drep env gp150 EC: NYVAC CB: ANRS peptidesC: Gp140 CN54 protein
VI997CF056
VI991
83CD003
TM7808p1795
p2911MSC4057
SE659497TZ02
KEQ23UG037
SE8891CM240
TH253
CAR402
DJ263DJ264
IbNGSE7812
CAM5288
BFP9095ML8
Z321
G6165NG083
HH8793
CY032GR11GR84
SE9280SE9173
MP535cEGTB117
F9363VI850MP257
CAM5365
MP255
LAICAM1RF
Z2Z6ELI
NDK
ETH2220BR025
93IN999
U
H
C
D
B J
F2 F K
G
A
100
100
100
100
100
100100
100
100
100
100
100
100100 100
98
99
94
100100
100
100
Vaccination againstmany strains of HIV
E
A9%
D6%
C30%
AC
34%
CD6%
ACD6%
AD9%
TANZANIA
Acknowledgements: The volunteers
SMITTSKYDDSINSTITUTETSwedish Institute for Infectious Disease Control
SMI/KIBritta WahrenAndreas BråveDavid HallengärdMargaret LiuKarl LjungbergGunnel BiberfeldJorma HinkulaErik RollmanGunnel EngströmKristian HallermalmLindvi GudmundsdotterAndreas BobergSusanne JohanssonAnne KjerrströmMaria IsaguliantsCharlotta NilssonKatarina Karlén
Karolinska/SöS
Eric Sandström
Bo Hejdeman
Lars Eriksson
Walter Reed Army Institute of Research
Josephine Cox
Mary Marovich
Nelson Michael
Merlin Robb
Deborah Birx
Richard Stout
Pontus BlombergJenny Enger
NIH/NIAID
Bernard Moss
Patricia Earl
Members of the AVIP ConsortiumUniversity of MunichVolker ErleGeorg GasteigerISS, RomeBarbara Ensoli
Bambino GesúPaolo RossiPaolo Palma
MUHAS, Dar es SalaamMuhammad BakariEligius Luyamuya
CytoPulseRichard WaltersAnna-Karin Roos
CellectisJulia BerrettaAlan KingCarole Desseaux
Nils Carlin
Staffan PauliBartek ZuberKopek Nihlmark
EuropriseRobin ShattockNatasha Polyanskaya