Chimeric Langat/Dengue Viruses Protect Mice from Heterologous Challenge with the Highly Virulent Strains of Tick-Borne Encephalitis Virus

Pletnev, Alexander G.; Karganova, Galina G.; Dzhivanyan, T. I.; Lashkevich, V A; Bray, Michael

doi:10.1006/viro.2000.0426

Cited by 38 publications

(39 citation statements)

References 12 publications

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“…Currently, LGTV is being developed as a backbone for live-attenuated chimeric virus vaccines for protection against TBEV infection (44,45). If NS5 of these chimeric viruses also interferes with IFN signaling, identification and alteration of the NS5 sequences responsible might further attenuate the viruses and increase immune responsiveness, thus reducing the risk of possible complications associated with a live vaccine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Best

Morris

Shannon³

et al. 2005

J Virol

285

276

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Section: Discussionmentioning

confidence: 99%

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Best

Morris

Shannon³

et al. 2005

J Virol

285

276

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“…Significantly, both chimeras proved to be highly attenuated in mice with respect to peripheral virulence, the ability of a virus to spread to the central nervous system (CNS) from a peripheral site of inoculation and cause encephalitis. Nonetheless, the chimeras proved to be immunogenic and able to induce resistance in mice against challenge with TBEV or LGT (6)(7)(8). It appeared that a favorable balance between reduction in virus replication in vivo (attenuation) and induction of protective immunity had been achieved.…”

mentioning

confidence: 99%

West Nile virus/dengue type 4 virus chimeras that are reduced in neurovirulence and peripheral virulence without loss of immunogenicity or protective efficacy

Pletnev

Putnak

Speicher³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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118

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A candidate live attenuated vaccine strain was constructed for West Nile virus (WN), a neurotropic flavivirus that has recently emerged in the U.S. Considerable attenuation for mice was achieved by chimerization with dengue virus type 4 (DEN4). The genes for the structural premembrane and envelope proteins of DEN4 present in an infectious cDNA clone were replaced by the corresponding genes of WN strain NY99. Two of 18 cDNA clones of a WN͞DEN4 chimera yielded full-length RNA transcripts that were infectious when transfected into susceptible cells. The two infectious clones shared a motif in the transmembrane signal domain located immediately downstream of the NS2B-NS3 protease cleavage site that separates the DEN4 capsid protein and the WN premembrane protein of the chimera. This motif, Asp and Thr at a position 3 and 6 amino acids downstream of the cleavage site, respectively, was not present in the 16 noninfectious cDNA clones. The WN͞DEN4 chimera was highly attenuated in mice compared with its WN parent; the chimera was at least 28,500 times less neurovirulent in suckling mice inoculated intracerebrally and at least 10,000 times less virulent in adult mice inoculated intraperitoneally. Nonetheless, the WN͞DEN4 chimera and a deletion mutant derived from it were immunogenic and provided complete protection against lethal WN challenge. These observations provide the basis for pursuing the development of a live attenuated WN vaccine.protective immunity ͉ dengue virus ͉ viral chimera W est Nile virus (WN) belongs to the family Flaviviridae that comprises more than 60 viruses, many of which are important human pathogens. WN is a member of the Japanese encephalitis virus (JE) serocomplex of mosquito-borne flaviviruses that includes St. Louis encephalitis, JE, and Murray Valley encephalitis viruses (1, 2). Like other members of the JE antigenic complex, WN is maintained in a natural cycle that involves mosquito vectors and birds, whereas humans are usually an incidental host. For many years, WN has been recognized as one of the most widely distributed flaviviruses with a geographic range including Africa, Australia, Europe, the Middle East, and West Asia (2, 3). During 1999, WN first established itself in the U.S. in the northeast and mid-Atlantic states, and more recently, this virus extended its range to include the southeastern states (4, 5). In endemic regions, most human WN infections are asymptomatic or cause mild illness with symptoms of low-grade fever, headache, body aches, rash, myalgia, and polyarthropathy. However, human epidemics with severe disease have been reported in Israel, France, Romania, and Russia. In acute severe illness, the virus can cause hepatitis, meningitis, and encephalitis, leading to paralysis and coma, resulting in death. The neuropathologic lesions are similar to those of JE, with diffuse central nervous system inflammation and neuronal degeneration. The virus is also found in the spleen, liver, lymph nodes, and lungs of infected individuals. During the 1999 outbreak of WN in the U.S....

