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Doctoral Industrial School for Vaccine Design through Structural Mass Spectrometry

Periodic Reporting for period 2 - VADEMA (Doctoral Industrial School for Vaccine Design through Structural Mass Spectrometry)

Okres sprawozdawczy: 2018-11-01 do 2020-10-31

Scientific progress has been a major driving force for the development of effective vaccines. The first golden age of vaccines started when Pasteur, Koch, Ramon, and Mérieux established the germ theory and developed vaccines based on live‐attenuated or inactivated pathogens or inactivated toxins. A second golden age in vaccine development was a consequence of innovation in cloning and cell culture technologies allowing the release of protein recombinant vaccines such as vaccines against the hepatitis B, pertussis or papilloma virus. The following implementation of glyco-conjugation chemistry allowed very effective vaccines against H. influenzae, pneumococcus, and meningococcus. In the last decade, progress in genomics has strongly contributed to vaccine development. The rational selection of candidate antigens based on genomic information, called ‘reverse vaccinology’ allowed the discovery of three protective antigens resulting in the first universal vaccine against type B meningococcus. Despite these major achievements, vaccine generation or improvement for diseases such as HIV, tuberculosis, malaria, dengue, and influenza still represent a global health challenge. These “big five” claim a toll of ~3.5 million deaths per year. A new wave of technologies in the fields of human immunology and structural biology provides the molecular information will allow the discovery and design of vaccines against pathogens that have been impossible thus far. In this context, the aim of VADEMA is to develop mass spectrometry tools to dissect the immune response following infection or vaccination and to assess the structure of vaccine candidates in their native state and how patient-derived antibodies bind to these. Taken together, such information will guide selection and optimization of vaccine candidates, promoting antigen design at molecular level with the objective of focusing the immune response toward highly protective epitopes.
To cite Rappuoli, Santoni and Mantovani, (Rappuoli R, et al., 2018), three reference scientists in the fields of vaccinology and immunology, “in the developed world, life expectancy has increased from an average of 40 yr to over 80 yr, and remarkable progress has been made in the developing world as well. Vaccines have played a major role in this dramatic improvement, which is unprecedented in the history of human-kind. Vaccines are the most effective health intervention, and it has been estimated that they will save ~25 million deaths over 10 yr from 2010 to 2020, which is equivalent to five lives saved per minute.”
Recent technological advances in human immunology and structural biology have provided new reagents and improved tools to allow a better understanding of the basic biological and molecular mechanisms leading to a protective human immune response to pathogens, inspiring new strategies for vaccine design. In this context, VADEMA proposed to combine the characterization of the epitope repertoires recognized during the immune response to pathogens and antigen structure through structural mass spectrometry, with the ultimate goal to provide the rationale for the design of new and more efficacious vaccines against infectious diseases.
VADEMA delivered a state-of-the-art Research Program in the competitive field of “infection biology” with the goal to identify novel strategies for efficient vaccine design. By bringing together the project partners’ expertise in mass spectrometry, vaccinology, and project management, VADEMA created a multidisciplinary environment in which four researchers will contribute to the development of a Structural Mass Spectrometry Platform for the identification of protective epitopes from antigens in native state.
The grant was centred on two topics, the first one focused on gaining conformational information of antigens in native state (i.e. those are present in the bacterial outer membrane) and the second one deals with dissecting the humoral response following infection or vaccination.
Conformational information of antigen in native state: The scientific and technological goals so far reached include the construction of a combination of a strong transcription promoter with an adequate chaperone to express and localize membrane antigens in outer membrane vesicles; the definition of a tag to enrich low expressed proteins compatible with the structural mass spectrometry protocol, and the set-up of a new protocol to separate lipids and proteins to enable mass spectrometry analysis. This last approach allowed to evidence conformational difference of antigens in their native (membrane -associated) and recombinant forms.
Dissecting the humoral response following infection or vaccination: The basis for a new protocol for epitope mapping of a polyclonal population has been put in place using sera from immunized animals. This new protocol has been applied with success to identify immuno-dominant epitope in human vaccines. Moreover, new method for de novo sequencing of IgG purified from vaccinated subjects is currently under development.
Training: The fellows are affiliated to the Drug Research Academy where they benefited from interactions with a wide and diverse scientific network within the academic and industrial pharmaceutical research community. The fellows are attending courses foreseen at the Graduate School in Copenhagen which make up the main curriculum for their Ph.D. Complementary courses on mass spectrometry and vaccinology will also be held during the fellowship. The fellows could participate to numerous seminars provided by worldly recognized scientists either by the University of Copenhagen or GSK Vaccines.
Transferable skills: At the same time, the students acquired transferable skills e.g. in scientific communication and presentation of scientific data, project management and intellectual property as well as fund raising and entrepreneurship which will equip them to become future leaders of academic or industrial research.
VADEMA seek to develop structural mass spectrometry tools aimed at understanding how to design effective vaccines and addressing important open questions regarding response to vaccination or infection. It will lead to innovative methodologies for the development of vaccine candidates to fight diseases for which no vaccine is currently available. It may also have applications in more diverse medical fields such as oncology, autoimmune diseases and allergy. Moreover, VADEMA will contribute to expand the use of structural mass spectrometry in Europe. So far, this novel technology is used by few European laboratories even though it has potential applications in many areas of research including specific applications involving proteins.
Dissecting the humoral response following infection or vaccination (adapted from Guthals et al., 201
Conformational information of antigen in native state