Infection of humans by filoviruses has been shown to result in mortality rates that can exceed 85%. Of the filovirus outbreaks that have been documented thus far, the species Zaire (ZEBOV), Sudan (SUDV), and Marburg (MARV) have been the most prevalent. Recent findings suggest that the humoral immune system, in particular neutralizing antibodies, can play a critical role in viral control and protection. The main target of these protective neutralizing antibodies is the viral surface envelope glycoprotein GP, which is composed of two disulfide-linked subunits, GP1 and GP2. The GP1 subunit mediates interactions with the host cell receptors, while GP2 subunit anchors GP1 to the viral membrane and mediates fusion of the viral and host-cell membranes. Of the neutralizing antibodies that have been reported to be protective, most are species-specific and cannot neutralize across filovirus species.
While several vaccine candidates in development appear to provide protection in the context of an outbreak, they are largely based on replication-competent platforms that can potentially lead to clinical complications or are dependent on complex regimens of immunization. They also mainly target the Zaire (ZEBOV) or Sudan (SUDV) ebolaviruses, and do not appear to be effective against other filoviruses. We are therefore applying structure-based vaccine technologies to develop multi-valent vaccine candidates aimed at eliciting pan-ebolavirus and pan-filovirus protection. Utilizing macaque animal models, trials are being conducted to assess efficacy of candidate vaccines, to isolate protective monoclonal antibodies from immunized animals, and to investigate developmental pathways of protective antibody lineages. Structural approaches are being used to provide atomic-level definition of protective antibody binding to GP, to define key elements that yield pan-ebolavirus and pan-filovirus antibody reactivity and protection, and to design subsequent generations of GP immunogens that accurately focus immune responses onto these elements. For safety and compliance objectives, vaccine platforms are being developed that are non-replication-competent, and select adjuvants are being investigated that are aimed at reducing the required regimen for protection to a single immunization. In parallel, isolated pan-ebolavirus and pan-filovirus reactive monoclonal antibodies from vaccinated macaques are being optimized for therapeutic use.