title: VaxCelerate II: rapid development of a self-assembling vaccine for Lassa fever.
abstract: Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4(+) T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.
authors.affiliation: a Vaccine and Immunotherapy Center; Massachusetts General Hospital ; Charlestown , MA USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Leblanc
authors.forename: Leonard
authors.initials: L
authors.lastname: Moise
authors.forename: Cybelle
authors.initials: C
authors.lastname: Luza
authors.forename: Kanawat
authors.initials: K
authors.lastname: Chantaralawan
authors.forename: Lynchy
authors.initials: L
authors.lastname: Lezeau
authors.forename: Jianping
authors.initials: J
authors.lastname: Yuan
authors.forename: Mary
authors.initials: M
authors.lastname: Field
authors.forename: Daniel
authors.initials: D
authors.lastname: Richer
authors.forename: Christine
authors.initials: C
authors.lastname: Boyle
authors.forename: William D
authors.initials: WD
authors.lastname: Martin
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Fishman
authors.forename: Eric A
authors.initials: EA
authors.lastname: Berg
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Brandon
authors.initials: B
authors.lastname: Zeigler
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: William
authors.initials: W
authors.lastname: Taylor
authors.forename: Russell
authors.initials: R
authors.lastname: Coleman
authors.forename: H Shaw
authors.initials: HS
authors.lastname: Warren
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gelfand
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
authors.forename: Timothy
authors.initials: T
authors.lastname: Brauns
authors.forename: Mark C
authors.initials: MC
authors.lastname: Poznansky
mesh_terms: D000818:Animals; D001360:Avidin / Q000276:immunology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000276:immunology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D021821:Communicable Diseases, Emerging / Q000517:prevention & control; D005260:Female; D015803:HLA-DR3 Antigen / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000627:therapeutic use; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007835:Lassa Fever / Q000276:immunology* / Q000517:prevention & control*; D007836:Lassa virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D014765:Viral Vaccines / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D001426:Bacterial Proteins; D015803:HLA-DR3 Antigen; D018840:HSP70 Heat-Shock Proteins; C444642:HSP70 protein, Mycobacterium tuberculosis; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; D001360:Avidin; D007371:Interferon-gamma; D010047:Ovalbumin
keywords: 6MDP, 6-muramyl dipeptide; CGE, Capillary Gel Electrophoresis; CLO97, TLR7 ligand; CTL, Cytotoxic T-lymphocyte; CpG1826, Synthetic Oligodeoxynucleotide containing unmethylated dinucleotide sequences (Toll-like receptor 9 agonist); DARPA, Defense Advanced Research Projects Agency; EIDs, Emerging Infectious Diseases; Flu vaccine; GLP, Good Laboratory Practice; GMP, Good Manufacturing Practice; GP1, Glycoprotein-1; GP2, Glycoprotein-2; HLA, Human Leukocyte Antigen; HRP, Horseradish Peroxidase; LV, Lassa Fever Virus; Lassa fever virus; MAV, Mycobacterium tuberculosis Heat Shock Protein 70 – Avidin; MtbHSP70, Mycobacterium tuberculosis Heat Shock Protein 70; NHP, Non-human Primates; OVA, Ovalbumin; PAGE, Polyacrylamide Gel Electrophoresis; PBMC, Peripheral Blood Mononuclear Cell; PEG, Polyethyleneglycol; RVKR, Furin Cleavage Site (Arginine, Valine, Lysine, Arginine); SAV, Self-assembled vaccine; SAVL; Self-assembled vaccine formulated for Lassa Fever Virus; VaxCelerate; arenavirus; emerging infectious diseases; mycobacterium tuberculosis heat shock protein 70; peptide design; self-assembled vaccine; vaccine