Comparison of live and inactivated tick-borne encephalitis virus vaccines for safety, immunogenicity and efficacy in rhesus monkeys

Rumyantsev, Alexander A.; Chanock, Robert M.; Murphy, Brian R.; Pletnev, Alexander G.

doi:10.1016/j.vaccine.2005.07.067

Cited by 52 publications

(109 citation statements)

References 42 publications

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“…The mean serum neutralizing antibody titer was 1:39 and is lower than reported for other flaviviruses [9,[18][19][20][21]. Five of six monkeys inoculated with SLE/DEN4 developed viremia with a mean duration of 2.2 days.…”

Section: Replication and Immunogenicity In Rhesus Monkeysmentioning

confidence: 64%

“…However, the TBE/DEN4 chimeric virus exhibited greatly reduced neuroinvasiveness but retained a high level of neurovirulence for mice indicating that chimerization in this case did not result in a decrease in virulence for the murine CNS [19,33]. In addition, the TBE/DEN4 chimeric virus replicated efficiently in rhesus monkeys [19]. In the present study, we had expected that the chimerization of SLE with DEN4 would result in a pattern of neuroinvasiveness and neurovirulence in mice and replication in monkeys that was similar to the chimerization of its closest relative, WN, but this did not turn out to be the case.…”

Section: Discussionmentioning

confidence: 94%

“…Since the first reports of the generation of intratypic (DEN2/DEN4) and intertypic (TBE/ DEN4) antigenic chimeric flaviviruses using reverse genetics [15,22], numerous chimeric viruses have been created using genes from tick-borne and mosquito-borne flaviviruses, and many of these viruses are currently being evaluated as vaccines [10,16,19,20,[23][24][25][26]. Recent clinical studies have indicated that antigenic chimeric flaviviruses are attenuated and immunogenic in human volunteers and may serve as live attenuated virus vaccines for protection against disease caused by DEN, JE, WN, and TBE viruses [27][28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…In these examples, antigenic chimerization led to attenuation of both neuroinvasiveness and neurovirulence in mice for the neurotropic viruses or to restricted replication in rhesus monkeys for each of the four viruses. However, the TBE/DEN4 chimeric virus exhibited greatly reduced neuroinvasiveness but retained a high level of neurovirulence for mice indicating that chimerization in this case did not result in a decrease in virulence for the murine CNS [19,33]. In addition, the TBE/DEN4 chimeric virus replicated efficiently in rhesus monkeys [19].…”

Section: Discussionmentioning

confidence: 99%

“…The second mechanism that leads to attenuation of antigenic chimeric viruses is the presence of attenuating mutations either in the genetic background of the antigenic chimeric virus [19,34] or in the prM or E protein [33,35]. Several attenuated flaviviruses have been utilized to generate vaccine candidates including the yellow fever vaccine virus [35], a DEN2 virus that has been attenuated by serial in vitro passage [36], and, in the present study, a DEN4 virus attenuated by a deletion (the Δ30 deletion mutation) in the 3′UTR [37].…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of St. Louis encephalitis virus/dengue virus type 4 antigenic chimeric viruses in mice and rhesus monkeys

Blaney

Speicher

Hanson

et al. 2008

Vaccine

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SummaryTo develop a live attenuated virus vaccine against St. Louis encephalitis virus (SLE), two antigenic chimeric viruses were generated by replacing the membrane precursor and envelope protein genes of dengue virus type 4 (DEN4) with those from SLE with or without a 30 nucleotide deletion in the DEN4 3′ untranslated region of the chimeric genome. Chimeric viruses were compared with parental wild-type SLE for level of neurovirulence and neuroinvasiveness in mice and for safety, immunogenicity, and protective efficacy in rhesus monkeys. The resulting viruses, SLE/DEN4 and SLE/DEN4Δ30, had greatly reduced neuroinvasiveness in immunodeficient mice but retained neurovirulence in suckling mice. Chimerization of SLE with DEN4 resulted in only moderate restriction in replication in rhesus monkeys, whereas the presence of the Δ30 mutation led to overattenuation. Introduction of previously described attenuating paired charge-to-alanine mutations in the DEN4 NS5 protein of SLE/DEN4 reduced neurovirulence in mice and replication in rhesus monkeys. Two modified SLE/DEN4 viruses, SLE/DEN4-436,437 clone 41 and SLE/DEN4-654,655 clone 46, have significantly reduced neurovirulence in mice and conferred protective immunity in monkeys against SLE challenge. These viruses may be considered for use as SLE vaccine candidates and for use as diagnostic reagents with reduced virulence.

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Section: Replication and Immunogenicity In Rhesus Monkeysmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Evaluation of St. Louis encephalitis virus/dengue virus type 4 antigenic chimeric viruses in mice and rhesus monkeys

Blaney

Speicher

Hanson

et al. 2008

Vaccine

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Experimental Infection of Nonhuman Primates with Viruses of Medical Importance

Voevodin¹,

Marx

2009

Simian Virology

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Safety evaluation of chimeric Langat/Dengue 4 flavivirus, a live vaccine candidate against tick‐borne encephalitis

Pripuzova

Tereshkina

Gmyl

et al. 2009

Journal of Medical Virology

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The chimeric flavivirus LGT/DEN4 containing prM and E genes of naturally attenuated Langat virus with remaining sequence derived from low neuroinvasive Dengue 4 virus was previously produced and assessed as a candidate for live vaccine against tick-borne encephalitis (TBE) [Pletnev and Men (1998): Proc Natl Acad Sci USA 95:1746-1751; Pletnev et al. (2000): Virology 274:23-31; Pletnev et al. (2001): J Virol 75:8259-8267; Wright et al. (2008): Vaccine 26:882-890]. In this article we compared two animal species: mice and monkeys, in order to select most sensitive models for safety evaluation of new vaccine candidates against TBE. Direct neurovirulence in suckling mice, neuroinvasiveness upon peripheral inoculation, rate of virus multiplication and expansion in CNS and its ability to persist in the central nervous system (CNS) were studied in adult mice; virological and pathomorphological examination of the CNS and visceral organs after intrathalamic virus inoculation was selected as a safety neurovirulence test in monkeys. The chimera was substantially less virulent in both animal models compared to the Absettarov strain of TBE virus. LGT/DEN4 was highly attenuated in suckling and adult mice with no evidence of viral persistence in CNS. In contrast to the mouse model, the chimera was able to reproduce in the CNS of monkeys to moderate titers, caused pathomorphological lesions in two and even illness in one of four animals, and was registered in simian brain on the 30th day post-infection. The presented data show that tests in mice solely might not be a sufficient model for safety testing of chimeric viruses.

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Comparison of live and inactivated tick-borne encephalitis virus vaccines for safety, immunogenicity and efficacy in rhesus monkeys

Cited by 52 publications

References 42 publications

Evaluation of St. Louis encephalitis virus/dengue virus type 4 antigenic chimeric viruses in mice and rhesus monkeys

Evaluation of St. Louis encephalitis virus/dengue virus type 4 antigenic chimeric viruses in mice and rhesus monkeys

Experimental Infection of Nonhuman Primates with Viruses of Medical Importance

Safety evaluation of chimeric Langat/Dengue 4 flavivirus, a live vaccine candidate against tick‐borne encephalitis

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