Rift Valley fever virus MP-12 vaccine is fully attenuated by a combination of partial attenuations in the S, M, and L segments

Tetsuro Ikegami, Terence E. Hill, Jennifer K. Smith, Lihong Zhang, Terry L. Juelich, Bin Gong, Olga A L Slack, Hoai J. Ly, Nandadeva Lokugamage, Alexander Freiberg

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Abstract

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 Mand 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.

Original languageEnglish (US)
Pages (from-to)7262-7276
Number of pages15
JournalJournal of Virology
Volume89
Issue number14
DOIs
StatePublished - 2015

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Rift Valley fever virus
Rift Valley Fever
Rift Valley fever
Vaccines
vaccines
mutation
Mutation
Genome
genome
Phlebovirus
Bunyaviridae
abortion (animals)
Induced Abortion
blindness
Zoonoses
Ruminants
Encephalitis
Blindness
zoonoses
encephalitis

ASJC Scopus subject areas

  • Immunology
  • Virology

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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, Tetsuro; Hill, Terence E.; Smith, Jennifer K.; Zhang, Lihong; Juelich, Terry L.; Gong, Bin; Slack, Olga A L; Ly, Hoai J.; Lokugamage, Nandadeva; Freiberg, Alexander.

In: Journal of Virology, Vol. 89, No. 14, 2015, p. 7262-7276.

Research output: Contribution to journalArticle

Ikegami, Tetsuro ; Hill, Terence E. ; Smith, Jennifer K. ; Zhang, Lihong ; Juelich, Terry L. ; Gong, Bin ; Slack, Olga A L ; Ly, Hoai J. ; Lokugamage, Nandadeva ; Freiberg, Alexander. / Rift Valley fever virus MP-12 vaccine is fully attenuated by a combination of partial attenuations in the S, M, and L segments. In: Journal of Virology. 2015 ; Vol. 89, No. 14. pp. 7262-7276.
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abstract = "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 Mand 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.",
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AU - Ikegami, Tetsuro

AU - Hill, Terence E.

AU - Smith, Jennifer K.

AU - Zhang, Lihong

AU - Juelich, Terry L.

AU - Gong, Bin

AU - Slack, Olga A L

AU - Ly, Hoai J.

AU - Lokugamage, Nandadeva

AU - Freiberg, Alexander

PY - 2015

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AB - 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 Mand 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.

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