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T-cell HIV Vaccines

T-cell HIV Vaccines. Giuseppe Pantaleo, M.D. Professor of Medicine Director, Swiss Vaccine Research Institute Lausanne, Switzerland. Challenges In The Development Of An HIV Vaccine. Identification of immune correlates of protection Induction of a broad neutralizing antibody response

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T-cell HIV Vaccines

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  1. T-cell HIV Vaccines Giuseppe Pantaleo, M.D. Professor of Medicine Director, Swiss Vaccine Research Institute Lausanne, Switzerland

  2. Challenges In The DevelopmentOf An HIV Vaccine • Identification of immune correlates of protection • Induction of a broad neutralizing antibody response • Induction of effective T cell responses • Viral diversity • Viral escape • Super-infection • Influence of genetic background • Induction of mucosal and systemic immunity • Complexity of immunization regimens

  3. Vaccine Concepts and Designs • Live Vectors • DNA • Combination of Elements • Peptide Epitopes (limitedimmunogenicity) • Pseudovirions (pre-clinical) • Live-Attenuated (Not Under Study in Humans) • Whole-Killed (Not Under Study in Humans) • Recombinant Viral Proteins

  4. Due to the Lack of Protein-BasedEnv Vaccines Able To InduceNeutralizingAntibodies, Candidate HIV Vaccines Have Been DesignedPrimarily to Induce T-Cell Immune Responses

  5. T-cell HIV Vaccines Concept T-cell Vaccines Do Not Prevent Infection But They Will Be EventuallyAssociatedwith Control of Virus Replication and Prevention of HIV-AssociatedDisease

  6. Vaccine   T-Cell HIV Vaccine Concept Virus exposure Placebo   Help CTL Virus ----

  7. Rationale for the Effectiveness of HIV T-Cell Vaccines • -Certain experimental vaccines confer protection in monkeys infected with SIV • - There is evidence that HIV-1-specific T-cellresponses may confer protection (e.g. exposed non-infected subjects) • -A small percentage (<5%) of HIV-1-infected subjects show no signs of disease progression (e.g. long-term nonprogressors) • - A decrease in viral load is associated with clinical benefit

  8. Effective immunity induced by rAd5 HIV (SIV) vaccine in a SIV challenge model Low responder High responder

  9. Interpretation This cell-mediated immunity vaccine did not prevent HIV-1 infection orreduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

  10. Vol. 307 November 29, 2008

  11. Vol. 307 November 29, 2008

  12. Vol. 307 November 29, 2008 Interpretation Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nefvaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.

  13. Messages from the StepStudy • The Stepstudy marks the end of the HIV T-cell vaccine concept (at least of the Ad5 vectorusedalone) • It draws the attention on the potential danger of pre-existingimmunity • It shows a potentialsinergybetween Ad5 pre-existingimmunity and circumcisionwith regard to the observedincreased in HIV acquisition • It indicatesthat the magnitude and the quality (breadth) of the vaccine-induced T-cellresponses (particularly CD8 T-cellresponses) are not optimal

  14. CONCLUSIONS This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

  15. Major Messages from the RV-144 Study The vaccine combination is potentially more effective (61% reduction of HIV acquisition at 1 year post vaccination) The vaccine protective effect is waning over time (31.2% at 3 years post-vaccination) The delta in the reduction of the number of infections is 18 (30 in the placebo vs. 12 in the vaccine group) at 1 year and 23 (74 in the placebo vs. 51 in the vaccine group) at 3 years Therefore, most of the protective effect is gained during the 1st year post-vaccination

  16. RV-144 Results and Immunological Issues The limited set of immunological results of the RV-144 trial do not allow to rule out or to favor any specific cellular or humoral mechanism of protection. In this regard: The same protein component of the vaccine combination was not associated to protection when used alone in the Vaxgen phase III trial. However, due to differences in the target population, i.e. high risk IVDU population in the Vaxgen trial versus low risk in the RV-144 trial, the two studies cannot be compared. The poxvirus component of the vaccine, i.e. ALVAC, was never previously tested in phase III trial.

  17. RV-144 Results and Immunological Issues The results of the RV-144 trial re-underscore a number of immunological issues that have been repetitively raised in the recent past but have never been concretely addressed. These include: the need of developing an integrated vaccine-induced immune response (innate plus humoral plus adaptive) the exploration of additional mechanisms of protection beyond the conventional CD4 and cytotoxic CD8 T-cell and neutralizing antibody responses

  18. What Is Next?

  19. Improvement of the Current Vaccine Combination Augment (above the 61% efficacy observed at 1 year post-infection) the overall protection from infection Induce durable protection Improve both components of the vaccine, i.e. the priming component (ALVAC) and the boosting component (the Env protein)

  20. What Is Next? Vaccine candidates Poxvirus-based vectors - NYVAC - MVA - ALVAC Adenovirus - Ad26 - Ad35 DNA vectors Protein - gp140 monomer or trimer

