La recherche vaccinale contre le VIHFrançoise BARRE-SINOUSSI

Key scientific challenges and Priorities in HIV science

HIV Vaccine discovery Comorbidities on ART HIV Cure discovery

Still no correlates of

protection but

significant progresses

in HIV vaccine

research with new

perspectives since the

Thai trial in 2009..

HIV infection, a

chronic condition

on life long cART

but non AIDS

related

comorbidities

Persistent HIV

infection on HAART

is the main hurdle

science must tackle

to achieve an HIV

“Cure”

Better knowledge on HIV basic

science on latency, immunology

and pathogenesis

Novel Vaccine and

Therapeutic Strategies?

Vaccines: scientific gaps and challenges

Host genetic polymorphism

Genetic Variability of HIV

Viral evasion of the immune response

Mechanisms of protection still undefined

Cell to cell transmission

Early establishment of HIV latency and of viral reservoirs

Very rapid induction of both innate and adaptative immune

response dysfunctions (chronic inflammation…)

Animal model limitations

First “wave” (1984-late 90s): Vaccine candidates to induce neutralizingantibodies,mostly using rgp, immunogenic, good binding Ab, some ADCC, but narrow strain specific neutralization and no efficacy

Second “wave” (late 90s-2005 ): T cell based vaccinesInduction of CTLs, using live vectored vaccines (especially canarypox) or naked DNA.

Third “wave” (2005-2009): Different types of prime-boost strategies (to induce both Abs and CTLs, or to induce better CTLs); new vaccine constructs(i.e., Ad vectors); induction of immune responses also to regulatory proteins(TAT, NEF).

Fourth “wave” (from 2009): Post-Thai RV144: prime-boost strategies (Poxvectors +rGp), in particular to understand correlates of protection and new targets for immunogen designin particular to induce bNabs, but not only…

HIV vaccine research, an history of overlapping “waves”…

Over 200 trials but only few Phase IIb/III prophylactic trials

Dates

Clinical

efficacy

studies

Strategy Viral targetsImmune

response

1999-2003 AidsVax

Protein

subunit

(AIDSVAX)

monomeric

rgp120

Type specific

binding AbNo

2005-2007Step

Phambili

Viral vector

(Ad5)

gag/pol/nefCD8+T (+++) No

2005-2009RV144

(Thai trial)

Prime:

ALVAC-

vCP152

+

Boost:

AIDSVAX

gag/pol/env

+

Monomeric

rgp120 B/E

CD4+ T cell

(+/-)

+

Type specific

binding Ab

Yes

31% reduction

2009- 2013 HVTN505

Prime: DNA

+

Boost:

Ad5

gag/pol/nef/env

No

(around 20

infections in

each arm)

Efficacy

Post-RV 144: 6 correlates related to

Vaccine Efficacy or not.V

E

Binding of IgG antibodies to the

V1V2 region of gp 120

Binding of Abs to env

Avidity of IgG antibodies for envV

E

NnAbs (ADCC..)

N Abs

Polyfunctional CD4 T cell responses to

HIV-1 env

In vaccinees with

low plasma IgA

responses

2010: Pox Protein Public Private Partnership (P5) ALVAC/Protein Phase 3 program

Optimize regimen by increasing potency & durability

Construction of ALVAC-

HIV-C (vCP2438)

Construction of Bivalent Subtype C gp120/MF59

Booster at 12 months

HVTN 100: Evaluation of Immunogenicity (N:252)

HVTN 702: 3 year Efficacy trial (N: 2x 2700)

8

Janssen/Crucell Vaccine Program

Ad26 Mosaic vectors

gag-pol-env

MVA Mosaic vectors

gag-pol-env

Soluble trimer gp140 env

protein

Soluble trimer gp140 env

protein

+/-

+/-

or

Prime Boost

0 3 12months 6

Regimen to be selected after Phase 1/2a

Ad26 Mosaic vectors

gag-pol-env

Ad26 Mosaic vectors

gag-pol-env

• Identification of new very potent broadly neutralizing antibodies in HIV+ patients (“elite neutralizers”), structurally and functionally characterized.

• Identification of new sites of vulnerability of HIV env(MPER, CD4bs, V1/V2 and V3, glycan side chain on outer domain)

• Non neutralizing but protective antibodies (ADCC, Fc-mediated, others…)?

