Convergent antibody signatures for the measles virus in transgenic rats expressing a human B cell repertoire. (Doctoral thesis)

The enormous diversity of immunoglobulins (IG) allows the specific recognition of an almost infinite number of antigens, and ensure a long-term protection against pathogens previously encountered by the organism. The complementarity-determining region 3 (CDR3) of the immunoglobulin heavy chain (IGH) is the major antigen binding domain and determinant of antigen-specificity of the antibody molecule. Using next-generation sequencing, we tested whether immunization resulted in the generation and accumulation of similar IGH CDR3 sequences that are antigen-specific and shared across individuals, i.e. public IGH CDR3s. Such public "antigen-specific signatures" can potentially be used to retrospectively reconstruct past antigenic challenges. To test this hypothesis, transgenic rats with fully functional human Ig heavy and light chain loci (OmniRatTM) have been immunized with diverse antigens, and particularly measles virus (MV)-derived antigen. We demonstrated a strong public immune response within the different groups of rats characterized by convergent IGH CDR3 amino acid sequences in the animals that received the same vaccine. These clusters of CDR3s represent complex antigen-specific IGH CDR3 signatures. We are now transposing this concept to human studies by performing infection and vaccination follow ups to test whether similar CDR3 signatures can also be found in peripheral blood B cells. In the context of the MV eradication campaign of the World Health Organization, new epidemiological tools that enable to distinguish between immunized and infected individuals would be valuable assets