Abstract
Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) causes a range of illnesses that include retinitis, fulminant hepatitis, neurologic disease, and hemorrhagic fever. In hospitalized individuals, case fatality rates can be as high as 10–20%. There are no vaccines or antivirals approved for human use to prevent or treat severe RVFV infections. We previously tested the efficacy of the MP-12 vaccine strain and related variants with NSs truncations as a post-exposure prophylaxis in mice infected with wild-type pathogenic RVFV strain ZH501. Post-exposure efficacy of the rMP12-C13type, a recombinant MP-12 vaccine virus which encodes an in-frame truncation removing 69% of the NSs protein, resulted in 30% survival when administering the virus within 30 min of subcutaneous ZH501 challenge in mice, while the parental MP-12 virus conferred no protection by post-exposure vaccination. Here, we demonstrate uniform protection of hamsters by post-exposure vaccination with rMP12-C13type administered 6 h post-ZH501 infection while no efficacy was observed with the parental MP-12 virus. Notably, both the MP-12 and rMP12-C13type viruses were highly effective (100% protection) when administered 21 days prior to challenge. In a subsequent study delaying vaccination until 8, 12, and 24 h post-RVFV exposure, we observed 80, 70, and 30% survival, respectively. Our findings indicate that the rapid protective innate immune response elicited by rMP12-C13type may be due to the truncated NSs protein, suggesting that the resulting functional inactivation of NSs plays an important role in the observed post-exposure efficacy. Taken together, the data demonstrate that post-exposure vaccination with rMP12-C13type is effective in limiting ZH501 replication and associated disease in standard pre-exposure vaccination and post-challenge treatment models of RVFV infection, and suggest an extended post-exposure prophylaxis window beyond that initially observed in mice.
Highlights
Rift Valley fever virus (RVFV) causes a devastating mosquitoborne disease in ruminants throughout Africa and the Arabian Peninsula, which results in abortion storms and high mortality among young animals (Bird et al, 2009)
We have previously described the use of a recombinant MP-12 modified vaccine virus, rMP12-C13type, which contains an inactivating deletion in the NSs gene based on the naturally attenuated RVFV clone 13 vaccine candidate, (Muller et al, 1995; Dungu et al, 2010; von Teichman et al, 2011), as a potential vaccine and post-exposure intervention in mouse models of RVFV infection (Lihoradova et al, 2012; Gowen et al, 2013)
Our results indicate that replication of the rMP12-C13type virus more consistently induces IFN-β gene expression compared to the rMP-12 virus at the draining lymph nodes (LNs)
Summary
Rift Valley fever virus (RVFV) causes a devastating mosquitoborne disease in ruminants throughout Africa and the Arabian Peninsula, which results in abortion storms and high mortality among young animals (Bird et al, 2009). We have previously described the use of a recombinant MP-12 modified vaccine virus, rMP12-C13type, which contains an inactivating deletion in the NSs gene based on the naturally attenuated RVFV clone 13 vaccine candidate, (Muller et al, 1995; Dungu et al, 2010; von Teichman et al, 2011), as a potential vaccine and post-exposure intervention in mouse models of RVFV infection (Lihoradova et al, 2012; Gowen et al, 2013). We demonstrate significantly enhanced prophylactic capacity of the rMP12-C13type vaccine lacking functional NSs in a more rapidly progressing hamster model of RVF disease and shed light on species variations in the context of post-exposure vaccine efficacy and therapeutic window in rodent infection models
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