Final Report Summary - IMMUNEXPLORE (New approaches to analyze and exploit the human B and T cell response against viruses)
In the project entitled “New approaches to analyze and exploit the human B and T cell response against viruses” funded by the ERC we used two novel high throughput approaches to interrogate the human memory B cell repertoire in order to isolate broadly neutralizing monoclonal antibodies against viruses that cause respiratory infections. An antibody capable of neutralizing all influenza viruses (dubbed FI6) was isolated from plasma cells following booster vaccination. Two crystal structures revealed that the antibody FI6 binds to a site in the stem region of the influenza virus hemagglutinin that is conserved in all 17 different subtypes (including the human H1N1 and H3N2 viruses). When tested in an in vivo model of influenza virus infection, FI6 conferred protection through mechanisms that involved both viral neutralization and antibody-mediated cellular cytotoxicity. Using a similar strategy we isolated from memory B cells another antibody (MPE8) that neutralizes four different paramyxoviruses: human RSV, human MPV, bovine RSV and mouse PVM. MPE8, as well as 90% of the RSV-neutralizing antibodies we isolated, is specific for the pre-fusion F protein, indicating that the pre-fusion rather than the post-fusion conformation is the best candidate for a vaccine. Therefore, FI6 and MPE8 represent promising candidates for prophylaxis and therapy of viral infections as well as tools for vaccine design. Using the new technologies we also addressed fundamental aspects of the antibody response. To understand the mechanisms that increase antibody affinity and breadth, we systematically reconstructed the genealogy trees of B cell clones producing antibodies to influenza virus and complemented this analysis with functional and structural studies. We discovered that somatic mutations could rapidly increase antibody affinity for the target antigen, usually via a single mutation in a critical residue. Mutations, however, continue to accumulate in large numbers, resulting in a continuous diversification of the antibody specificity within a given clone. This mechanism was found to be responsible for the generation of broadly neutralizing antibodies such as FI6 and MPE8. In conclusion, the research funded by the ERC not only advanced our understanding of fundamental mechanisms of antibody affinity maturation, effector function and pathogenesis, but also generated new technologies and monoclonal antibodies that represent attractive candidates to combat human infections.