Vectored Vaccines for HIV: Status and Path Forward Rick King International AIDS Vaccine Initiative Thailand 2011
Acknowledgements IAVI R&D Chris Parks Wayne Koff Mike Caulfield ld Adrian McDermott Thomas Hassell Pat Fast Thanks for Providing Data Louis Picker David Watkins Dan Barouch Harriett Robinson Gary Nabel Jack Rose Tomas Hanke CAVD Chris Parks/ Nina Russell NIH grant R01-AI084840 2
Goals for presentation Identify challenges What do we know about efficacy of vectored vaccines and howcanweusetheinformation? we Human trials SIV system Opportunities Incorporating both prevention of infection and control of disease in a vectored vaccine
Underlying Challenges of HIV Vaccine Development: Diversity of Epidemic B D Walker, D R Burton Science 2008;320:760-764 A vaccine must attack multiple or common targets on HIV
Underlying Challenges of HIV Vaccine Development: Chronic Infection and Rapid Mutation Is the game over following escape from the local site of infection?
Vectored Vaccines are showing efficacy: Prevention of Infection and Control of Disease X Viral Load Can the next generation of vectored vaccines incorporate both?
The best data for improving vectored vaccines will come from clinical trial efficacy results 2010 2011 2012 2013 2014 2015 2016 2017 RV144 Thai Trial : Correlates RV 144 Licensure Trial in Thailand RV 144 Phase IIb Efficacy in High Risk Groups DNA + Ad5: Phase IIb Efficacy Ad35/Ad26 Mosaic Platform: Phase IIb Efficacy MVA/Ad26 Mosaic Platform: Phase IIb Efficacy Prevention of infection in RV144 New efficacy data will emerge to guide vector design
Improving Vectored Vaccines: Prevention of Infection RV144 and follow up studies will be a rich source of information for vaccine design SIV protection is possible and requires Envelope in vaccine SIV protection mechanisms under investigation Binding antibodies Antibody avidity Neutralizing antibodies CD4 responses
Adenovector type 5 prime boost (Ad gag pol nef) No effect on preventing SIV E660 infection 100 90 Vaccinees (n=8) Controls (n=8) Percen nt Uninfect ted 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Challenges Provided by David Watkins
Ad35 prime Ad26 boost: Protection associated with Env response % Uninfec cted 100 80 60 40 20 GagPol (N=16) GagPolEnv (N=16) Sham (N=8) 0 0 2 4 6 Number of IR Challenges Provided by Dan Barouch
DNA Prime Ad5 boost: Protection associated with Neutralizing Ab
DNA Prime MVA boost: Protection associated with higher avidity Abs nfected Perce ent uni P = 0.0009 Index SIVE66 60 Env Avidity 55 50 45 40 35 30 r=0.9 p=<0.0001 25 0 2 4 6 8 10 12 14 No. of challenges Number of Challenges to Infection
Protection from Infection Titered Mucosal Challenge of Rhesus Macaques with SIVmac251 Recapitulates HIV Vaccine Efficacy in Humans G Franchini, P Pegu. M Vaccari, S Gordon, B Keele, M Doster, Y Guan, G Ferrari D Montefiori, D Venzon, C Fenzia, J Lifson, N Michael, J Kim, J Tartaglia AIDS Vaccine 2011
Approaches to Improving Protection from Infection Goal: Improve responses to Envelope Identify the nature of protective responses so we can optimize Improve display of native Envelope Improve immunogenicity Prime boost combinations Replicating vectors Combine with protein based vaccine
Are vectors delivering most appropriate Env immunogens? Tier 2 Envelope Binds bnabs Does not bind nonneutralizing antibodies RV-144 Proteins Tier 1 Envelope Binds many Abs Common vector delivered Protein gp140
