Infection and Activation of Immune Cells by Rabies Virus-Based Vaccines

Rabies is a zoonotic viral encephalitis caused by rabies virus (RABV), and remains a global health threat of the 21st century, responsible for over 55,000 deaths annually. Post-exposure prophylaxis (PEP) consisting of several immunizations with inactivated RABV is a safe and effective treatment for RABV exposure, yet remains expensive and cumbersome for use in areas of the developing world most afflicted by endemic rabies. A primary goal of our lab is the development of a safe and highly effective single-dose RABV-based vaccine, and to this end we have investigated the interactions of RABV-based vaccines with host immune cells. A recombinant live RABV-based vaccine rRABV, and its derivative replication-deficient counterpart rRABV-DM missing the matrix (M) gene of the rabies genome, were found to infect primary mouse and human B cells in vitro and initiate their activation towards a potent antigen presenting costimulatory phenotype capable of priming and activating naïve CD4 T cells in vitro in an antigen-specific manner. rRABV-ICAM1, expressing the gene for mouse intercellular adhesion molecule-1 (ICAM-1), exhibited elevated in vitro infection and activation of mouse B cells in vitro, and demonstrated increased potency over rRABV immunization in the induction of a protective anti-RABV antibody response. Finally, rRABV-based vaccines were demonstrated to infect primary mouse macrophages in vitro, and via clodronate-loaded liposome (CLL)-mediated macrophage depletion, lymph node macrophage subsets were implicated as essential contributors to the antibody response to rRABV-DM immunization in mice. Together, these studies contribute to our understanding of RABV-based vaccine functionality, and open doors to further mechanistic investigation of the response to RABV-based vaccines, as well as the development of more effective vaccines for rabies PEP