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Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex.

ABSTRACT: The molecular basis of attenuation for live-attenuated vaccines is poorly understood. The yellow fever (YF) 17D vaccine virus was derived from the wild-type, parental strain Asibi virus by serial passage in chicken tissue and has proven to be a very safe and efficacious vaccine. We have previously shown that wild-type Asibi is a typical RNA virus with high genetic diversity, while the 17D vaccine virus has very little genetic diversity. To investigate this further, we treated Asibi and 17D viruses with ribavirin, a GTP analog with strong antiviral activity that increases levels of mutations in the viral genome. As expected, ribavirin treatment introduced mutations into the Asibi virus genome at a very high frequency and decreased viral infectivity while, in contrast, the 17D vaccine virus was resistant to ribavirin, as treatment with the antiviral introduced very few mutations into the genome, and viral infectivity was not lost. The results were confirmed for another YF wild-type parental and vaccine pair, a wild-type French viscerotropic virus and French neurotropic vaccine. Using recombinant Asibi and 17D viruses, ribavirin sensitivity was located to viral nonstructural genes. Thus, two live-attenuated YF vaccine viruses are genetically stable even under intense mutagenic pressure, suggesting that attenuation of live-attenuated YF vaccines is due, at least in part, to fidelity of the replication complex resulting in high genetic stability.IMPORTANCE Live-attenuated viral vaccines are highly safe and efficacious but represent complex and often multigenic attenuation mechanisms. Most of these vaccines have been generated empirically by serial passaging of a wild-type (WT) virus in cell culture. One of the safest and most effective live-attenuated vaccines is yellow fever (YF) virus strain 17D, which has been used for over 80?years to control YF disease. The availability of the WT parental strain of 17D, Asibi virus, and large quantities of clinical data showing the effectiveness of the 17D vaccine make this WT parent/vaccine pair an excellent model for investigating RNA virus attenuation. Here, we investigate a mechanism of 17D attenuation and show that the vaccine virus is resistant to the antiviral compound ribavirin. The findings suggest that attenuation is in part due to a low probability of reversion or mutation of the vaccine virus genome to WT, thus maintaining a stable genotype despite external pressures.

SUBMITTER: Davis EH

PROVIDER: S-EPMC6805994 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex.

Davis Emily H EH Beck Andrew S AS Strother Ashley E AE Thompson Jill K JK Widen Steven G SG Higgs Stephen S Wood Thomas G TG Barrett Alan D T ADT

mBio 20191022 5

The molecular basis of attenuation for live-attenuated vaccines is poorly understood. The yellow fever (YF) 17D vaccine virus was derived from the wild-type, parental strain Asibi virus by serial passage in chicken tissue and has proven to be a very safe and efficacious vaccine. We have previously shown that wild-type Asibi is a typical RNA virus with high genetic diversity, while the 17D vaccine virus has very little genetic diversity. To investigate this further, we treated Asibi and 17D virus ...[more]

PMID: 31641088

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Project description:The yellow fever (YF) live attenuated vaccine strain 17D (termed 17D) has been widely used for the prevention and control of YF disease. However, 17D retains significant neurovirulence and viscerotropism in mice, which is probably linked to the increased occurrences of serious adverse events following 17D vaccination. Thus, the development of an updated version of the YF vaccine with an improved safety profile is of high priority. Here, we generated a viable bicistronic YF virus (YFV) by incorporating the internal ribosome entry site (IRES) from Encephalomyocarditis virus into an infectious clone of YFV 17D. The resulting recombinant virus, 17D-IRES, exhibited similar replication efficiency to its parental virus (17D) in mammalian cell lines, while it was highly restricted in mosquito cells. Serial passage of 17D-IRES in BHK-21 cells showed good genetic stability. More importantly, in comparison with the parental 17D, 17D-IRES displayed significantly decreased mouse neurovirulence and viscerotropism in type I interferon (IFN)-signaling-deficient and immunocompetent mouse models. Interestingly, 17D-IRES showed enhanced sensitivity to type I IFN compared with 17D. Moreover, immunization with 17D-IRES provided solid protection for mice against a lethal challenge with YFV. These preclinical data support further development of 17D-IRES as an updated version for the approved YF vaccine. This IRES-based attenuation strategy could be also applied to the design of live attenuated vaccines against other mosquito-borne flaviviruses. IMPORTANCE Yellow fever (YF) continually spreads and causes epidemics around the world, posing a great threat to human health. The YF live attenuated vaccine 17D is considered the most efficient vaccine available and helps to successfully control disease epidemics. However, side effects may occur after vaccination, such as viscerotropic disease (YEL-AVD) and neurotropic adverse disease (YEL-AND). Thus, there is an urgent need for a safer YF vaccine. Here, an IRES strategy was employed, and a bicistronic YFV was successfully developed (named 17D-IRES). 17D-IRES showed effective replication and genetic stability in vitro and high attenuation in vivo. Importantly, 17D-IRES induced humoral and cellular immune responses and conferred full protection against lethal YFV challenge. Our study provides data suggesting that 17D-IRES, with its prominent advantages, could be a vaccine candidate against YF. Moreover, this IRES-based bicistronic technology platform represents a promising strategy for developing other live attenuated vaccines against emerging viruses.

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Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex.

Publications

Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex.

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