Periodic Reporting for period 1 - SVNanoVax (Structural Vaccinology in the design of bionanoparticles with multi-copy antigen display for vaccines with enhanced efficacy)
Periodo di rendicontazione: 2015-06-15 al 2017-06-14
Compared to early vaccines containing killed or live-attenuated pathogens, modern sub-unit vaccines are safer but tend to be less immunogenic. Therefore, a key issue in vaccine research is how to improve their immunogenicity without reducing safety or tolerability.
SVNanoVax aimed to combine the approach of Structural Vaccinology with vaccine antigen display on protein bionanoparticles (BNPs).
Neisseria meningitidis serogroup B (MenB) causes severe sepsis and meningococcal meningitis, resulting in death or devastating long-term sequelae. Bexsero, an innovative research-based vaccine, is a multi-component vaccine composed of three meningococcal proteins plus outer membrane vesicles, and is conservatively estimated to provide 66-91% coverage against MenB strains worldwide. Thanks to the large amount of structural and immunological information of its components Bexsero represents an excellent tool to validate a BNPs-based antigen engineering strategy.
The first objective was to engineer stable antigens eliciting broadly protective antibody responses. Secondly, we sought to determine the most significant epitopes from an immunomodulatory perspective. The following objectives were conceived to design recombinant self-assembling protein BNPs for multicopy and surface display of the selected epitopes, thus recreating the antigen vast exposure format of virus like particles. Lastly, we set out to determine if presentation of multiple copies of these antigens on self-assembling BNPs will induce stronger immune responses.
The overall objectives of SVNanoVax focussed on the development of multi-copy antigen-BNPs for a second-generation vaccine against MenB that protects against all strains. Moreover, in addition to driving the development of an improved second-generation meningococcal vaccine with enhanced coverage, tolerability and efficacy, this research aimed at potentiating antigen-BNP technology possibly applicable to vaccines targeting other pathogens representing currently unmet medical needs.
During the SVNanoVax period we have determined the 3D structure of a broadly reactive human bactericidal antibody Fab targeting an important MenB antigen. To our knowledge, this work represents the first crystal structure of a vaccine-elicited human antibody bound to a bacterial antigen. We have also developed a system for the recombinant expression of BNPs with surface exposed, multi-copy and ordered arrays of a potent MenB antigen epitope. These BNPs will be tested in parallel with the current vaccines in order to determine the scope of protection against MenB.
These results have been compiled into a manuscript for publication in a peer-review scientific journal in an open access format. We have also deposited the structural data of the Fab-fHbp complex in the Protein Data Bank (PDB) for its public release.
In addition to saving lives and suffering by relieving the medical burden of meningococcal and other diseases, the successful development of new vaccines would further establish the position of GSK Vaccines in Siena as a ‘Centre of Excellence’ for vaccines research and development in the heart of Europe. At a time when a number of other pharmaceutical companies have withdrawn from Italy, GSK and SVNanoVax together represented a fine example of continued European development in a field where we are globally competitive. Also, the movement of the Fellow from Chicago (USA) to GSK Siena has enriched the pool of highly-trained European researchers with multi-sector experience, an important objective for the structuring of the European research area. During SVNanoVax, the Fellow also developed BNPs by working briefly at a Spanish research centre. Collectively, these interactions may lead to future job opportunities for the Fellow. SVNanoVax has contributed to European Excellence and competitiveness by allowing the preparation of high impact scientific publications (one published, one under submission) and presentations at top European and international conferences, thus endorsing continued investment in the research sector.