La recherche vaccinale contre le VIH Françoise BARRE-SINOUSSI

La recherche vaccinale contre le VIH Françoise BARRE-SINOUSSI

Key scientific challenges and Priorities in HIV science HIV Vaccine discovery Comorbidities on ART 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 Better knowledge on HIV basic science on latency, immunology and pathogenesis HIV Cure discovery Persistent HIV infection on HAART is the main hurdle science must tackle to achieve an HIV Cure 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

HIV vaccine research, an history of overlapping waves First wave (1984-late 90s): Vaccine candidates to induce neutralizing antibodies,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 (Pox vectors +rgp), in particular to understand correlates of protection and new targets for immunogen designin particular to induce bnabs, but not only

Over 200 trials but only few Phase IIb/III prophylactic trials Dates Clinical efficacy studies Strategy Viral targets Immune response Efficacy 1999-2003 AidsVax Protein subunit (AIDSVAX) monomeric rgp120 Type specific binding Ab No 2005-2007 Step Phambili Viral vector (Ad5) gag/pol/nef CD8+T (+++) No 2005-2009 RV144 (Thai trial) Prime: ALVACvCP152 + 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)

VE VE Post-RV 144: 6 correlates related to Vaccine Efficacy or not. Binding of IgG antibodies to the V1V2 region of gp 120 In vaccinees with low plasma IgA responses NnAbs (ADCC..) Binding of Abs to env Avidity of IgG antibodies for env N Abs Polyfunctional CD4 T cell responses to HIV-1 env

2010: Pox Protein Public Private Partnership (P5) ALVAC/Protein Phase 3 program HVTN 100: Evaluation of Immunogenicity (N:252) HVTN 702: 3 year Efficacy trial (N: 2x 2700) Construction of Bivalent Subtype C gp120/mf59 Construction of ALVAC- HIV-C (vcp2438) Optimize regimen by increasing potency & durability Booster at 12 months

Janssen/Crucell Vaccine Program Prime Boost Ad26 Mosaic vectors gag-pol-env Ad26 Mosaic vectors gag-pol-env +/- Soluble trimer gp140 env protein Ad26 Mosaic vectors gag-pol-env MVA Mosaic vectors gag-pol-env or +/- Soluble trimer gp140 env protein months 0 3 6 12 Regimen to be selected after Phase 1/2a 8

Significant progresses in HIV vaccine research since 2009: Nabs New perspectives for both HIV vaccine and cure 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 )? Christina Corbaci, Andrew Ward, V3-glycan gp41 MPER V1V2-glycan CD4 binding site gp120/41 interface Structure-based immunogen design & novel delivery systems Only antibodies that have advanced the clinic (VRC01, 3BNC117) - Genetic engineering (CAR, TCR ) and gene transfer in T cells - DC targeting

Candidate vaccines Development & in vitro validation NH2-IRIQRGPGRAFVTIG-CO-NH-CH-CO-NH2 Lipopeptides Fusion proteins From 2012 in France: DC Targeting combined with other immunogens Delivery In vivo Imaging Vaccine biodistribution & Antigen persistence MVA NYVAC DNA No antigen Gag peptides SEA SEB 2500 6.31 0.12 6.43 6.83 7.35 0.53 25.2 3.86 29.1 2000 13742 MultiHIV MultiHIV EP MultiHIV Biojector MVA 13754 13778 13875 DC targeting Ex vivo pulsed DC CD69 93.3 0.25 92.3 Gene IL-2 profiling 0.38 70.6 Cell 6.29 0.14 5.52 1.83 22.6 6.43 0.35 responses Total number of CD69+ cells Cytokines Responses Cell count al CD4 1500 1000 2000 1500 1000 500 0 0 50 100 150 200 250 300 0 PLA-p24 2000 CD3+CD4+ CD3+CD4- Innate Adaptive 6 4 immunity 3 Lenti VIRxSYS 1500 1500 1000 1000 500 500 500 4 0 CD3+CD4+ CD3+CD4-2000 0 CD3+CD4+ CD3+CD4- Tissue changes 10 8 6 2000 1500 1000 500 0 10 8 6 CD3+CD4+ CD3

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