Live Viral Vaccine Neurovirulence Screening: Current and Future Models

Fulton, Corey; Bailey, Wendy J.

doi:10.3390/vaccines9070710

Cited by 5 publications

(6 citation statements)

References 131 publications

(140 reference statements)

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“…However, there were mixed results in the adult animals indicating both higher neurovirulence or greater attenuation compared to the approved YF 17DD vaccine depending on the rodent species and age. These mixed results warranted further evaluation in the MNVT, considered the gold-standard test [21,22,32].…”

Section: Resultsmentioning

confidence: 99%

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Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential

et al. 2022

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Nipah virus (NiV) disease is a bat-borne zoonosis responsible for outbreaks with high lethality and is a priority for vaccine development. With funding from the Coalition of Epidemic Preparedness Innovations (CEPI), we are developing a chimeric vaccine (PHV02) composed of recombinant vesicular stomatitis virus (VSV) expressing the envelope glycoproteins of both Ebola virus (EBOV) and NiV. The EBOV glycoprotein (GP) mediates fusion and viral entry and the NiV attachment glycoprotein (G) is a ligand for cell receptors, and stimulates neutralizing antibody, the putative mediator of protection against NiV. PHV02 is identical in construction to the registered Ebola vaccine (Ervebo) with the addition of the NiV G gene. NiV ephrin B2 and B3 receptors are expressed on neural cells and the wild-type NiV is neurotropic and causes encephalitis in affected patients. It was therefore important to assess whether the NiV G alters tropism of the rVSV vector and serves as a virulence factor. PHV02 was fully attenuated in adult hamsters inoculated by the intramuscular (IM) route, whereas parental wild-type VSV was 100% lethal. Two rodent models (mice, hamsters) were infected by the intracerebral (IC) route with graded doses of PHV02. Comparator active controls in various experiments included rVSV-EBOV (representative of Ebola vaccine) and yellow fever (YF) 17DD commercial vaccine. These studies showed PHV02 to be more neurovirulent than both rVSV-EBOV and YF 17DD in infant animals. PHV02 was lethal for adult hamsters inoculated IC but not for adult mice. In contrast YF 17DD retained virulence for adult mice inoculated IC but was not virulent for adult hamsters. Because of the inconsistency of neurovirulence patterns in the rodent models, a monkey neurovirulence test (MNVT) was performed, using YF 17DD as the active comparator because it has a well-established profile of quantifiable microscopic changes in brain centers and a known reporting rate of neurotropic adverse events in humans. In the MNVT PHV02 was significantly less neurovirulent than the YF 17DD vaccine reference control, indicating that the vaccine will have an acceptable safety profile for humans. The findings are important because they illustrate the complexities of phenotypic assessment of novel viral vectors with tissue tropisms determined by transgenic proteins, and because it is unprecedented to use a heterologous comparator virus (YF vaccine) in a regulatory-enabling study. This approach may have value in future studies of other novel viral vectors.

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Section: Resultsmentioning

confidence: 99%

“…Tests for neurovirulence of novel live vaccines are required on a case-by-case basis [21,22]. Neurovirulence tests, and in particular the MNVT, are mandatory when the parental virus or the transgene(s) donor (or both) are inherently neurotropic.…”

Section: Plos Pathogensmentioning

confidence: 99%

Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential

et al. 2022

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“…Although MNVT is the gold standard for detecting vaccine neurotoxicity, it cannot explain many potential neurotoxicity mechanisms and lacks reproducibility [ 20 , 21 ]. The WHO also recommended detection methods other than MNVT.…”

Section: Discussionmentioning

confidence: 99%

Comparative Study on MNVT of OPV Type I and III Reference Products in Different Periods

Wang

Ren

et al. 2023

Diseases

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Widespread vaccination using the oral live attenuated polio vaccine (OPV) and Sabin strain inactivated vaccine (sIPV) have greatly reduced the incidence of polio worldwide. In the period post-polio, the virulence of reversion of the Sabin strain makes the use of OPV gradually becoming one of the major safety hazards. The verification and release of OPV has become the top priority. The monkey neurovirulence test (MNVT) is the gold standard for detecting whether OPV meets the criteria, which are recommended by the WHO and Chinese Pharmacopoeia. Therefore, we statistically analyzed the MNVT results of type I and III OPV at different stages: 1996–2002 and 2016–2022. The results show that the upper and lower limits and C value of the qualification standard of type I reference products in 2016–2022 have decreased compared with the corresponding scores in the 1996–2002 period. The upper and lower limit and C value of the qualified standard of type III reference products were basically the same as the corresponding scores in the 1996–2002. We also found significant differences in the pathogenicity of the type I and III in the cervical spine and brain, with the decreasing trend in the diffusion index of the type I and type III in the cervical spine and brain. Finally, two evaluation criteria were used to judge the OPV test vaccines from 2016 to 2022. The vaccines all met the test requirements under the evaluation criteria of the above two stages. Based on the characteristics of OPV, data monitoring was one of the most intuitive methods to judge changes in virulence.

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“…Nevertheless, WHO recommendations require that each vaccine virus seed lot is tested for viscerotropism, immunogenicity and neurotropism in NHP by intracranial inoculation before it is used for eggbased YF17D production [137]. However, the consistency, reliability and hence relevance of results obtained by this historically established (in 1943) monkey safety test are under debate [138][139][140] and regulatory requirements may need to be adapted, in particular for YF17D-based vaccines employing other technologies. Innovations in vaccine quality control and safety testing may lead to a shift towards alternatives that are easier to standardize and interpret, for example recently validated small animal models for in vivo testing [42,47,140,141].…”

Section: Box 1 -Animal Models For Preclinical Assessment Of Yf17d-bas...mentioning

confidence: 99%

YF17D‐based vaccines – standing on the shoulders of a giant

Sanchez‐Felipe,

Alpizar,

et al. 2024

Eur J Immunol

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SummaryLive‐attenuated yellow fever vaccine (YF17D) was developed in the 1930s as the first ever empirically derived human vaccine. Ninety years later, it is still a benchmark for vaccines made today. YF17D triggers a particularly broad and polyfunctional response engaging multiple arms of innate, humoral and cellular immunity. This unique immunogenicity translates into an extraordinary vaccine efficacy and outstanding longevity of protection, possibly by single‐dose immunization. More recently, progress in molecular virology and synthetic biology allowed engineering of YF17D as a powerful vector and promising platform for the development of novel recombinant live vaccines, including two licensed vaccines against Japanese encephalitis and dengue, even in paediatric use. Likewise, numerous chimeric and transgenic preclinical candidates have been described. These include prophylactic vaccines against emerging viral infections (e.g. Lassa, Zika and SARS‐CoV‐2) and parasitic diseases (e.g. malaria), as well as therapeutic applications targeting persistent infections (e.g. HIV and chronic hepatitis), and cancer. Efforts to overcome historical safety concerns and manufacturing challenges are ongoing and pave the way for wider use of YF17D‐based vaccines. In this review, we summarize recent insights regarding YF17D as vaccine platform, and how YF17D‐based vaccines may complement as well as differentiate from other emerging modalities in response to unmet medical needs and for pandemic preparedness.

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Live Viral Vaccine Neurovirulence Screening: Current and Future Models

Cited by 5 publications

References 131 publications

Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential

Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential

Comparative Study on MNVT of OPV Type I and III Reference Products in Different Periods

YF17D‐based vaccines – standing on the shoulders of a giant

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