Chimeric Live, Attenuated Vaccine against Japanese Encephalitis (ChimeriVax‐JE): Phase 2 Clinical Trials for Safety and Immunogenicity, Effect of Vaccine Dose and Schedule, and Memory Response to Challenge with Inactivated Japanese Encephalitis Antigen

Monath, Thomas P.; Guirakhoo, Farshad; Nichols, Richard A.; Yoksan, Sutee; Schrader, Robert; Murphy, Chris; Blum, Paul S.; Woodward, Stephen; McCarthy, Karen; Mathis, Danell; Johnson, Casey; Bedford, Philip

doi:10.1086/378356

Cited by 208 publications

(150 citation statements)

References 39 publications

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“…Data from Phase 1 and 2 trials of this vaccine indicated that it was well tolerated and highly immunogenic at all dose levels tested (5.8 to 1.8 log 10 PFU). 17 We found no unexpected safety concerns with ChimeriVax™-DEN2 vaccinations. The profile of AEs observed following ChimeriVax™-DEN2-vaccination was similar to that observed after vaccination with YF-VAX ® .…”

Section: Discussionmentioning

confidence: 61%

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Guirakhoo

Kitchener²,

Morrison³

et al. 2006

Human Vaccines

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187

136

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A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax™-DEN2) in comparison to that of YF vaccine (YF-VAX ® ). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX ® by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax TM -DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX ® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log 10 PFU of ChimeriVax TM -DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX ® seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX ® . In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax™-DEN2 vaccine is consistent with that of YF-VAX ® , and (2) preimmunity to YF virus does not interfere with ChimeriVax TM -DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.

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Section: Discussionmentioning

confidence: 61%

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Guirakhoo

Kitchener²,

Morrison³

et al. 2006

Human Vaccines

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187

136

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“…Subjects who received the lower (3 log 10 PFU) dose of ChimeriVax-WN02 had statistically higher viremias than those receiving a dose 100 times higher. This paradoxical response has been observed in the case of YF 17D vaccine (5) and a chimeric vaccine against Japanese encephalitis (19) and may be due to a lower innate and delayed adaptive immune response to the lower dose. Control of the early phase of flavivirus infection depends on type 1 IFN synthesis by plasmacytoid DC (20).…”

Section: Discussionmentioning

confidence: 93%

“…Future studies will address safety and tolerability for elderly and infirm persons at greatest risk of severe WN virus disease (18). Nearly all subjects experienced a transient low viremia, an expected observation with YF 17D (5) and other chimeric vaccines (19). Subjects who received the lower (3 log 10 PFU) dose of ChimeriVax-WN02 had statistically higher viremias than those receiving a dose 100 times higher.…”

Section: Discussionmentioning

confidence: 93%

A live, attenuated recombinant West Nile virus vaccine

Monath

Liu

Kanesa-thasan

et al. 2006

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

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authors note that Fig. 5 did not include all vaccine study groups. The corrected figure and legend appear below. This error does not affect the conclusions of the article. Confidence intervals for Spearman's rank correlation of log 10 IFN-␥ producing PBMC per million and log10 stimulation index were based on Fisher's transformation. On day 14, the correlation was 0.491 (95% CI, 0.231-0.686); on day 28, the correlation was 0.188 (95% CI: Ϫ0.112 to 0.456).

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“…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]. These positive results observed in several clinical trials support the further development and study of antigenic chimeric flaviviruses.…”

Section: Discussionmentioning

confidence: 87%

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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Chimeric Live, Attenuated Vaccine against Japanese Encephalitis (ChimeriVax‐JE): Phase 2 Clinical Trials for Safety and Immunogenicity, Effect of Vaccine Dose and Schedule, and Memory Response to Challenge with Inactivated Japanese Encephalitis Antigen

Cited by 208 publications

References 39 publications

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

A live, attenuated recombinant West Nile virus vaccine

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

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