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-g CD4C 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.

New Routes and Opportunities for Modular Construction of Particulate Vaccines: Stick, Click, and Glue

“…However, one can use monovalent streptavidin (four subunits but only one subunit binds biotin) or monomeric streptavidin (one subunit but lower biotin affinity) ( 47 – 50 ). Early studies only coupled short peptides to VLNPs ( 51 , 52 ), but the approach has since been adopted for full-length proteins up to 85 kDa ( 49 ). Even though biotin’s interaction to avidin/streptavidin has a high-affinity, half-times for biotin-conjugate dissociation are on the scale of hours ( 53 ), so re-shuffling is expected upon storage.…”

Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design

“…These issues can be addressed with post-assembly orthogonal functionalization (Figure 7). These strategies not only support independent folding and selfassembly, but also enable efficient substitution of a diversity of epitopes on a carrier nanoparticle, addressing the challenge of antigenic drift [123,124]. Non-covalent functionalization methods can take advantage of the moderate affinity between a poly-His sequence and nickel-coordinated nitrilotriacetic acid (Ni-NTA), or the strong affinity between streptavidin and biotin.…”

In silico Identification of Potential Peptides or Allergen Shot Candidates Against Aspergillus fumigatus

“…Two allergenic proteins, Asp f5 and Asp f7 , did not contain any high-affinity binding MHC class I T cell epitopes for mouse and human, respectively. We use all mouse MHC class I alleles and eight human alleles (A*0101, A*0201, A*2402, A*0301, A*1101, B*0702, B*0801, and B*1501) that cover 90% of the world population 39 (Tables 3–6). Furthermore, four allergenic proteins, Asp f1 , Asp f2 , Asp f4 , and Asp f5 , were predicted to have high-affinity binding mouse MHC class II-restricted epitopes, whereas all 10 allergenic proteins showed high-affinity human MHC class II-restricted T cell epitopes.…”