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570 000

550 000

29,4 millions

1,2 million

6 millions

15 000

980 000

440 000

1,5 million

1,2 million

Europe occidentale

Afrique subsaharienne

Europe orientale & Asie centrale

Asie du Sud & du Sud-Est

Australie & Nouvelle-Zélande

Amérique du Nord

Caraïbes

Amérique latine

Asie de l’Est & Pacifique

Afrique du Nord & Moyen-Orient

Adults and children living with HIV/AIDS

Pr Brigitte Autran

Lab. Immunité & Infection

Inserm-Université Pierre et Marie Curie,

Hôpital Pitié-Salpétrière

Paris France

brigitte.autran@psl.ap-hop-paris.fr

Vaccins anti-VIH: Actualités

Désillusions et Espoirs

Why hav’nt we an HIV vaccine yet?

• A failure but not a lack of researches

• Obstacles against HIV vaccines : HIV escape

– Immediate and definitive HIV Integration in host genome

= Trojan Horse

– HIV Variability in Antibody and T cell epitopes (Enveloppe, Tat, Nef, Gag)

– Weak neutralizing antibodies

Difficulties are illustrated by the lack of spontaneous recovery

from the infection

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Obstacles to HIV Vaccines: The Trojan Horse

Escape to immune recognition

Kinetics of early infection and HIV prevention A Haase, Nature Reviews Immunology 2010

Retrotranscription

Integration

of provirus

Silent

Integrated

state

Sites Hidden to

Neutral. Ab,

Limits to T cell

recognition:

of Replicating cells

= HLA down-modulation Limits to Immune

Recognition of

Latent cells:

=Lack of Ag expression

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Neut. Ab binding sites :

1- Hidden CD4 binding site

with

conformational changes

post CD4 binding,

2- CD4-induced epitopes

3- surface 2G12 bs

Poor efficacy of Neutralizing Abs against HIV:

Poor accessibility of the conserved Antigenic targets

gp120

gp41

CD4 Co-R

Target cell

Rare Broadly Neutralizing Antibodies (from D Burton)

CD4

binding

site conserved

Chemokine-R

2G12

site Variable,

glycosylated

regions

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Worldwide Distribution of HIV Clades

From

Is it possible to generate

Broad neutralizing antibodies and T cell responses?

HIV sequence Variability

at the pandemic and individual levels

Major HIV Variability

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Poor Immune Correlates of protection against HIV

• Antibodies against HIV?

No significant relationship between neutralizing Ab and viral control

BUT Control of SHIV/HIV after transfers of anti-Env Monoclonal Abs (Mascola, 98. Trkola 2000..).

• CD8 T Lymphocytes (CTLs or killer cells) specific for HIV:

Inverse relationship between viral load and HIV-specific CTL frequencies

during acute (Koup, 93…) or chronic infection (Ogg,98, Kiepela 2009…) and

in LTNP/Elite Controlers (Klein, 95, Kalams 99, Martinez 2005, Saez-Cirion 2008…)

Loss of SIV control after CD8 cell depletion in

Macaques ( Schmitz, Zhang, 99)

• CD4 Thelper-1 Lymphocytes specific for HIV :

Required for generation and maintenance of HIV-specific CTL and Ab

Inverse relationship between viral load and HIV-specific CD4 Th1cells during primary

infection and in LTNP (Rosenberg, 97, 2000, Martinez 2005…)

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Targets for vaccinal responses to HIV from

The search for an HIV vaccine:

1991 Inactivated SIV in macaques: Protection (Stott et al. )

BUT : species-dependent and only / SIV strains grown in human cells

1992

1996

Attenuated SIV in macaques:

Delta-Nef SIV => Protection / pathogenic SIV (Desrosiers et al. 94)

BUT : Pathogenic in new-born macaques (Ruprecht et al 96)

=> Security not managable

The whole virus vaccine experience

The first classical HIV vaccine experiments

=> Back to novel sub-unit strategies: Enveloppe-based strategies

T cell based strategies

Prime Boost strategies BA ACAD12

From G Pantaleo

The search for an HIV vaccine:

Enveloppe-based vaccines for Induction of Neutralizing Antibodies ?

• the « True » Neutralizing Ab binding sites:

1995 Broad Neutralizing Human Mab (2G12, B12, 4E10, 2F5..): against CD4bs, hidden sites

4 Mab Cocktail in: - Macaques : Prevention of SHIV challenge (J Mascola et al.1996………)

2008 - Humans: Decrease of HIV plasma load (Trkola et al. 2005)

BUT : Neut.Abs = Rare in natural infection,

Require extremely high titers (New generation: low titers)

No known immunogen able to induce such Abs in vivo

Other Ab Functions than Neutralization ???

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• the V3 « story »:

1983 HIV-Env Recombinant Vaccinia Vaccine trialsin Humans:

= low immunogenicity, some infections (B Moss et al.)

1990 Envelope protein + V3 peptide in chimps :

= Protection BUT / homologous HIV (M Girard et al)

2000-

2003

1st phase-3 trial : enveloppe protein-based vaccine :

= low immunogenicity, NO protection (6% vaccine efficacy)(D Francis et al.)

gp120

gp4

1

CD4 Co-R

Target cell

Lancet, 2009

440 000

B Autran Acad12

Progress towards development of an HIV vaccine

Rationale design of vaccines

The search for a T cell based HIV vaccine

1. Novel sub-unit vaccines :

Naked DNA : • Safe: Non replicative, non pathogenic,

• Combined to IL-2 (Barouch, 00):

or viral vectors (Amara, McMichael, Wharen, Werner, Nabel….)

