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