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Vacc4x: A Therapeutic HIV-1 Vaccine Based on Modified Peptides Maja A. Sommerfelt Ph.D. CSO. NAPWA’s Treatment Horizons: Pathways to a Functional Cure IAS 2011, Rome, Italy 19th July 2011. Therapeutic Vaccination and Functional Cure for HIV-1 Infection. Therapeutic vaccination - PowerPoint PPT Presentation
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NAPWA’s Treatment Horizons: Pathways to a Functional CureIAS 2011, Rome, Italy19th July 2011
Vacc4x: A Therapeutic HIV-1 Vaccine
Based on Modified Peptides
Maja A. Sommerfelt Ph.D.CSO
Therapeutic vaccination Antiviral responses
T-cell approaches:Kill infected cellsAntibody approaches: Block/inactivate the virus
Generalised immune activation induced by HIV
Immune responses induced by therapeutic vaccination can reach regions of the body not accessed by ART
An effective therapeutic vaccine will provide valuable information that can help towards a successful preventative vaccine
Therapeutic Vaccination and Functional Cure for HIV-1 Infection
Vacc-4x
Vacc-C5
Vacc-4x: Based on conserved domains of HIV-1 p24CA
*Weber et al. 1987 Lancet 1:119-22 ; Cheingsov-Popov et al. 1991 BMJ 302 :23-6 ;¤ Kiepiela et al. 2007 Nature Med. 13:46-53; Zuniga et al. 2006 J. Virol. 80:3122-5.§Dahirel et al. 2011 www.pnas.org/cgi/doi/10.1073/pnas.1105315108; # Schoofs 2011 Wall Street Journal (WSJ) 21st June
• 4 modified peptides to p24CA
• Sustained immune responses to p24CA are associated with delayed disease progression*
• Strong responses to Gag are associated with virus control (LTNP) in the absence of ART¤
• Conserved ‘Sectors’ within p24CA particularly immunologically vulnerable and important for virus control§
• Vacc-4x largely corresponds to ‘Sector 3’
p24CA
Image WSJ
Images Dahirel et al. 2011
Bionor Immuno Peptide Design Considers
Human Diversity Virus Diversity
Peptides are modified using a proprietary design technology to improve• Uptake
• Antigen processing & presentation• Simple & cost-effective manufacture
• Conserved Domains• Cross Clade
• Most prevalent HLA in diverse human populations• Human-like sequences excluded
Vacc-4x: Phase IIB Study
Inclusion criteria
Endpoints
Study design
• 18-55 y of age• Chronic HIV infection (>1 y)• Stable on ART >6 months (VL < 50 copies/mL)• Pre-study CD4 cell count > 400 x 106 / L• Nadir CD4 cell count > 200 x 106 / L
• Primary: Resumption of ART CD4 < 350 x106 / L or 50% decrease VL >300.000 copies/mL
• Co-primary: Change of CD4 • Secondary: Viral Load / ELISPOT / Proliferation / ICS
• 135 patients (US+EU); 2/3 active and 1/3 placebo• 6 immunizations (1,2 mg Vacc-4x + GMCSF over 18wks)• Off ART wk 28-52 (LTFU during year 2)
IIB Study Schedule
Vacc-4x IIB study: 18 sites
Last Patient Completed wk52: June 2010Last Patient Completed wk104: June 2011
No Vacc-4x -related SAE reported
UK Germany Italy Spain USAPeters Van Lunzen Lazzarin Clotet FischlFisher Rockstroh Gatell Hardy
Moyle Schürmann Podzamczer Mitsuyasu
Plettenberg Taiwo
Fätkenheuer Asmuth
Arasteh
Central Labs (Immunology)
USA UC Davis Pollard
EU Univ Lausanne Pantaleo
Bionor Labs Jelmert
Phase IIB Baseline Characteristics
Parameters Vacc-4x (n=92) Placebo (n=43)
Male 78 (85%) 38 (88%)Female 14 (15%) 5 (12%)
Age Median years 44 (40-48) 45 (40-50)Time of HIV infection, years 10.7 (5.7-14.3) 12.4 (10.0-17.1)
Time on ART, years 8.0 (3.3-11.7) 9.3 (3.4-12.3)
Nadir CD4 cells/µl 300 (240-374) 285 (241-363)
Pre ART CD4 339 (272-454) 370 (293-450)
Pre ART Viral Load 94 810 (35 722-184 476) 25 630 (9 644-85 000)
Pre Study CD4 712 (562-928) 619 (518-761)
Primary End Points
There was no difference in the time to return to ART (p=0.89)
There was no difference in mean change in CD4 counts over time (p=0.12)
Treatment difference week 52 (Subjects who remained OFF ART until week 52)
Vacc-4x
VL/mL
Placebo
VL/mLMedian week 28 0 (n=55) 0 (n=25)Median week 52 19,550 (n=56) 40,300 (n=25)Mean week 28 1,351 (n=55) 1,629 (n=25)Mean week 52 35,220 (n=56) 65,070 (n=25)P-value 0.0022
Secondary End Points: Viral Load
Treatment difference week 52 (Subjects who remained OFF ART until week 52)
Vacc-4x
VL/mL
Placebo
VL/mLMedian week 28 0 (n=55) 0 (n=25)Median week 52 19,550 (n=56) 40,300 (n=25)Mean week 28 1,351 (n=55) 1,629 (n=25)Mean week 52 35,220 (n=56) 65,070 (n=25)P-value 0.0022
Secondary End Points: Viral Load Change from PreARTSubjects who remained off ART until week 52. Vacc-4x group change from preART 0.55 log, p=0.0003, n=44.Placebo group change from preART 0.08 log, p=0.89, n=18
Secondary End Points: ELISPOT Responses
This indicates a potential qualitative rather than a quantitative difference in immunological responses to p24 between Vacc-4x and placebo groups. Further immunological analyses are ongoing.
Acknowledgments
All Participating Study Volunteers
Phase I & IIA Phase IIBHaukeland Hospital Participating Clinical Trial Sites
Ullevål University Hospital University of Lausanne & UC Davis
Mericon AS SRA Global Clinical Development Ltd.
Bionor Laboratories ASCovanceMericon AS
The phase IIB study is supported in part by a grant from the Research Council of Norway GLOBVAC program