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The Current State of RSV Vaccine Development Outline Respiratory 1/7/2014 The Current State of RSV Vaccine Development 2014 AAAAI Annual Meeting 4304: How Close Are We to Preventing Asthma by Vaccination? San Diego, CA Barney S. Graham, MD, PhD March 3, 2014 Vaccine Research Center National Institute of Allergy and For more information: Infectious Diseases 1-866-833-LIFE National Institutes of Health Department of Health and Human vrc.nih.gov Services [email protected] Outline • RSV epidemiology and pathogenesis • History and challenges for RSV vaccine development • F glycoprotein function, structure, and antigenic sites • Vaccine antigen design and immunogenicity • Considerations for vaccine development Respiratory Syncytial Virus 3 1 1/7/2014 Global RSV Disease Burden 28‐364 days of life Malaria (11.8%) RSV Lozano, R et al. The Lancet. 2012; 380:2095‐2128. RSV kills more children <1 year than any other single pathogen except malaria 4 Outline • RSV epidemiology and pathogenesis • History and challenges for RSV vaccine development • F glycoprotein function, structure, and antigenic sites • Vaccine antigen design and immunogenicity • Considerations for vaccine development RSV Disease Burden and Market Potential Vaccine market 34 million ALRI globally 3.4 million hospitalizations • Leading cause of hospitalization in children under 5 years of age • Leading cause of medically attended respiratory infection in children • Cause of excess mortality in elderly similar to seasonal influenza Passive mAb market 6 2 1/7/2014 Challenges for a RSV Vaccine • Young age of serious disease • Multiple mechanisms to interfere with induction and effector function of Type 1 interferons • Failure of natural immunity to protect against reinfection • Difficult to boost responses in adults • Legacy of vaccine-enhanced disease – Properties to Avoid • Antibodies with poor NT activity → Immune complex deposition • CD4+ Th2-biased response → Allergic inflammation 7 FI-RSV Vaccine-Enhanced Disease Vaccine n Infected (%) Hospitalized (%) Deaths FI- RSV 31 20 (65) 16 (80) 2 FI-PIV-1 40 21 (53) 1 (5) 0 Kim et al. Am J Epidemiol 1969;89:422 8 Overview of RSV Vaccine Clinical Development No Efficacy – No Efficacy – Low/No Efficacy – Efficacy unknown – Serious Adverse Inappropriate No Immediate Currently in Efficacious Effects Immune Response Safety Concerns Clinical Testing Formalin-inactivated Subunit vaccine Subunit vaccine Live attenuated RSV None alum-precipitated G protein – F glycoprotein in nasally in children whole virus streptococcal alum in adults rA2cp248/404/1030/∆SH conjugate ∆M2-2 Various live attenuated RSV Post-fusion F Rosettes nasally in children Live virus vaccine delivered IM in children BPIV-RSV live chimeric virus nasally 9 3 1/7/2014 Options for Vaccine Development Platforms Antigens Delivery Target Populations Live‐attenuated F Respiratory tract Neonate (<2 mo) • RSV • chimeric paramyxovirus vectors G Parenteral Infants and children (>6 mo) • Sero‐negative Gene‐based vectors • SH Other mucosal site Sero‐positive • Nucleic acid –DNA or RNA • Replication defective Siblings and parents of • Replication competent Internal neonates Subunit or particle‐based Multiple • Purified protein Young adult women • Virus‐like particle • Pregnant women • Virosome • Women of child‐bearing age • Nanoparticle • Peptides Elderly (>65 yr) Whole‐inactivated RSV 10 RSV Vaccine Pipeline Product Sponsor Type of Vaccine Target Antigen Target population Phase Sanofi RSV vaccine Sanofi Subunit F, G, M protein Elderly patients Phase II BBG2na Queen’s Univ Belfast Subunit G n/a Phase II MEDI-559 MedImmune Live-attenuated Whole virus Infants and children Phase I-IIa MEDI-534 MedImmune Live chimeric F Protein Infants Phase I-IIa MEDI ∆M2-2 & others NIAID +/- MedImmune Live-attenuated Whole virus Adults, infants and children Phase I Novavax RSV Novavax Nanoparticle F Protein n/a Phase I Sendai-RSV chimera St. Jude’s Live chimeric F n/a Pre-clinical RSV vaccine Merck/Nobilon Single-cycle Whole virus n/a Pre-clinical NanoBio RSV Nanobio/Merck Inactivated Whole virus n/a Pre-clinical MVA-BN RSV Bavarian Nordic Vector Subunit Adult high risk patients Pre-clinical GenVec RSV GenVec Vector F Children and infants Pre-clinical Universal RSV Crucell/J&J Vector Subunit Infants and elderly Pre-clinical RSV vac_Oka Okairos Vector F-N-M2-1 n/a Pre-clinical VEE-F Alphavax Vector F n/a Pre-clinical RNA replicon Novartis Vector-RNA F n/a Pre-clinical Mymetics RSV Mymetics VLP-Virosome Multiple Elderly patients Pre-clinical TechnoVax Technovax VLP Multiple n/a Pre-clinical SynGem Mucosis VLP-lactococcus F n/a Pre-clinical RSV VLP Vac LigoCyte VLP F n/a Pre-clinical F protein Novartis Subunit F n/a Pre-clinical RSV vaccine GSK Subunit F Pediatric Pre-clinical AMV601 / RespiVac AmVac Subunit n/a