Lay summary

Over the past decades, human arenaviruses, which cause severe hemorrhagic fevers with high mortality, have emerged as a growing public health issue. Lacking effective treatment, there is an urgent need for protective vaccines against these viruses. Successful anti-viral vaccines most importantly must generate neutralizing antibodies (nAb) that stick specifically to the virus’ surface, prevent it from infecting the host and decrease the chances for disease development. Some of the most virulent arenaviruses (such as Lassa virus, endemic in western Africa), use decoy mechanisms to avoid the host nAb response. One such is to shed their surface coat and fool the body to make massive antibodies against the shed surface. This diverts the resources of the body, so nAb cannot be made sufficiently to prevent the disease. Despite much success in anti-viral vaccine design over the past decades, the development of safe vaccines capable of inducing nAbs of sufficient strength and breadth remains an unmatched challenge. We propose to contribute a more systematic understanding – in other words, build immunoengineering design strategies – for how to induce protective nAb responses against the coat of viruses - glycoprotein antigens. This research will join the expertise of two laboratories. The Swartz Lab’s strengths in bioengineering and vaccine immunology will team up with the Kunz Lab arenaviral glycoprotein immunobiology, biochemistry, and viral immunology. The Swartz lab, in collaboration with the Hubbell lab (a key collaborator on this project), have spent the last 8 years developing vaccines based on chemically defined virus-sized particles.  With this combined expertise at hand, we will set out to define design criteria to elicit an optimal anti-viral nAb response against dangerous arenaviruses for which vaccines do not exist: LASV and Machupo virus (MACV). If successful, this project will provide the basis for a much-needed arenavirus vaccine as well as develop, more generally, new rational design guidelines for immunoengineered vaccine formulations.