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Novel Adenovirus Vector-Based Vaccines for HIV-1

Novel Adenovirus Vector-Based Vaccines for HIV-1. Dan H. Barouch Beth Israel Deaconess Medical Center November 20, 2008. Rationale for the Development of Novel Adenovirus Vector-Based Vaccines for HIV-1.

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Novel Adenovirus Vector-Based Vaccines for HIV-1

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  1. Novel Adenovirus Vector-Based Vaccines for HIV-1 Dan H. Barouch Beth Israel Deaconess Medical Center November 20, 2008

  2. Rationale for the Development of Novel Adenovirus Vector-Based Vaccines for HIV-1 • The Merck rAd5-Gag/Pol/Nef vaccine failed to show efficacy and may have resulted in increased HIV-1 acquisition in individuals with pre-existing anti-Ad5 immunity • Homologous rAd5 regimens may be limited by: • Pre-existing anti-Ad5 immunity • Skewed/inadequate quality of T lymphocyte responses • Limited magnitude and breadth of responses as a result of homologous vector re-administration • Minimal protective efficacy against SIV challenge in rhesus monkeys • Potential advantages of novel rAd vectors include: • Evasion of pre-existing anti-vector immunity • Enhanced polyfunctionality/quality of T lymphocyte responses • Augmented magnitude and breadth of responses utilizing heterologous rAd prime-boost regimens • Improved protective efficacy against SIV challenge in rhesus monkeys

  3. Protective Efficacy of Heterologous rAd Prime-Boost Regimens in Rhesus Monkeys • 22 Mamu-A*01/B*17-negative rhesus monkeys immunized with various rAd regimens expressing SIV Gag (week 0, 24): • rAd26-Gag prime, rAd5-Gag boost (N=6) • rAd35-Gag prime, rAd5-Gag boost (N=6) • rAd5-Gag prime, rAd5-Gag boost (N=4) • Sham (N=6) • High-dose i.v. SIVmac251 challenge (week 52) • Highly stringent challenge model (Mamu-A*01/B*17-negative rhesus monkeys, single SIV Gag antigen, i.v. SIVmac251) • rAd5 alone and DNA/rAd5 regimens do not reduce peak or setpoint SIV RNA levels in this model (Casimiro et al. J. Virol. 79: 15547-55; 2005) Liu et al. Nature, Nov 9, 2008 (advance online publication)

  4. Increased Magnitude and Breadth of Gag-Specific Responses in rAd26/rAd5 Vaccinated Monkeys As Compared with rAd5/rAd5 Vaccinated Monkeys Gag ELISPOT Magnitude Gag Epitope Breadth Week

  5. Improved Polyfunctionality of Gag-Specific Responses in rAd26/rAd5 Vaccinated Monkeys As Compared with rAd5/rAd5 Vaccinated Monkeys

  6. Significant 1.4 Log Decrease in Peak SIV RNA in rAd26/rAd5 Vaccinated Monkeys Post-Challenge Peak SIV RNA Levels; Day 14 Post-Challenge Mean Two-tailed Wilcoxon rank-sum tests

  7. Long-TermSignificant 2.4 Log Decrease in SIV RNA in rAd26/rAd5 Vaccinated Monkeys Post-Challenge Setpoint SIV RNA Levels; Mean Day 112-500 Post-Challenge Mean *death Two-tailed Wilcoxon rank-sum tests

  8. Clinical Survival Advantage in rAd26/rAd5 Vaccinated Monkeys for >500 Days Post-Challenge P=0.03* P=0.03 Fisher’s exact test

  9. Anamnestic Gag-Specific Cellular Immune Responses in rAd26/rAd5 Vaccinated Monkeys Post-Challenge Day 0 Day 28 Day 56 Day 14

  10. Anamnestic Gag-Specific Cellular Immune Responses in rAd26/rAd5 Vaccinated Monkeys Post-Challenge Gag Cytokine Functionality Gag Epitope Breadth

  11. Breadth and Magnitude of Gag-Specific Cellular Immune Responses Correlate with Setpoint Viral Loads Gag Epitope Breadth Gag ELISPOT Magnitude Pre-Challenge Post-Challenge Spearman rank-correlation tests

  12. Protection Correlated with Reduced Ki67+ Proliferation of CCR5+ Central and Effector Memory CD4+ T Lymphocytes Central Memory CCR5+ CD4+ Effector Memory CCR5+ CD4+ Day

