TRUSTEES OF BOSTON UNIVERSITY
The Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID) have classified the filoviruses (Ebola, Marburg) and arenaviruses (e.g., Lassa, Junin, Machupo) that cause hemorrhagic fever (HF) as Category A priority pathogens. These viruses cause severe and often fatal disease in humans and in nonhuman primates. A vaccine that would provide protective immunity against these viruses is highly desirable. Recently, we developed promising monovalent HF virus vaccines based on recombinant vesicular stomatitis virus (rVSV). Each vaccine expresses a single HF virus glycoprotein (GP). We demonstrated that these vaccines can protect nonhuman primates against: 1) Ebola virus (EBOV); 2) Marburg virus (MARV); or 3) Lassa virus (LASV) when used as single-injection vaccines. The goal of this proposal is to develop a multivalent rVSV vaccine that can express up to four different HF viral genes and provide broad spectrum immunity to the Category A HF viruses that occur in Africa. Specifically, we will: (1) Select HF viral glycoproteins for incorporation into a multivalent vaccine vector. For EBOV, previous studies suggest that protection against the Zaire and Sudan species will require inclusion of both the Zaire and Sudan GPs. However, our research suggests that a single HF GP may be sufficient to generate cross-protective immunity against multiple, if not all, EBOV strains. We will test this hypothesis by generating and characterizing rVSV viruses that express potential “pan-EBOV protection” GPs. In addition, we will perform pilot studies to establish the protective immunity generated by these viruses in guinea pig models of EBOV infection.
(2) Develop and evaluate multivalent rVSV vectors. A multivalent rVSV backbone including the MARV Musoke strain GP and the LASV Josiah strain GP will be constructed. Our results from Aim 1 will inform our choice of EBOV antigen(s). We will test the ability of the multivalent vector to provide protective immunity against the different HF viruses in guinea pigs following immunization. The efficacy of three different vaccine backbones will be determined to assess the impact of different mechanisms of rVSV attenuation on vaccine efficacy. The neurovirulence of each of these three different multivalent constructs will be assessed to determine the multivalent vaccine with the greatest efficacy and best safety profile.
Relevance: Ebola, Marburg, and Lassa viruses are enigmatic emerging pathogens that cause severe HF in humans and nonhuman primates. Outbreaks occur regularly in the case of Lassa and sporadically in the case of the filoviruses in parts of Africa with human case fatality rates ranging between 15 and 90 percent. Currently, there are no licensed vaccines or treatments against these agents. The multivalent vaccine strategy proposed here may well represent an effective countermeasure for preventing filovirus and Lassa infection.