Broadly protective influenza vaccines: Redirecting the antibody response through adjuvation

Influenza virus infections are responsible for significant morbidity worldwide and current vaccines have limited coverage, therefore it remains a high priority to develop broadly protective vaccines. With the discovery of broadly neutralizing antibodies (bnAbs) against influenza these vaccines became within reach. However, a basic understanding of the mechanisms by which bnAbs mediate protection is essential to effectively design the next generation of influenza vaccines. In this thesis we discuss the role of the Fc part of bnAbs in mediating antibody dependent cellular cytotoxicity (ADCC) and we demonstrate that additional interactions between HA on host cells and sialic acids on the surface of immune cells are required. Furthermore, we demonstrate that bnAbs in human serum samples induce cross-protection in influenza challenge models in mice. The potential to induce bnAbs against influenza by adjuvation of current influenza vaccines is discussed and the protective efficacy of the saponin-based adjuvant Matrix-M that in combination with a seasonal trivalent virosomal vaccine (TVV) was studied in mice and ferrets. In mice, protection against heterologous and avian H5N1 and H7N7 strains was achieved. In ferrets only partial protection against H5N1 was obtained but no protection against H7N7. We demonstrated that the protection against H5N1 in mice required both the humoral and cellular arms of the immune system. In summary, this thesis provides insight into the immunological mechanisms involved in broadly protective immunity and thereby contributes to the development of a universal influenza vaccine.