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“…The human trial reported here is part of the development plan for a live attenuated TBEV vaccine [10,[16][17][18][19][20] that is based on chimerization of a non-neuroinvasive, mosquito-borne dengue type 4 virus (DEN4) with a neurotropic, tickborne LGT virus. The chimeric virus tested here is referred to as LGT/DEN4.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, chimeric LGT/DEN4 virus was created by replacing the membrane precursor (prM) and envelope (E) structural protein genes of DEN4 with the corresponding genes from LGT strain TP21 [18,20]. The resulting LGT/DEN4 virus exhibited greatly reduced neuroinvasiveness and neurovirulence in mice compared to the LGT parent and was immunogenic, providing complete protection against lethal challenge with TBEV or LGT [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the LGT/DEN4 virus failed to infect mosquitoes after intrathoracic inoculation [10], indicating that the chimeric virus has a limited potential for transmission by mosquitoes. Based on these preclinical studies, LGT/DEN4 was selected as the initial TBEV vaccine candidate for evaluation in a clinical trial in humans at a dose of 10 3 PFU, since this dose of vaccine candidate was able to induce protective immunity against LGT or TBEV in mice and monkeys [10,[18][19][20]. Similarly attenuated vaccine constructs have been generated using a Far Eastern TBEV strain as the tick-borne virus parent [16,20].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

Wright

Ankrah

Henderson

et al. 2008

Vaccine

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With the steady rise in tick-borne encephalitis virus (TBEV) infections in Europe, development of a live attenuated vaccine that will generate long-lasting immunity would be of considerable benefit. A chimeric flavivirus, designated LGT/DEN4, was previously constructed to have a genome containing the prM and E protein genes of Langat virus (LGT), a naturally attenuated member of the TBEV complex, and the remaining genetic sequences derived from dengue 4 virus (DEN4).LGT/ DEN4 was highly attenuated in rodents and non-human primates, and clinical trials in humans were initiated. Twenty-eight healthy seronegative adult volunteers were randomly assigned in a 4:1 ratio to receive 10 3 PFU of LGT/DEN4 or placebo. Volunteers were closely monitored for clinical responses and for blood chemistry and hematological changes, and the level of viremia and the magnitude and duration of the neutralizing antibody response were determined. The LGT/DEN4 vaccine was safe and viremia was seen in only one vaccinee. Infection induced a neutralizing antibody response to wild-type LGT in 80% of volunteers with a geometric mean titer (GMT) of 1:63 present on day 42 post-immunization; however the antibody response against TBEV was both much less frequent (35%) and lower in magnitude (GMT = 1:9). To assess the response to a booster dose, 21 of the original 28 volunteers were re-randomized to receive a second dose of either 10 3 PFU of vaccine or placebo given 6 to 18 months after the first dose. The immunogenicity against either LGT or TBEV was not significantly enhanced after the second dose of vaccine. Thus, chimerization of LGT with DEN4 yielded a vaccine virus that was highly attenuated yet infectious in humans. The level of replication was sufficiently restricted to induce only a weak cross-reactive antibody response to TBEV. To provide a sufficient level of immunity to widely prevalent, highly neurovirulent strains of TBEV in humans, vaccine candidates will likely need to be based on the TBEV structural protein genes.

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Chimeric Langat/Dengue Viruses Protect Mice from Heterologous Challenge with the Highly Virulent Strains of Tick-Borne Encephalitis Virus

Cited by 38 publications

References 12 publications

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist

West Nile virus/dengue type 4 virus chimeras that are reduced in neurovirulence and peripheral virulence without loss of immunogenicity or protective efficacy

Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

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