  21. November 15, 2008, Vol. 198

  22. November 15, 2008, Vol. 198

  23. DNA-C + NYVAC-C PlatformHarari et al. JEM, 2008; Bart et al., Vaccine, 2008; McCormack, Vaccine, 2008 Supported by the European Union, EuroVacc, ANRS and CAVD

  24. Clinical Trial Design 0 4 8 20 24 28 48 72 Weeks Group 1 (n=74) Group 2 (n=73) DNA-C (4 mg) priming at week 0, 4 and 8 for group 1 at week 0 and 4 for group 2 NYVAC-C (107.5 PFUs) boosting at week 24 for group 1 and at week 20 and 24 for group 2 • Randomized trial with a parallel group design • Open to the participants and investigators but blind to laboratory personnel • Attendance to clinics at least 14 occasions over 72 weeks

  25. Proportion of Responders at Primary Endpoints (Week 26/28) Chi2 Test: p = 0.053; Risk difference: 11.4% (95% CI 0.0 – 22.9%) Chi2 Test: p = 0.021; Risk difference: 13.1% (95% CI 2.2 – 24.1%)

  26. Proportion of Responders Over Time

  27. Magnitude of IFN-g ELISpot Responses at Week 26/28 Overall (SFUs/106 cells) Note: Sum of SFU/Mio cells from all peptide pools with a positive response per participant

  28. Magnitude of IFN-g ELISpot Responses at Week 26/28 (ITT) Note: Magnitude statistically different between groups for Env at both weeks but not for Gag/Pol/Nef (Other) SFUs/Mio cells 2200 3 x DNA 2 x DNA 2000 1800 1600 1400 1200 1000 800 600 400 200 0 ENV Other ENV Other ENV Other ENV Other Week 26 Week 28 Week 26 Week 28 30

  29. 2.39e-3 2.99e-3 0.013 0.033 5 5 10 10 4 4 10 10 3 3 10 10 2 10 2 10 0 0 100 100 1.79e-3 1.2e-3 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 <APC-A> <APC-A> 0.013 0.036 0 8.5e-3 5 5 10 10 4 4 10 10 3 3 10 10 2 2 10 10 0.04 0.11 0.069 0.13 0 5 5 10 10 0.067 0.027 0.016 2.66e-3 0 5 5 10 10 100 0 100 8.5e-3 4 4 10 10 2 3 4 5 4 2 3 4 5 0 10 10 10 10 4 10 10 0 10 10 10 10 3 3 10 10 3 3 10 10 2 10 2 10 0.031 0.017 0.05 0.019 2 2 5 5 10 10 10 10 0 0 0 99.8 0.032 99.8 7.13e-3 0 4 4 99.9 3.54e-3 10 100 0.017 10 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 3 3 10 10 2 10 2 10 0 0 99.9 3.71e-3 99.9 1.65e-3 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 0.22 0.093 0.077 0.019 5 5 10 10 4 4 10 10 3 3 10 10 2 2 10 10 0 0 99.7 4.18e-3 99.8 0.12 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 Functional Profile of HIV-Specific T-Cell Responses CD4 T-cell responses CD8 T-cell responses Subject#1042 Gr#1 TNF-α TNF-α IL-2 IL-2 Neg Env 1 Env 2 IFN- IFN-

  30. 0.4 0.3 0.2 0.1 0 IFNg + + + + - - - IL-2 + + - - + + - TNFa + - + - + - + Functional Profile of HIV-Specific T-Cell Responses CD4 T-cell responses CD8 T-cell responses Gr#1 Gr#2 Gr#1 Gr#2 Gr#1 Gr#1 0.4 Gr#2 Gr#2 0.3 0.2 Frequency of CD4 T-cells Frequency of CD8 T-cells 0.1 0 IFNg + + + + - - - IL-2 + + - - + + - TNFa + - + - + - +

  31. 8 6 Number of responses per subject 4 2 0 Number of Pools Recognized P=0.02 Median CD4 T cells CD8 T cells CD4 T cells CD8 T cells Gr1 N=14 Gr2 N=11

  32. GAG POL NEF ENV Distribution of HIV Regions Targeted By CD4 T-Cell Responses P=0.06 Gr#1 N=44 responses Gr#2 N=28 responses Number of responses Gr#1 Gr#2 Gag, Pol or Nef ENV

  33. GAG POL NEF ENV Distribution of HIV Regions Targeted By CD8 T-Cell Responses P=0.01 Gr#1 N=22 responses Gr#2 N=8 responses Number of responses Gr#1 Gr#2 ENV Gag, Pol or Nef

  34. 2.0 1.5 Percentage of T-cells 1.0 0.5 0.0 CD4 T cells CD8 T cells CD4 T cells CD8 T cells Total Magnitude of T-Cell Responses (Sum of Responding Pools) Gr1 N=14 Gr2 N=11

