Abstract
Rift Valley fever virus (RVFV) causes severe disease in humans and ungulates. The virus can be transmitted by mosquitoes, direct contact with infected tissues or fluids, or aerosol, making it a significant biological threat for which there is no approved vaccine or therapeutic. Herein we describe the evaluation of DEF201, an adenovirus-vectored interferon alpha which addresses the limitations of recombinant interferon alpha protein (cost, short half-life), as a pre- and post-exposure treatment in a lethal hamster RVFV challenge model. DEF201 was delivered intranasally to stimulate mucosal immunity and effectively bypass any pre-existing immunity to the vector. Complete protection against RVFV infection was observed from a single dose of DEF201 administered one or seven days prior to challenge while all control animals succumbed within three days of infection. Efficacy of treatment administered two weeks prior to challenge was limited. Post‑exposure, DEF201 was able to confer significant protection when dosed at 30 min or 6 h, but not at 24 h post-RVFV challenge. Protection was associated with reductions in serum and tissue viral loads. Our findings suggest that DEF201 may be a useful countermeasure against RVFV infection and further demonstrates its broad-spectrum capacity to stimulate single dose protective immunity.
Highlights
Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) has been the cause of multiple epizootics throughout sub-Saharan Africa and the Arabian Peninsula [1]
In the present study we evaluated DEF201 as a pre- and post-exposure prophylactic intervention in the hamster RVFV infection model to demonstrate its activity against the highly pathogenic ZH501 strain of the virus
We first evaluated DEF201 as a pre-exposure prophylaxis in the hamster RVFV infection model by intranasal (i.n.) instillation at either −21, −14, −7, or −1 day relative to time of subcutaneous (s.c.)
Summary
Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) has been the cause of multiple epizootics throughout sub-Saharan Africa and the Arabian Peninsula [1]. Administration of recombinant or native human IFN-alpha were highly effective when given prophylactically 1 day prior or 6 h post RVFV challenge [14]. Despite this success, a number of factors including cost, the requirement for multiple injections by healthcare workers, and high bolus dosing to counter the short half-life have precluded recombinant IFN use. In the present study we evaluated DEF201 as a pre- and post-exposure prophylactic intervention in the hamster RVFV infection model to demonstrate its activity against the highly pathogenic ZH501 strain of the virus. This dose is well tolerated in hamsters and induces considerable levels of IFN for enhancing antiviral activity [10]
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