Significant progresses in HIV vaccine research since 2009: Nabs…

New perspectives for both HIV vaccine and cure…

Structure-based immunogendesign & novel delivery systems

Christina Corbaci, Andrew Ward,

gp120/41 interface

CD4 binding site

V3-glycan V1V2-glycan

gp41 MPER

Only antibodies that have advanced the clinic (VRC01,

3BNC117)

- Genetic engineering (CAR, TCR…) and gene transfer in T cells- DC targeting…

Delivery

Innate Adaptiveimmunity

0

500

1000

1500

2000

2500

0 50 100 150 200 250 300

MultiHIV

MultiHIV EP

MultiHIV Biojector

MVA

PLA-p24

Lenti VIRxSYS

0

500

1000

1500

2000

2500

0 50 100 150 200 250 300

MultiHIV

MultiHIV EP

MultiHIV Biojector

MVA

PLA-p24

Lenti VIRxSYS

No antigen Gag peptides SEA SEB

CD

69

IL-2

6.43

6.31 0.12

0.2593.3

7.35

6.830.53

0.3892.3

29.1

25.2 3.86

0.3570.6

CD

69

IFN-

6.29 0.14

0.1893.4

5.52 1.83

0.4992.2

22.6 6.43

0.4870.5

IFN

-

IL-2

1.63 0.44

0.2797.7

0.15 7.85e-3

0.2599.6

4.26 1.62

2.1192

13742

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13754

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13778

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13875

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

Responses

of CD3+CD4+

cells

Total number

of CD69+ cells

Responses

of CD3+CD4-

cells

Cell

count

% o

f to

tal C

D4

% o

f to

tal C

D8

0

2

4

6

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

1

2

3

4

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

3

6

9

12

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,3

0,6

0,9

1,2

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

No antigen Gag peptidesStimulation with:

No antigen Gag peptides SEA SEB

CD

69

IL-2

6.43

6.31 0.12

0.2593.3

7.35

6.830.53

0.3892.3

29.1

25.2 3.86

0.3570.6

CD

69

IFN-

6.29 0.14

0.1893.4

5.52 1.83

0.4992.2

22.6 6.43

0.4870.5

IFN

-

IL-2

1.63 0.44

0.2797.7

0.15 7.85e-3

0.2599.6

4.26 1.62

2.1192

No antigen Gag peptides SEA SEB

CD

69

IL-2

6.43

6.31 0.12

0.2593.3

6.43

6.31 0.12

0.2593.3

7.35

6.830.53

0.3892.3

7.35

6.830.53

0.3892.3

29.1

25.2 3.86

0.3570.6

29.1

25.2 3.86

0.3570.6

CD

69

IFN-

6.29 0.14

0.1893.4

6.29 0.14

0.1893.4

5.52 1.83

0.4992.2

5.52 1.83

0.4992.2

22.6 6.43

0.4870.5

22.6 6.43

0.4870.5

IFN

-

IL-2

1.63 0.44

0.2797.7

1.63 0.44

0.2797.7

0.15 7.85e-3

0.2599.6

0.15 7.85e-3

0.2599.6

4.26 1.62

2.1192

4.26 1.62

2.1192

13742

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13754

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13778

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13875

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

Responses

of CD3+CD4+

cells

Total number

of CD69+ cells

Responses

of CD3+CD4-

cells

Cell

count

% o

f to

tal C

D4

% o

f to

tal C

D8

0

2

4

6

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

1

2

3

4

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

3

6

9

12

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,3

0,6

0,9

1,2

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

No antigen Gag peptidesStimulation with:

13742

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13754

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13778

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

13875

0

500

1000

1500

2000

CD3+CD4+ CD3+CD4-

Responses

of CD3+CD4+

cells

Total number

of CD69+ cells

Responses

of CD3+CD4-

cells

Cell

count

% o

f to

tal C

D4

% o

f to

tal C

D8

0

2

4

6

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

1

2

3

4

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

3

6

9

12

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,2

0,4

0,6

0,8

1,0

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0

2

4

6

8

10

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

0,0

0,3

0,6

0,9

1,2

IFN-

IL2+

IFN+

IL2+

IFN+

IL2-

No antigenNo antigen Gag peptidesGag peptidesStimulation with:

Gene profiling

Tissue changesCell

responses

DNA

MVA

NYVAC

NH2-IRIQRGPGRAFVTIG-CO-NH-CH-CO-NH2

Lipopeptides

Fusion proteins

DC

targetingEx vivopulsed DC

Vaccinebiodistribution

& Antigenpersistence

In vivo Imaging

Cytokines

Candidate vaccines

From 2012 in France:DC Targeting combined with other immunogens

Development &in vitro validation

Conclusion

• Considerable energy in the HIV vaccine field

• Initiation of test of concept studies of both neutralizing and non neutralizing antibody approaches that will set the stage for the entire design and development field for the next decade…

• For the first time the basic science agenda will be based on human clinical trials

No Dogma…

Strategy integrating Basic and Clinical

Science

New technologies

Innovative and hign risk concepts

Vaccine

discovery

?

Still a long way…. But…