Temperature-sensitive mutations for live-attenuated Rift Valley fever vaccines: implications from other RNA viruses

Abstract

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to the African continent. RVF is characterized by high rate of abortions in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by the Rift Valley fever virus (RVFV: genus Phlebovirus, family Bunyaviridae). Vaccination is the only known effective strategy to prevent the disease, but there are no licensed RVF vaccines available for humans. A live-attenuated vaccine candidate derived from the wild-type pathogenic Egyptian ZH548 strain, MP-12, has been conditionally licensed for veterinary use in the U.S. MP-12 displays a temperature-sensitive (ts) phenotype and does not replicate at 41°C. The ts mutation limits viral replication at a specific body temperature and may lead to an attenuation of the virus. Here we will review well-characterized ts mutations for RNA viruses, and further discuss the potential in designing novel live-attenuated vaccines for RVF.

Keywords: MP-12; Rift Valley fever virus; bunyavirus; temperature sensitivity; vaccine.

FIGURE 1

Mapping of temperature-sensitive (ts) mutations for selected negative-stranded RNA viruses. The genome structures of RVFV MP-12 strain, Respiratory syncytial virus (RSV) cpts 248/404/1030, Influenza A virus (MDV-A), Influenza B virus (MDV-B), and Vesicular stomatitis virus (VSV) ts114 strain are shown. Viral genes are shown in different colors: Nucleocapsid protein (green), phosphoprotein (orange), RNA-dependent RNA polymerase (gray), envelope protein (yellow), matrix proteins (blue), and accessory or non-structural proteins (brown). Conserved six functional regions of RNA-dependent RNA polymerase (RdRp) among non-segmented negative-stranded RNA viruses are shown as I, II, III, IV, V, and VI, and those aligned to RdRp of bunyavirus and influenza virus are also indicated. Location of representative mutations and ts mutations (red square) are indicated by arrowheads. Putative ts mutations in the L-segment of MP-12 are shown in green squares. For RSV mutations, the name of clone, which encodes the mutation, is also shown in quotation.