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 [email protected]Vaccins anti-VIH: Actualités Désillusions et Espoirs
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Vaccins anti-VIH · 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
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= 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,