  13. Protection Correlated with Preservation of Central Memory CD4+ T Lymphocytes CD28+CD95+CD4+/CD4+ Cells; Day 14 Post-Challenge * two-tailed Wilcoxon rank-sum test

  14. Protection Correlated with Preservation of CCR5+CD4+ T Lymphocytes CCR5+CD4+/CD4+ Cells; Day 14 Post-Challenge * two-tailed Wilcoxon rank-sum test

  15. Protection Correlated with Preservation of Duodenal Memory CD4+ T Lymphocytes CD4+/CD3+ Cells; Day 21 Post-Challenge * two-tailed Wilcoxon rank-sum test

  16. Protective Efficacy of Heterologous rAd Prime-Boost Regimens in Rhesus Monkeys • The heterologous rAd26/rAd5 regimen elicited improved quality, breadth, and magnitude of cellular immune responses as compared with the homologous rAd5/rAd5 regimen • The heterologous rAd26/rAd5 regimen afforded a significant 1.4 log reduction of peak and 2.4 log reduction of setpoint SIV RNA as compared with controls for >500 days post-challenge • The homologous rAd5/rAd5 regimen failed to afford a significant reduction of peak or setpoint SIV RNA, consistent with prior studies Liu et al. Nature, Nov 9, 2008 (advance online publication)

  17. Protective Efficacy of Heterologous rAd Prime-Boost Regimens in Rhesus Monkeys • Thus, heterologous rAd prime-boost regimens can afford durable partial protection in the stringent SIV challenge model in which the homologous rAd5 regimen fails • Protection correlated with Gag epitope-specific T lymphocyte responses and did not involve a homologous Env immunogen • These data suggest that T cell based vaccines that are superior to the homologous rAd5 regimen may afford better protection against HIV-1 • We are not at the end of the road in terms of the development of T cell-based HIV-1 vaccines Liu et al. Nature, Nov 9, 2008 (advance online publication)

  18. Safety of Novel rAd Vectors • Are anamnestic Ad5-specific T lymphocyte responses following rAd5 vaccination a safety concern in individuals with baseline Ad5 NAb titers? • Potential concern regarding cross-reactive T lymphocytes between Ad5 and rare serotype Ads? • Collaborative study with D. Casimiro and M. Robertson, Merck • 116 subjects from Merck phase 1 studies of rAd5-Gag • Dose: 1010 or 1011 vp • Samples: week 0 (pre-vaccine) and week 8 (post-2nd vaccine) serum and PBMC • Assays: Ad NAb and ELISPOT assays with 104 MOI virus • Peptide-specific assays and ICS assays in progress

  19. Ad5 ELISPOT Responses Are Nearly Universal and Do Not Correlate with Ad5 NAb Responses at Baseline Baseline Serum and PBMC Samples P=0.83

  20. Higher Ad5 NAb Responses Following Vaccination in Individuals with Baseline Ad5 NAbs >18 vs <18 P=2.4x10-3 P=5.4x10-4 P=2.1x10-5 P=2.0x10-6 P=5.8x10-4 P=2.0x10-6 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  21. No Detectable Ad26 NAb Responses Following Vaccination P=0.88 P=0.87 P=0.81 P=0.95 P=0.79 P=0.97 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  22. No Detectable Ad35 NAb Responses Following Vaccination P=0.48 P=0.75 P=0.35 P=0.86 P=0.51 P=0.95 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  23. No Detectable Ad48 NAb Responses Following Vaccination P=0.86 P=0.64 P=0.84 P=0.70 P=0.79 P=0.99 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  24. Lower Ad5 ELISPOT Responses Following Vaccination in Individuals with Baseline Ad5 NAbs >18 vs <18 P=0.91 P=0.95 P=2.3x10-3 P=8.3x10-3 P=8.9x10-5 P=0.043 P=4.2x10-3 P=0.53 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  25. No Detectable Ad26 ELISPOT Responses Following Vaccination P=0.85 P=0.27 P=0.95 P=0.39 P=0.32 P=0.83 P=0.64 P=0.80 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  26. No Detectable Ad35 ELISPOT Responses Following Vaccination P=0.49 P=0.17 P=0.47 P=0.55 P=0.57 P=0.75 P=0.84 P=0.56 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  27. No Detectable Ad48 ELISPOT Responses Following Vaccination P=0.59 P=0.85 P=0.55 P=0.29 P=0.40 P=0.98 P=0.75 P=0.90 >18 >18 < 18 < 18 Baseline Ad5 NAb 1010 vp Ad5-Gag 1011 vp Ad5-Gag

