Over the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. However, despite these advances, many diseases are not yet preventable by vaccination and some groups (e.g. the elderly, populations of developing countries, pregnant women and neonates) remain vulnerable. Infectious diseases also demand further efforts. The highly mutagenic potential of many pathogens and the increasing prevalence of drug-resistance germs stresses the need of broadly protective vaccines capable of preventing disease.
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.
