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BA ACAD12
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
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
BA ACAD12
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
BA ACAD12
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
BA ACAD12
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
BA ACAD12
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…)
BA ACAD12
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 ???
BA ACAD12
• 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
BA ACAD12
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 ?
BA ACAD12
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
BA ACAD12
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
BA ACAD12
1/28 protection 6/12 protections 5/12 protections 0/9 protection
Nature 2011
B Autran Acad12
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