Rift Valley fever virus MP-12 vaccine encoding Toscana virus NSs retains neuroinvasiveness in mice

Indran, Sabarish V.; Lihoradova, Olga; Phoenix, Inaia; Lokugamage, Nandadeva; Kalveram, Birte; Head, Jennifer A.; Tigabu, Bersabeh; Smith, Jennifer K.; Zhang, Lihong; Juelich, Terry L.; Gong, Bin; Freiberg, Alexander N.; Ikegami, Tetsuro

doi:10.1099/vir.0.051250-0

Cited by 19 publications

(30 citation statements)

References 43 publications

(80 reference statements)

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“…Meanwhile, we previously showed that 90 to 100% of mice infected with MP-12 survive challenges with 1 ϫ 10 3 or 1 ϫ 10 5 PFU (i.p. ), while up to 10% of mice die or become moribund at 11 dpi or later and have abundant viral antigens in the brain (68). Thus, RST-MP12-S, RST-MP12-M, and RST-MP12-L are more pathogenic than MP-12.…”

Section: Resultsmentioning

confidence: 99%

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Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

Ikegami

Hill

Smith

et al. 2015

J Virol

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Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and characterized by a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), which has a tripartite negative-stranded RNA genome (consisting of the S, M, and L segments). Further spread of RVF into countries where the disease is not endemic may affect the economy and public health, and vaccination is an effective approach to prevent the spread of RVFV. A live-attenuated MP-12 vaccine is one of the best-characterized RVF vaccines for safety and efficacy and is currently conditionally licensed for use for veterinary purposes in the United States. Meanwhile, as of 2015, no other RVF vaccine has been conditionally or fully licensed for use in the United States. The MP-12 strain is derived from wild-type pathogenic strain ZH548, and its genome encodes 23 mutations in the three genome segments. However, the mechanism of MP-12 attenuation remains unknown. We characterized the attenuation of wild-type pathogenic strain ZH501 carrying a mutation(s) of the MP-12 S, M, or L segment in a mouse model. Our results indicated that MP-12 is attenuated by the mutations in the S, M, and L segments, while the mutations in the M and L segments confer stronger attenuation than those in the S segment. We identified a combination of 3 amino acid changes, Y259H (Gn), R1182G (Gc), and R1029K (L), that was sufficient to attenuate ZH501. However, strain MP-12 with reversion mutations at those 3 sites was still highly attenuated. Our results indicate that MP-12 attenuation is supported by a combination of multiple partial attenuation mutations and a single reversion mutation is less likely to cause a reversion to virulence of the MP-12 vaccine. IMPORTANCERift Valley fever (RVF) is a mosquito-transmitted viral disease that is endemic to Africa and that has the potential to spread into other countries. Vaccination is considered an effective way to prevent the disease, and the only available veterinary RVF vaccine in the United States is a live-attenuated MP-12 vaccine, which is conditionally licensed. Strain MP-12 is different from its parental pathogenic RVFV strain, strain ZH548, because of the presence of 23 mutations. This study determined the role of individual mutations in the attenuation of the MP-12 strain. We found that full attenuation of MP-12 occurs by a combination of multiple mutations. Our findings indicate that a single reversion mutation will less likely cause a major reversion to virulence of the MP-12 vaccine.

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Section: Resultsmentioning

confidence: 99%

“…Immunohistochemistry of tissue sections was performed using anti-RVFV N antibody as described previously (68).…”

Section: Methodsmentioning

confidence: 99%

Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

Ikegami

Hill

Smith

et al. 2015

J Virol

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“…These results suggest that, although the insertion of TOSV, PTV, or SFSV NSs contributes to the attenuation of RVFV, each NSs itself still contributes to virus virulence. Such a clear conclusion could not be obtained using an attenuated RVFV encoding other phlebovirus NSs proteins since there was no clear difference in survival in mice infected with MP-12 and mice infected with rMP-12 encoding TOSNSs, 24 PTVNSs, or SFSNSs. 25 This is probably because MP-12 is highly attenuated by several mechanisms, masking the function of NSs as a virulence factor.…”

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confidence: 75%

“…13 The interesting idea that Ikegami's group next put forward was not to completely disrupt NSs, but "to replace the RVFV NSs with a functional NSs derived from other phleboviruses." 24,25 RVFV belongs to the sandfly fever phlebovirus group, which also includes the Naples serocomplex (e.g., Toscana virus [TOSV]), Punta Toro serocomplex (e.g., Punta Toro virus (PTV) Adames strain [PTA]), Sicilian serocomplex (e.g., Sandfly fever Sicilian virus [SFSV]), Icoaraci serocomplex (e.g., Icoaraci virus), and Frijoles serocomplex (e.g., Frijoles virus). 27 The fact that the NSs proteins of TOSV, PTV, and SFSV all have the ability to inhibit the expression of the IFN-b gene 24,25,28,29 implies that RVFV possessing a functional NSs derived from other phleboviruses can replicate in vivo, providing effective immunity to vaccinated animals.…”

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confidence: 99%

“…21,22 The research group led by Tetsuro Ikegami has had a longtime interest in developing an effective RVF vaccine with a DIVA marker by genetically manipulating the NSs gene. [23][24][25] They have previously generated a recombinant MP-12 lacking a functional NSs by the deletion of amino acid residues 16 to 198 [rMP-12-DNSs 16/198 (also referred as rMP-12-C13type)] and used the mouse model to demonstrate that rMP-12-DNSs 16/198 vaccination fails to produce detectable viremia but does induce detectable IFN-a in the sera. 23 Conversely, MP-12 vaccination induces viremia in 30% of mice without any detectable induction of IFN-a.…”

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