FUNDERS UPDATE- BMGF Third HIV Env Manufacturing Workshop Sponsored by DAIDS-NIAID-NIH and the HIV Global Vaccine Enterprise July 20-21, 2017 Susan Barnett Senior Program Officer, Product and Clinical Development HIV Program
STRATEGIC VISION OF OUR HIV PROGRAM Accelerate the decline of the global burden and incidence of HIV infection by ensuring development and use of impactful prevention and treatment interventions Bill & Melinda Gates Foundation 2
HIV PROGRAM INTEGRATED INITIATIVES Strategic areas 1 2 3 4 5 Increase the fraction of PLHIV initiated on effective highly suppressive treatment, particularly in high transmission populations Increase the fraction of PLHIV who sustain effective highly suppressive treatment Optimize the use of existing prevention interventions to decrease incidence Develop effective long-acting prevention interventions to further decrease incidence Develop a highly efficacious and broadly used vaccine to achieve the greatest impact on decreasing incidence Cross-cutting Initiatives HIV diagnosis and linkage of PLHIV to therapy in high-transmission populations Retention of PLHIV on effective suppressive therapy Use of existing prevention interventions Long-acting anti-retrovirals development Prophylactic neutralizing antibody and biologics development Effective vaccine development Resources and policies Defining and understanding the burden and incidence of HIV infection Bill & Melinda Gates Foundation 3
VISION: EFFECTIVE VACCINE DEVELOPMENT Broad coverage of a vaccine with high efficacy and durable protection will transform the HIV epidemic by dramatically reducing incidence. 4
ADVANCED DEVELOPMENT PROGRAMS PRECLINICAL/EARLY DEVELOPMENT ALVAC/gp120/MF59 Ad26/gp140 VSVΔG Chimera hcmv-hiv P5 Janssen IAVI Picker/VirBio RV144 Trial: 31% VE @ 3.5 yrs, 60% VE at 12 mos Multiple immune correlates of risk defined Added boost, MF59 aim to improve magnitude and duration of response Need to repeat trial in humans to validate the result with P5 clade C products in RSA Go decision in May 2016 for Phase 2b efficacy trial (HVTN 702) - opened Oct 2016 Phase I safety & immunogenicity studies ongoing Need human efficacy trial to validate NHP protection correlated to non-nabs Q3 2017 GNG decision for Phase 2b efficacy trial (HVTN 705) VSV protein-expressing vector demonstrates significant protection in NHP model Elicits specific non-neutralizing antibody response that appears to correlate with protection Repeating NHP study to confirm result in larger numbers of animals in parallel with structural/physical analysis of vector Preparatory work ongoing for potential first-in-human clinical studies Clinical testing of the prototype HCMV-vector to demonstrate safety and ability of the vector to recapitulate the magnitude and novel immune responses induced in the NHP model Challenges developing manufacturing process to support initial clinical studies $20M PRI to VirBio. Modifying program to incorporate VirBio capabilities 5
HIV ENV-RELATED VACCINE INVESTMENTS AND ACTIVITIES Advanced HIV Vaccine Development Manufacture of bivalent subtype C gp120 boost for P5 clinical program (1086.C, TV1.C) Cell lines and methods for future production post-rv144 gp120 boosts (A244.AE, 6420.B) Phase 2b/3 clinical studies with lead candidates (P5, Janssen) to evaluate whether the efficacy and putative correlates of risk observed in prior studies can be replicated in a southern Africa population. Exploratory Research and Early Development Design and develop Env immunogens that induce broadly active neutralizing antibodies in animal models and evaluate in early phase clinical studies. Provide high quality, standardized immune assays, statistical services, data platforms and product development support services in order to substantially improve the translational efficiency and quality of promising candidate vaccines. Bill & Melinda Gates Foundation 6
CAVD COLLABORATIVE MODEL (2005-PRESENT) Vaccine Discovery Consortia (VDC) brought together: To form communities of interest centered around scientific ideas To share prepublication data To exchange knowledge and ideas Central Service Facilities (CSF) provide: Best-in-class services to VDCs Enable comparative analysis of standardized data Enable translational efficiency Alliance Management facilitates via: Scientific & logistical coordination and collaboration Incentives for sharing: legal agreements, contingent funding Mechanisms for sharing: web portal, meetings Bill & Melinda Gates Foundation