  28. Safety of Novel rAd Vectors • Ad5 T cell responses nearly universal in subjects prior to vaccination; likely driven by cross-reactive hexon-specific T cell responses among multiple common subgroup C Ads • Ad26, Ad35, Ad48 T cell responses also common • No correlation observed between Ad5 NAb titers and Ad5 T cell responses prior to vaccination • Suggests that Ad5 NAb titers are not simply a “surrogate” marker for Ad5 T cell responses • Similar baseline Ad5 T cell responses in subjects with baseline Ad5 NAbs >18 as compared with <18

  29. Safety of Novel rAd Vectors • Following rAd5 vaccination: • Ad5 NAb responses higher in subjects with baseline Ad5 NAbs >18 as compared with <18 • Ad5 T cell responses lower in subjects with baseline Ad5 NAbs >18 as compared with <18 • No detectable increase in NAb or T cell responses to Ad26, Ad35, Ad48 • Consistent with STEP data to date (J. McElrath, N. Frahm) • These data reduce the plausibility of the hypothesis that enhancement of HIV-1 acquisition in subjects with baseline Ad5 NAbs >18 in the STEP study was due to anamnestic vaccine-elicited Ad5 T cell responses • Cross-reactive T cell responses against rare serotype Ad vectors would pose even less of a concern • Caveats: functional ICS and mucosal responses TBD

  30. Rationale for the Development of Novel Adenovirus Vector-Based Vaccines for HIV-1 • Novel rAd vectors are biologically different than rAd5 vectors • Different cellular receptors • Different tropism • Different intracellular trafficking pathways • Different innate immune responses • Different phenotypes of adaptive immune responses • Novel rAd vectors outperform rAd5 vectors in rhesus monkeys • Evade pre-existing anti-vector immunity • Enhance polyfunctionality/quality of T lymphocyte responses • Augment magnitude and breadth of responses when combined into heterologous rAd prime-boost regimens • Substantially improve protection against SIVmac251 in rhesus monkeys • Novel rAd vectors likely safer than rAd5 vectors in humans • Designed to circumvent anti-vector immunity • No significant cross-reactive anti-vector humoral immunity with Ad5 • Extent of cross-reactive anti-vector cellular immunity under investigation • NIH, FDA, and IRB approved initiation of our rAd26 phase 1 study

  31. Ad26.ENVA.01 Phase 1A StudyNIH IPCAVD Program • Single-site, randomized, double-blinded, placebo-controlled phase 1A study to evaluate the safety and immunogenicity of the Ad26.ENVA.01 vaccine vector (PI: L. Baden) • First-in-human study of a rAd26 vector • 48 subjects at low risk for HIV infection and Ad26 seronegative • Groups: • 109 vp dose months 0, 1, 6 10 vaccinees, 2 placebos • 1010 vp dose months 0, 1, 6 10 vaccinees, 2 placebos • 1011 vp dose months 0, 1, 6 10 vaccinees, 2 placebos • Max dose months 0, 6 10 vaccinees, 2 placebos • Study in progress; vaccine safe and well tolerated to date

  32. Ad5HVR48.ENVA.01 Phase 1A StudyNIH IPCAVD Program • Single-site, randomized, double-blinded, placebo-controlled phase 1A study to evaluate the safety and immunogenicity of the Ad5HVR48.ENVA.01 vaccine vector (PI: L. Baden) • First-in-human study of a hexon-chimeric rAd5 vector • FDA clinical hold re: risk criteria lifted October 29, 2008 • Enrollment expected to begin in Jan 2009 • Likely more regulatory challenges for future development of rAd5HVR48 as compared with rare serotype rAd vectors

  33. Design of Optimal Heterologous rAd Prime-Boost Regimen: rAd5HVR48/rAd26 in Rhesus Monkeys Prime Boost IFN-g ELISPOT responses prior to and following boost immunization

  34. Design of Optimal Heterologous rAd Prime-Boost Regimen: rAd35/rAd26 and rAd48/rAd26 in Mice Boost Prime IFN-g ELISPOT responses following boost immunization

  35. Desired Features of a Next-Generation T Cell-Based HIV-1 Vaccine Candidate • Key features desired in a next-generation T cell-based HIV-1 vaccine: • Vectors that avoid pre-existing vector-specific NAbs and that can be combined into a heterologous prime-boost regimen • Antigens that improve cellular immune breadth and that optimize coverage of global virus diversity