Pre-clinical PEV4 Pevion Subunit F n/a Pre-clinical Epitope-scaffold U. Wash/ TSRI) Epitope-scaffold F epitope Pediatric and at-risk adults Pre-clinical SHe Ghent/Immunovaccine Subunit SH n/a Pre-clinical T4-214 TI Pharma n/a Pre-clinical TWi RSV vaccine TWi Biotech n/a Pre-clinical Sources: Company Website, Fierce Vaccines, RSV 2012 Symposium, Clinicaltrials.gov 11 Outline • RSV epidemiology and pathogenesis • History and challenges for RSV vaccine development • F glycoprotein function, structure, and antigenic sites • Vaccine antigen design and immunogenicity • Considerations for vaccine development 4 1/7/2014 RSV Genome Organization and Protein Functions M2-1 M2-2 NS1 NS2 N P M SH G F L le tr 3´ 15,222 nt total 024106 8 15 kb plasma envelope spikes membrane G (298) - attachment - neutralization target nonstructural - antibody decoy (secreted G) - fractalkine mimic NS1 (139) - inhibit Type I IFN induction - inhibit Type I IFN signaling - TLR antagonist NS2 (124) - activate PI3K and NF-B F (574) - fusion and entry - inhibit apoptosis - neutralization target - TLR4 agonist 150 nm nucleocapsid-associated SH (64) - putative viroporin regulatory - inhibits apoptosis N (391) - RNA-binding M2-2 (90) P (241) - phosphoprotein - viral transcription inner envelope face - RNA replication L (2165) - polymerase M (256) - assembly M2-1 (194) - transcription processivity factor 13 Organization of RSV F Glycoprotein F2 F1 27* 70 116 126 500 * FP HR1 HR2 TM Regions of high mobility 1 21 37 69 212313 322 333 343 358 367 382 393 416 422 439 550 574 Antigenic sites II I IV * Unique to RSV •Type I integral membrane protein Signal peptide Fusion peptide •pH‐independent class I viral fusion protein Heptad repeat •Two furin cleavage sites Transmembrane domain •Two heptad repeat regions that form an anti‐ Cysteine parallel six‐helix bundle in post‐fusion state Disulfide bond N-linked glycosylation •F1 has cysteine‐rich domain and a relatively large C-linked palmitylation interspace between the two heptad repeats Furin cleavage site •Short cytoplasmic tail Neutralizing antibody epitope Infection inhibiting peptide 14 Comparison of other Class I Fusion Proteins in Native Prefusion Conformation RSV Flu HIV‐1 Modified from Colman and Lawrence, Nat Rev Mol Cell Biol (2003) 4, 309‐19 15 5 1/7/2014 Mechanism of F-mediated membrane fusion Fusion peptide Receptor Pierces target cell Hemifusion Full fusion triggering membrane Target cell Virion Prehairpin Postfusion Prefusion intermediate six‐helix bundle 16 Mechanism of F-mediated membrane fusion Target cell Fusion pore established Delivery of nucleocapsid and genome Virion 17 Antigenic sites present on post-fusion F are not major targets for in vivo NT activity Site I 131‐2a, 2F Site IV 101F mAb19 Site II Palivizumab Motavizumab Magro et al, PNAS (2012) 7, 3089‐94 McLellan et al, J Virol. (2011) 18 6 1/7/2014 Stabilization of Prefusion RSV F with Human mAbs (D25/AM22) Reveals New Antigenic Site McLellan et al. Science April 2013 19 Vaccine Antigen Selection: Rationale for Choosing F Reasons for choosing F: • Target of Synagis • Higher sequence conservation than G • Unlike G, F is absolutely required for virus entry 20 RSV F Has One Extremely Mobile Domain and Another that is Relatively Fixed McLellan et al. Science April 2013 21 7 1/7/2014 Antigenic Site Ø McLellan et al. Science April 2013 22 Properties of Antigenic Site Ø mAbs McLellan et al. Science April 2013 23 Antigenic Sites on RSV F Associated with Neutralization McLellan et al. Science April 2013 24 8 1/7/2014 Implications of Using Prefusion or Postfusion F 25 Antigenic Sites on RSV F Under Immune Pressure antigenic site Ø antigenic site II antigenic site IV Possible antigenic site III as defined in metapneumovirus antigenic site I – P389 McLellan et al. Science April 2013 26 Outline • RSV epidemiology and pathogenesis • History and challenges for RSV vaccine development • F glycoprotein function, structure, and antigenic sites • Vaccine antigen design and immunogenicity • Considerations for vaccine development 9 1/7/2014 S155C/S290C mutations (DS) can form disulfide bond only in prefusion state Val154 Ser290 Ser155 Lys156 Prefusion Postfusion Jason McLellan 28 DS version of stabilized prefusion RSV F can be purified to homogeneity RSV F Δ141‐150 ΔTM ~1,000 particles 2D averages Ulrich Baxa 29 DS version of prefusion RSV F induces potent neutralizing activity Week 7 vs. Prefusion Postfusion RSV Line 19 (Subtype A) RSV 18537 (Subtype B) Man Chen 30 10 1/7/2014 DS does not stabilize antigenic site Ø D25‐bound DSRSV F Δ141‐150 ΔTM McLellan et al. Science November 2013 31 Design Approach for Stabilizing Antigenic Site Ø on Trimeric F Antigenic site Ø Peter Kwong, Jason McLellan, Gordon Joyce, Guillaume Stewart‐Jones 32 Alternative Method of Stabilization: Cavity-Filling
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