  35. 5 5 5 10 10 10 4 4 4 10 10 10 0.52 1.13 10.1 3 3 3 10 10 10 0 0 0 2 3 4 5 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 0 10 10 10 10 5 5 5 10 10 10 4 4 4 10 10 10 11.9 0.87 6.42 3 3 3 10 10 10 0 0 0 2 3 4 5 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 0 10 10 10 10 5 5 5 10 10 10 4 0.57 4 4 10 10 10 0.5 4.85 3 3 3 10 10 10 0 0 0 2 3 4 5 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 0 10 10 10 10 5 5 5 10 10 10 4 4 4 10 10 10 0.34 10.6 24 3 3 3 10 10 10 0 0 0 2 3 4 5 2 3 4 5 2 3 4 5 0 10 10 10 10 0 10 10 10 10 0 10 10 10 10 EV03/ANRS VAC20: NYVAC- and HIV-Specific CD4 and CD8 T-Cell Responses in the Gut Gated on CD3+CD4+ Gated on CD3+CD8+ unstimulated NYVAC HIV unstimulated NYVAC HIV Blood Blood Gut Gut CD4 CD8 CFSE CFSE

  36. What Is Next? Potential vaccine commbinations (withnovelenvprotein candidates) Poxvirus-based vaccine combinations - NYVAC (2X or 4X) plus gp120/140 (2X or multiple) - DNA (3X) plus NYVAC (1X) plus gp120/140 (2X or multiple) - ALVAC (4X) plus gp120/140 (2X or multiple) Adenovirus-based vaccine combinations - Ad26 (1X) plus Ad35 (1X) plus gp120/140 (2X or multiple) - Ad26 (2X) plus MVA (1X) plus gp120/140 (2X or multiple)

  37. Current and Future Poxvirus Vectors Portfolio Vaccinia Virus Ankara (MVA) Canarypox virus Vaccinia Virus Copenhagen NYVAC 200 passages in CEF cells Deletion of 18 ORFs Reinsertion of K1L & C7L Gene deletion 571 passages In CEF cells MVA ALVAC NYVAC Attenuated Rc NYVAC KC Gene deletion mutants Combined NYVAC Rc Plus Gene deletion

  38. Conclusions T-cell vaccines remain an important component of the overall HIV vaccine strategy They serve as the priming component in combination regimens with env proteins It is conceivable that improved T-cell vaccines may substantially impact the magnitude, quality and durability of the antibody response induced by env protein vaccines The Step and RV-144 efficacy trials have indicated that the current NHPs challenge model is not suitable for the prediction of the clinical efficacy of vaccine candidates in humans The evaluation of improved vaccine combinations in efficacy clinical trials is the only strategy for the correct evaluation of the vaccine effectiveness

  39. Acknowledgements Vaccine Immunotherapy Centre Div. of Immunology and Allergy CHUV – Lausanne, Switzerland Pierre-Alexandre Bart Erika Castro David Bonnet Kim Ellefsen-Lavoie Alexandre Harari St. Mary Hospital, Imperial College London, UK Jonathan Weber Rebecca Chandler Lucy Garvey Ken Legg Ngaire Latch University of Regensburg, Germany Bernd Salzberger Ralf Wagner Hans Wolf Birgit Fritsch FalitsaMandraka Gabriele Birkenfeld Caspar Franzen Josef Köstler ANRS Jean-Francois Delfraissy Yves Levy Anne de Saunière Véronique Rieux EuroVacc Foundation Song Ding Sanofi Pasteur, France Jim Tartaglia Claude Meric Collaboration for AIDS Vaccine Discovery (CAVD) Nina Russell Jose Esparza Cochin, Paris, France • Odile Launay • Pierre Loulergue • Yvette Henin Henri Mondor, Paris, France • Yves Lévy • Jean-Daniel Lelièvre • Christine Lacabaratz Tenon, France • Gilles Pialoux Marseille, France • Isabelle Poizot-Martin • Catherine Farnarier Toulouse, France • Lise Cuzin • Florence Nicot INSERM CTU U897, France • Genevieve Chene • Philippe Reboud • Inga Tschöpe • Carine Grondin • Valérie Boilet MRC CTU, London, UK • Sheena McCormack • Abdel Babiker • Wolfgang Stöhr • Liz Brodnicki • Patrick Kelleher • Mary Rauchenberger • Shabana Khan European Commission EuroVacc Foundation ANRS CAVD & All Study Volunteers

  40. Proportion of Responders at Week 26/28 per Peptide Group

  41. Primary Immunogenicity Endpoints Chi2 Test: p = 0.047; Risk difference: 15.4% (95% CI 0.5 – 30.3%) Risk atio: 1.7 (95% CI 1.0 – 2.9) Chi2 Test: p = 0.059; Risk difference: 14.9% (95% CI -0.3 – 30.2%) Risk ratio: 1.7 (95% CI 1.0 – 2.9)

  42. Magnitude of IFN-g ELISpot Responses at Week 26/28 by Peptide Group (median (IQR) SFUs/106 cells)

  43. Challenges in HIV Vaccine Development • 30 commerciallyavailable effective vaccines • 16 vaccine derivedfrom live replcationcompetentattenuatedpathogens • 12 vaccine derivedfrompathogen modifications • Only 2 vaccines, HPV and HBV derivedfromsyntheticproducts

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