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Approaches to genetic vaccines. Britta Wahren Karolinska Institutet Riga 2013. Selection of immunogen DNA, RNA or (glyco)protein Whole genes to cover polymorphic MHC in humans All genes to cover structural and regulatory genes

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approaches to genetic vaccines

Approaches to genetic vaccines

Britta Wahren

Karolinska Institutet

Riga 2013

slide2

Selection of immunogen

DNA, RNA or (glyco)protein

Whole genes to cover polymorphic MHC in humans

All genes to cover structural and regulatory genes

Several subtypes for virus variability and polymorphic MHC

Vectors like vaccinia or adeno

Physical approach

Small total vector size

Intracellular delivery (skin)- electroporation

Delivery devices

Total cell targets – repeated injections

Divided delivery-avoid immunocompetition

Additional adjuvant like cytokine gene, carrier compound

slide3

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5

Minicircle1x

650 bp

% nicked

Minicircle3x

1 900 bp

sc

sc

sc

nicked

nicked

Plasmid

3 579 bp

1: untreated

2: linearized

3: UV-nicked

4: shot to empty vial

5: shot through mouse hide

Small minicircles were more robust when exposed to shearing forces than the corresponding plasmid. Also as splice correcting vectors, they exhibited a more long-term expression as compared to plasmids in vivo.

slide4

Electroporation after needle/jet stream injection

Needle injection

Jet stream injection

Intracellular delivery

Dermis

slide5

Electroporation after needle/jet stream injection

Needle injection

Jet stream injection

Dermis

Secreted antigens

1. Transfection of somatic and professional antigen presenting cells (APCs)

Somatic

cell

APC

MHC I

MHC II

MHC I

APC

2. Antigen presentation to and activation of lymphocytes in the draining lymph nodes

CD4

T cell

APC

T cell

receptor

Co-

stimmulatory signals

MHC II

MHC I

Y

T cell

receptor

CD8

T cell

Y

B cell

3. Activated lymphocytes

slide6

Delivery device

Biojector

im

id

spacer

Left arm: Env/rev, 3 inj

+/- GMCSF sc (needle)

Left arm: Env/rev, 1 inj

+/- GMCSF im

Right arm: Gag/RT, 1 inj

Right arm: Gag/RT, 2 inj

slide7

2x450V

Voltage

8x110V

Time

Total length of pulse-train: 0,27 seconds

Delivery device electroporator

slide9

Volume and concentration

  • Comparison of different immunization protocols using ID EP
    • BALB/c mice
    • Imm w 0, 4 and 8 with GagB
    • ID+EP (15ug) or IM (50ug)
    • IFNg ELISpot
  • Comparison of different immunization methods
    • BALB/c mice
    • 1 imm with GagB
    • IFNg ELISpot
slide10

Divided delivery of env and gag genes, subtypes A, B, C

Vial 1

Envelope and rev plasmids

Vial 2

gag and RT plasmids

Vaccine intramuscularly delivered

Vial 1 in the left arm, Vial 2 in the right

dna vaccines licenced and clinical
DNA vaccines, licenced and clinical

Licenced

  • West Nile virus for horses
  • Hematopoietic necrosis (rhabdovirus) for salmon
  • Melanoma (tyrosine kinase) for dogs, humans?
  • Pig hormonal treatment

Clinical small trials

  • HCV for chronic disease, Sällberg et al, SE
  • Prostate heterologous antigen, Pisa et al, SE
  • CEA heterologous and homologous antigen for gi cancer Mellstedt, Wahren et al, SE
  • HIV for healthy individuals, Ho et al, USA and China,
  • HIV for healthy or chronic disease, Wahren et al, SE, IT, TZ, MC; Pantaleo et al, CH, Robinson et al US
slide12

Acknowledgements: The volunteers

Walter Reed Army Institute of Research

Josephine Cox

Mary Marovich

Nelson Michael

Merlin Robb

Deborah Birx

SMI/KI

Britta Wahren

Andreas Bråve

Margaret Liu

Karl Ljungberg

Gunnel Biberfeld

Jorma Hinkula

Erik Rollman

Gunnel Engström

Kristian Hallermalm

Lindvi Gudmundsdotter

Andreas Boberg

Susanne Johansson

Anne Kjerrström

Maria Isaguliants

Charlotta Nilsson

Katarina Karlén

Reinhold Benthin

Pontus Blomberg

Jenny Enger

Sofia Stenler

Nils Carlin

NIH/NIAID

Bernard Moss

Patricia Earl

Richard Stout

Members of the AVIP Consortium

University of Munich

Volker Erle

Georg Gasteiger

ISS, Rome

Barbara Ensoli

Bambino Gesú

Paolo Rossi

Paolo Palma

CytoPulse

Richard Walters

Anna-Karin Roos

Cellectis

Karolinska/SöS

Eric Sandström

Bo Hejdeman

Lars Eriksson

Viveca Holmberg

MUHAS, Dar es Salaam

Fred Mhalu

Muhammad Bakari

Eligius Lyuamuya

Staffan Pauli

Bartek Zuber

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