Current Env Trials: Few vectors express gp160 Trial OrganizerDeveloper Vaccine VRC 012 (07 I 0167) NIAID, VRC Ad 35 Env gp140 A; Ad 5 Env gp140 A VRC 015 (08 I 0171) NIAID, VRC Ad 5 GagPol B, Env gp140 A/B/C Tiantian vaccinia HIV Vaccine Chinese CDC, Guangxi CDC Replicating Tiantian vaccinia; DNA HIV 1 CN54 gag, pol and env genes HVTN 205/ HVTN 65 GeoVax, HVTN DNA Gag, PR and RT, and Env gp120 and gp41, Tat, Rev, Vpu B; MVA gag pol env truncated gp41 and gp120 B IAVI B001 U. Rochester Medical Center, Ad35 GRIN,Ad35 gp140 IAVI HVTN 073 SAAVI HVNT DNA and MVA prime boost same antigens: Gag RT Tat Nef and truncated gp160 Ad5HVR48.ENVA.01 NIAID Ad 5 Ad48 chimera Env gp140 A HVTN 077 NIAID, HVTN Ad 35 Env gp140 A; Ad 5 gp140 Env A; DNA Env gp140 A HVTN 505; HVTN 204; HVTN NIAID, HVTN DNA Env gp140 A/B/C, gag B, pol B, nef B; Ad 5 GagPol B, Env gp140 A/B/C 082; HVTN 076 HVTN 078 NIAID, EuroVacc, HVTN Pox Env gp120 B, gag pol nef B; Ad 5 Env gp140 A HVTN 083 NIAID, HVTN Ad 35 Env gp140 A; Ad 5 Env gp140 A; Ad 5 Env gp140 B HVTN 084 NIAID, HVTN Ad 5 GagPol lb, Env gp140 A/B/C; Ad 5 gag pol B IAVI B003 IAVI Ad35 gp140a, Ad26 gp140a RV262 NIAID, U.S. Military HIV Research Program (MHRP) DNA Env A, Env C, Env D, Gag; MVA gag pol CM 240, env CM235 E cytoplasmic tail of env truncated HVTN609/VRC HVTN, VRC DNA gag pol nef Env gp140 A/B/C HIVIS 07 Swedish eds Institute tute for Infectious DNA and MVA pkcmvgp160a,,pkcmvgp160b,,pkcmvgp160c Disease Control Ad26.ENVA.01 NIAID Ad 26 Env gp140 A HPTN 027 NIAID, Sanofi Pox Env gp120 BE HVRF 380 131004 Moscow Institute of Protein Env B Immunology, Russian Federation NCHECR AE1 NCHECR, University i of New DNA Gag, RT, Protease, mrnaseh, Rev, Tat, Nef and Env containing i a deletion dl in the middle South Wales 1/3 of the gene; Pox identical seq Gag, Pol, Env, Tat and Rev AE RV 138; B011 WRAIR USMHRP Pox gp120 MN tm/gag/protease LAI Cervico vaginal CN54 St George's, University of London Protein CN54gp140 glycoprotein hsp70 conjugate
Can vector design exploit the new discoveries of Env structure and antibody recognition? PGT Abs Provided by Bill Schief
Using Conformation dependent antibodies PG9/16 EnvG Hybrid Ti Trimers Env Clade C VSV G tm/ct t VI10 (VSV G) VRC01 PG16 PG9 b12 2F5 Secondary Ab only Cell Surface Staining detected by FACS Maoli Yuan, Aaron Wilson, Kevin Wright, Sanjay Phogat Parks et al (IAVI)
Engineering Env to bind most broad neutralizing antibodies Antibodies 16055 16055 modified B12 ++ ++ PG9 ++++ ++++ PG16 +++ +++ VRC01 ++++ ++++ VRCPG04 +++ +++ PGT121 - ++++ PGT122 - ++ PGT123 - ++++ PGT125 - ++ PGT126 - ++++ PGT130 - +++ PGT135 - ++++ PGT136 - ++++ PGT141 - - Denise Wagner Sanjay Phogat Pascal Poignard Burton et al (IAVI)
Targeting Functional Env: CDV and VSV based Vectors VSV G Can engineer live replication competent HIV-like vector particles CDV preferentially replicates in lymphoid tissues Functional Env Chris Parks et al (IAVI CAVD) CDV GFP / Ferret abdominal cavity von Messling, Milosevic, Roberto Cattaneo, 2004, PNAS 101:14216 14221
CDV vectors: delivery of cleaved Env to cell surface 1: parental rcdv 2: rcdv SIVEnvΔct4 3: rcdv SIVEnvΔct6 4: rcdv SIVEnvΔct6uncleaved Viral mrna NON-PERMEABILIZED N N P M Env F H VAC L 1 2 3 4 5 6 7 P M F H VAC Env L Chris Parks Jason Zhang et al (IAVI CAVD)
CDV vector Tissue targeting and Immunogenicity 1.0E+10 3.5 Average Env genome e cps/gram tissue 1.0E+08 1.0E+06 1.0E+04 1.0E+02 10E 1.0E+0000 Peyer's Patch rich intestine Mesenteric Lymph Node Nasal Turbinates Day 1 Day 7 Day 21 Brain Brain Stem Olfactory Bulb OD (450nm m) 3 2.5 2 1.5 1 0.5 0 naive CDV parental CDV SIVEnv Endpoint Titer Chris Parks Gavin Morrow John Coleman et al (IAVI CAVD)
Improving Vectored Vaccines: Control of Disease RV144 seems not to reduce viral load Vaccination can control SIV Control of Disease seems not to require Envelope Mechanisms of control are under investigation
Ad5 gag,pol,nef (3X): Limited effect on Control of Disease: asma ic mean of py Eq/ml pl Geometr vrna co 10 6 p=0.10 Vaccinees 10 5 Controls 10 4 10 3 p=0.33 p=0.62 p=0.28 p=0.54 p=0.95 10 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Weeks after detectable SIVsmE660 infection Provided by David Watkins
CMV Vector: Control Associated with CD8 Effecter Memory 6 CD8+ Plasma Vir ral Load 5 10 9 Group A (CMV/CMV) 4 n = 6 p =.0017 3 10 8 2 10 7 1 10 6 0 10 5 A B C 10 4 10 3 n = 6 10 2 75 0 28 56 84 112 140 168 196 224 50 Effector (CD28-/CCR7-) 100 A CMV CMV B CMV Ad C DDD Ad 25 0 Group A Group B Group C