  36. Desired Features of a Next-Generation T Cell-Based HIV-1 Vaccine Candidate • Importance of cellular immune breadth increasingly clear • Gag breadth critical for vaccine control of SIV challenge in NHPs • Gag breadth critical for immune control of HIV in humans (B. Walker) • In the STEP study, only limited breadth achieved by Merck rAd5-Gag/Pol/Nef vaccine (J. McElrath, N. Frahm, F. Li): • Mean of only 2-3 epitopes per vaccinee (and only 1 Gag epitope) • Gag epitopes not directed against conserved regions of Gag • 0 (zero) Gag epitopes in vaccinees with pre-existing Ad5 NAbs • Trend observed between Gag breadth and setpoint viral loads • Critical to improve breadth of Gag-specific cellular immune responses in a next-generation T cell-based HIV-1 vaccine

  37. Desired Features of a Next-Generation T Cell-Based HIV-1 Vaccine Candidate • We are currently exploring several antigen strategies together with B. Korber to improve cellular immune breadth • M mosaic Gag/Pol/Env antigens (2-valent) • M consensus Gag/Pol/Env antigens • Optimal natural clade C Gag/Pol/Env antigens

  38. Desired Features of a Next-Generation T Cell-Based HIV-1 Vaccine Candidate • Next generation T cell-based HIV-1 vaccines will face a higher “bar” to advance into efficacy studies • Novel vector regimen: • Heterologous rAd prime-boost regimen using serologically distinct rare serotype rAd vectors • Preclinical evidence of superior protective efficacy compared with the homologous rAd5 regimen against SIV challenge in rhesus monkeys • Novel antigen concept: • Antigen set optimized for augmented cellular immune breadth and improved coverage of global viral diversity • Preclinical evidence of superior breadth compared with best natural clade C sequences using global PTE peptides in rhesus monkeys

  39. Conclusions • The failure of the Merck rAd5-Gag/Pol/Nef vaccine clearly represents a “product failure” but may not represent a “concept failure” of T cell based vaccines in general • SIV challenge studies in rhesus monkeys show that heterologous rAd prime-boost regimens with rAd26 vectors outperform homologous rAd5 regimens • Prototype rAd26 vector under evaluation in a phase 1 study • Novel antigen sets aimed at improving cellular immune breadth under evaluation in NHP studies • Evaluation of a heterologous rAd prime-boost regimen using two rare serotype rAd vectors expressing HIV-1 Gag/Pol/Env optimized for global coverage may therefore be warranted

  40. Beth Israel Deaconess, Harvard Medical School Peter Abbink Ritu Bradley Sarah Clark Rebecca Dilan David Kaufman Sharon King Annalena LaPorte Hualin Li Jinyan Liu Diana Lynch Lori Maxfield Joseph Nkolola Kara O’Brien Elizabeth Rhee Ambryice Riggs Larissa Sasgen Nate Simmons Faye Stephens Betty Sun Flow Cytometry Core Brigham and Women’s, Harvard Medical School Lindsey Baden Raphael Dolin Marissa Wilck Acknowledgements • Crucell Holland BV • Marcel Brink • Nico Bunnik • Jerome Custers • Frans Delemarre • Jaap Goudsmit • Anneke Griffioen • Guus Hateboer • Menzo Havenga • Evert Heemskerk • Lennart Holterman • Karin Hoogendoorn • Peter Karels • Erica Kerkvliet • Matthijs Koorevaar • Fija Lagerwerf • Angelique Lemckert • Giuseppe Marzio • Maria Grazia Pau • Frank Raaphorst • Giulia Schirru • Jolande Schoemaker • Govert Schouten • Herman Van Herk • Mark Van Ooy • Crucell Holland BV cont. • Ronald Vogels • Miranda Weggeman • Mo Weijtens • Sander Worst • Children’s Hospital, Harvard Medical School • Bing Chen • Stephen Harrison • New England Primate Research Center • Angela Carville • Keith Mansfield • IAVI • Nick Jackson • Wayne Koff • SRI • Joan Roelands • Bridge GPS • Bin He • Yefan Wang • CHAVI • Bart Haynes • Bette Korber • Norman Letvin • Merck Research Labs • Danny Casimiro • Sheri Dubey • John Shiver • VRC, NIAID, NIH • Charla Andrews • Phil Gomez • Gary Nabel • Rebecca Sheets • DAIDS, NIAID, NIH • Chris Butler • Massimo Cardinali • Woody Dubois • Mary Ann Luzar • Nancy Miller • Michael Pensiero • CAVD, Gates Foundation • Jose Esparza • Nina Russell

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