• Immunogenic for CD4 & CD8 T cells:

Mice >> Macaque >> Human

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Peptides, lipopeptides (ANRS….):

• Induce CD4, CD8 T cells and Abs

• Limitations : Narrow repertoire and risk of escape HIV RNA and specific CD8 T cells

after SHIV 89-6P challenge:

3 log decrease in viral load

DNA vaccine + IL-2 Barouch et al. 2000

2. Recombinant Attenuated viral Vectors

Pox Viruses: vCP, MVA, NY-VAC: Naturally or genetically attenuated, non replicative

• safe but moderately immunogenic for CD8 T cells (15-50%)

• alone or combined to DNA: (Robinson, McMichael et al. Pantaleo et al)

Adenoviruses : Ad5: genetically attenuated, non replicative.

• Alone or combined to DNA, MVA... (Shiver 01) :

• Safe and highly immunogenicfor CD8 T cells,

BUT limited by Pre-existing immunity and Toxicity of high doses

Other Vectors: Measles (F Tangy et al.) …. CMV (L Picker et al….)

From A McMichael NRI, 03

T cell-based vaccines : Macaques Protection from virus challenge :

Time for Hope ?

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NO Protection in macaques :

BUT : Control of SIV disease (CD4 loss, SIV replication, time to AIDS)

BUT limited to : some SIV strains (SHIV or some SIVs)

MHC types (macaques : MaMuO1)

Vaccine Challenge Result Notes References

Vaccinia –nef SIV-macJ5 Reduction in VL Gallimore, 97

MVA-gag-Pol-env SIV 50-100 x Barouch, 2001

SHIV 89-6P Reduction in VL Seth, 2000

DNA-gag-env SHIV 89-6P Survival Barouch, 2000

+IL-2+ 3log reduction in VL

DNA+MVA SHIV 89-6P Survival, no CD4 loss DNA prime + Amara ; 2001

Gag-env-pol 3log reduction in VL MVA boost

mucosal challenge

VSV-env-gag SHIV-89-6P Survival, no CD4 loss early control Rose, 2001

3log reduction in VL

Ad-5 –gag SHIV-89-6P Survival, no CD4 loss l Shiver 2002

+IL-2+ 3log reduction in VL

S Buchbinder et al. Lancet 2008

S Buchbinder et al.

DSMB: Definitive arrest of the trial

Increased frequency of HIV infections :

- Vaccinees vs Placebo

No reduction in Viral Load after HIV infection

B Autran Acad12

No significant differences

between Cases and Non Cases

in vaccine recipients for anti-HIV responses

N Engl J Med. 2009 Nov 9

Vaccination with ALVAC and AIDSVAX to Prevent

HIV-1 Infection in Thailand. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, …..

• Design: A randomized, multicenter, double-blind, placebo-controlled efficacy (RV144) trial,

– in 16,402 healthy men and women 18 and 30 years, primarily at heterosexual risk for HIV infection,

– 4 priming injections : HIV-recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521])

+ 2 booster injections : HIV recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E).

– 2 coprimary end points: HIV-1 infection and early HIV-1 viremia,

• Results: Modified intention-to-treat analysis:

– (excluding 7 subjects HIV-1 infected at baseline),

– vaccine efficacy : 31.2% (P=0.04).

• Conclusions of the RV144 Trial

This ALVAC-HIV and AIDSVAX B/E vaccine regimen :

may reduce the risk of HIV infection

in a heterosexual risk population

• Vaccination did not affect

the viral load or CD4+ count after HIV infection

B Autran Acad12

The search for an anti-HIV Vaccine:

The Post-RV144 Era:

The Antibody Come back

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A Boost for HIV Vaccine Design D R. Burton and R A. Weiss

Broad Neutralizing Human Abs that potently neutralize almost all HIV isolates at low doses

Frequent (20%)

But late (> 0.5-3 years),

in highly viremic patients

Require long maturation :

• Long CDR3 regions

• Numerous somatic

mutations

Non-Neutralizing Abs against

the V1-V2 loop

Science 2010

PG9, PG16

(V1/V2 and V3 loops)

2G12 (glycans)

b12, VRC01,

HJ16

(CD4bs)

2F5, 4E10,

Z13e1

(MPER)

gp120

gp41

Viral

membrane

could aid the rational design of a vaccine :

But: No good immunogen yet available

to induce such Neutralizing Abs

B Autran Acad12

Sensitive clone :

• short V1V2 loop

• without PNGS at N302.

DNA/ MVA

MVA/MVA

Ad26/MVA

MVA/Ad26

Sham

The search for an anti-HIV Vaccine:

The Post-STEP and Post-RV144 Era:

Immune control

of neutraliziation-resistant

viruses:

A window of opportunity

for T cell based vaccines

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1/28 protection 6/12 protections 5/12 protections 0/9 protection

Nature 2011

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A live REPLICATING attenuated HIV-recombinant

Rh-CMV vector vaccine induces in macaques :

- strong and durable T cell responses

- strong and durable control of SIV replication post-challenge

The search for an anti-HIV Vaccine:

The Post-STEP and Post-RV144 Era

The search for an anti-HIV Vaccine:

The Post-STEP and Post-RV144 Era:

B Autran Acad12

Antibody-based vaccine approach :

The only strategy

able to prevent infection

─ Numerous models of broadly neutralizing

or anti-V1/V2 Abs

─ But no immunogen able to induce such Abs

T cell based Vaccines approach ?

A strategy to control Neut.Ab. escape mutants

– New conserved HIV antigens for broader Immunity : Mosaic multiclade or Conserved Chimeric Immunogens

– New Vectors : – Chimeric or animal AdenoVirus constructs: Ad26 or 35

– New PoxViruses ?

– Live replicating Vectors? the CMV approach

HIV vaccines :

The combined approach:

Ab + CD8 T cells

Hopes for the FUTURE