CAVD AS A TRANSLATIONAL ENGINE CAVD-I (RFP in 2005) Diversified pipeline of novel product concepts Big science approach collaboration, coordination, data-sharing Milestones based, emphasis on project management Centralized assay capacity for standardized comparisons CAVD-II (RFPs in 2010/2011) Focus on critical underfunded areas (replicating vectors, non-neutral. Abs, mucosal, passive immunization) Shorter, smaller grants with tighter management, more hard milestones linked to payments Vaccine Product Development Center (VXPDC at IAVI) created to provide a translational emphasis to the largely academic network CAVD-III (2012 present) Leveraging of CAVD model to 1) support community of functional cure-related grants and 2) create a similar model to accelerate vaccine translation across Global Health Build on prior investments to advance promising concepts to clinical evaluation Bill & Melinda Gates Foundation 8
CAVD VACCINE PORTFOLIO-FROM CONCEPT TO CLINIC Concept Preclinical Clinical Active Advanced Clinical Development +/- DNA +/- ALVAC + clade C gp120s + MF59/ASO1b (correlates program) ALVAC + clade C gp120s/mf59 (Phase 2b) (P5) Ad26.Mos.HIV + gp140 (Janssen) CMV NAC & Protective Ab-inducing Novel vectors & Immunogens Efficient Translation Services & Platforms pp71 UL 128-130-expressing HCMVgag vector (Picker) HLA-E Restricted CD8 Responses (McMichael) Trimer & epitope-based immunogens Next-gen SOSIP trimers (Moore) gp140 proteins (Barouch) Nearest neighbor (Kelsoe) Adjuvanted nanoparticle ENV (Pulendran) MPER-nanoparticle (Reinherz) Glycan-modified Env (Alter) Correlates of protection (Alter) Llama Anti-Env Immunogen (Jolicoeur) Ab effector function (Ackerman/Alter) GH-VAP (Atreca, IDRI, Stanford, Lee), Kymab pp71 UL 128-130-deletant HCMVgag vector (Picker) BG505 SOSIP Adj Comparison (McElrath) eod-gt8 (Schief) MPER-Peptide Liposome (Haynes) Designer SHIVs (Shaw) FLSCgp120-CD4 (Gallo) DNA gp140 (Shattock) VSV (Parks) DNA + MVA (mosaic vs. cons vs. wt) (Haynes) rcad26 (Barouch) Vx Product Development Center (IAVI) GLP Protein Core (Haynes) Env Analytics (Ward) Ab Vx Imm Monitoring Center (Montefiori/Seaman) Cellular Vx Imm Monitoring Center (Koup) Vx Immunology Statistical Center (Gottardo)
VXPDC SERVICES FOR CLINICAL PRODUCT DEVELOPMENT The VxPDC at IAVI (T. Hassell, PI) delivers value by applying the knowledge and experience of trusted professionals across the unique service areas required for vaccine development to accelerate the path from bench to clinic Project Management & Leadership Drive process with efficiency and support development / project planning (e.g., timeline, milestones, budget, deliverables) Pre-Clinical Development Process & Product Development Manufacturing Management Quality Assurance Regulatory Management Clinical Development Advise on design and outcome of toxicology studies, and facilitate data management, sample testing and tissue binding studies Identify specialized CROs / other contractors and manage the relationship throughout the development process Accelerate manufacturing by ensuring all systems and processes comply with required standards, and support assay development Support quality management by conducting audit of vendors, providing quality standards, and managing release of investigational products Provide regulatory expertise to support CTA/IND submissions (incl. sponsorship as needed); track health authority correspondences Build clinical strategy and protocol design incl. identifying sites for clinical testing, TPP development, and data management 10
DESIGN AND DEVELOP IMMUNOGENS THAT INDUCE BROADLY ACTIVE NEUTRALIZING ANTIBODIES GL-DIRECTED IMMUNOGENs WELL-ORDERED TRIMERs GL: Can we prime Ab responses to initiate bnab lineages with appropriately designed epitope immunogens? Most often followed by a trimer Can we induce bnabs by immunization (either serially or as a cocktail) with variants of wellordered trimers? [SOSIP;NFL;Foldon] eod-gt8 NAC (eod-gt8) Moore (GL trimers) NAC Moore Barouch Prime Ab responses to initiate bnab lineages with appropriately designed epitope immunogens or trimers eod-gt8 60-mer (Schief) to activate CD4bs class bnabs via germline binding Germline trimers (Moore) to activate CD4bs, V2 apex germline
DEVELOPMENT OF MPER PEPTIDE LIPOSOME VACCINE TO INITIATE 2F5 B CELL LINEAGE (B. HAYNES) Bill & Melinda Gates Foundation 12
RELATED PRESENTATIONS TODAY SHORT UPDATES AND ONGOING PROGRAMS BG505 SOSIP.664 Antu Dey (IAVI) eod-gt68 60mer Vadim Tsvnetvitsky (IAVI) GTH1-656 MPER peptide liposome Vadim Tsvnetvitsky PRODUCT DEVELOPMENT FOR EARLY STAGE CLINICAL VACCINE STUDIES Accelerated Product Development for Ph 1/2 Balancing Science, Time, Cost Antu Dey Bill & Melinda Gates Foundation 13
THANK YOU Bill & Melinda Gates Foundation 14