DNA + IL12 Prime, Ad5 Boost: Control of disease improved by the right prime P=0.002 P=0.004 1 9 3.9 DNA+IL1 EP SIV- 2 rad5 EP SIV-DNA rad5 Naïve Controls Set point Virus Load (>8 weeks)
DNA Prime + Boost: Improved by cytokine expression in prime DNA and Protein Vaccination Confers Protection Upon Mucosal Challenge with Heterologous SIVsmE660 (OA 10.04) 04) Rashmi Jalah, Barbara Felder, George Pavlakis Human Retrovirus Pathogenesis Section, Vaccine Branch, CCR, National Cancer Institute at Frederick, Frederick, Maryland, USA DNA/Recombinant Modified Vaccinia VirusVaccinated with Simian DNA/Recombinant Modified Vaccinia VirusVaccinated with Simian Immunodeficiency Virus Half of Infected Female Rhesus Macaques Nasally Virus mac251 Viremia to Undetectable Levels in Long-Term Control of Simian Immunodeficiency
Approaches to improving Control of Disease Capitalize in information regarding mechanism of control Improve immunogenicity Replicating vectors Prime boost combinations Dealing with diversity Broadening the immune response Focusing on immutable regions
Prime boost combinations of vectors Many combinations under test Ad-Ad, Ad-Pox, DNA-vector, Vector-Protein 11 of 22 current clinical trials Avoid antibody responses to the vector Not all combinations are equivalent
Rationale for replicating vectors: Attenuated vaccines work Many commonly used vaccines are live attenuated Live attenuated SIV can both prevent infection and control disease
Replicating Vectors: Immunogenicity data Replication Competent Pox (Tiantan) Clinical trials underway [China CDC] (NYVAC) Preclinical (Panteleo, CAVD) Measles virus vector- Clinical Trials underway. Key data Safety/Immunogenicity [GSK, NIBSC, St Georges, GentU, I Pasteur] Vesicular stomatitis virus- Clinical Trials to start soon. Key data Safety/Immunogenicity [Profectus HVTN] Sendai virus Advance Preclinical for Mucosal delivery [DNAVEC/IAVI] Cytomegalovirus Preclinical and Research systemic & persistent immunongen expression [OSRU] Replicating Adenovirus- Preclinical & Research [BIDMC, NIH, Panvax] Canine distemper virus Vaccine delivery to lymphoid tissues / mucosal delivery [IAVI CAVD] Vesicular stomatitis virus-hiv chimeras engineered to mimic HIV particles [IAVI CAVD] 31
Insert design for improved T-cell responses Concepts are best tested in clinical trial Increase the number of epitopes recognized Mosaic strategy Clinical trial data ~2013 (?) Direct responses to conserved epitopes Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael Mi laj, Hanke T. PLoS One. 2007 Rolland M, Nickle DC, Mullins JI. PLoS Pathog. 2007 Dahirel V, Shekhar K, Pereyra F, Miura T, Artyomov M, Talsania S, Allen TM, Altfeld M, Carrington M, Irvine DJ, Walker BD, Chakraborty AK. Proc Natl Acad Sci U S A. 2011
HIVcons: preliminary evidence of immunogenicity HIV-CORE002 Healthy, Low-Risk Volunteers in Oxford (Multiple l Prime Boost Combinations under test) t) 700 600 500 400 300 200 100 0 100 Screen week 0 week 1 week 2 week 4 week 8 week 9 week 12 week 20 week 28 ChAd MVA Pool 1 Pool 2 Pool 3 Pool 4 Pool 5 Pool 6 FEC Provided by Tomas Hanke, Oxford University
Paths forward Vectors can be effective: both protection and control RV144 30% protection Multiple cases of efficacy in SIV low dose challenge Opportunities exist to combine protection from infection and control of disease in a single vaccine Understanding mechanisms of efficacy is important Improved immunogenicity Improved inserts
Designs for Particle Display of Envelope VSV G Potential for: High density display of gp160 Env & EnvG trimers G + MPER Specific regions (eg mper) Selection of Envelopes with specific properties VSV G-Stem + MPER Chris Parks Ivo Lorenz Caulfield et al (IAVI CAVD NIAID)
VSV vector prime replicon boost: Protection associated with antibody responses Neutralizing antibodies to E660 were generated but did not correlate with protection T-cell responses were detected but did p not correlate with protection