POST-EXPOSURE TREATMENT OF MARBURG VIRUS ANGOLA DISEASE IN NON-HUMAN PRIMATES USING RECOMBINANT VESICULAR STOMATITIS VIRUS VECTORS
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No licensed vaccines or treatments exist for Marburg virus (MARV) disease. As a preventative vaccine, a recombinant vesicular stomatitis virus (rVSV) expressing the Musoke strain glycoprotein (GP) of MARV protects macaques against MARV Musoke and Angola variants, as well as Ravn virus. The vector is also effective as a post-exposure treatment against a high dose homologous MARV Musoke challenge. To determine post-exposure efficacy against the most pathogenic MARV isolate, Angola, we engineered rVSV vectors expressing homologous Angola GP for use as a potential therapeutic. In this study, rhesus monkeys were challenged with a high or low, uniformly lethal dose of MARV Angola and administered rVSV treatment thirty minutes after infection. Although treated macaques had a delayed time-to-death, the treatment was incompletely protective (25%) against a high dose challenge. For the low dose challenge, 60-89% survived and treated animals exhibited fewer signs of disease. To determine immune correlates associated with treatment protection or failure, we performed RNA sequencing and flow cytometry. Humoral responses were assessed via enzyme-linked immunosorbent assays and plaque-reduction neutralization tests. In survivors, we found upregulation of STAT4, an early transcription factor associated with T helper 1 (Th1) and T follicular helper differentiation, and genes mapping to antiviral responses and interferon signaling. In contrast, animals that succumbed had T helper 2 and regulatory T cell signatures; upregulation of genes associated with T-cell exhaustion; and delayed interferon signaling. Only survivor macaques formed MARV GP-specific IgM and IgG with low levels of neutralizing antibodies, and these animals had more antigen-specific Th1 (IFN-gamma and IL-2 positive) cells late in disease. These results suggest survival is correlated with antibody production and Th1-skewed immunity. The rapid disease progression of MARV Angola compared to other variants may account for the failure of rVSV treatment against the high dose challenge. For the low dose challenge, rVSV-mediated antiviral signaling likely reduces viral replication to delay disease progression until a protective adaptive response is formed. MARV Angola sets a high bar for achieving protection with vaccines and therapeutics in the rhesus macaque model. Combination therapy with Th1-skewing adjuvants might enhance post-exposure protection in non-responders.
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