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Stephen S Whitehead - One of the best experts on this subject based on the ideXlab platform.
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the live attenuated Chimeric Vaccine rwn den4δ30 is well tolerated and immunogenic in healthy flavivirus naive adult volunteers
Vaccine, 2013Co-Authors: Anna P Durbin, Stephen S Whitehead, Peter F. Wright, Wangeci Kagucia, Daniel Elwood, Susan Henderson, Kimberli Wanionek, Jim Speicher, Amber Cox, Alexander G. PletnevAbstract:Abstract WNV has become the leading vector-borne cause of meningoencephalitis in the United States. Although the majority of WNV infections result in asymptomatic illness, approximately 20% of infections result in West Nile fever and 1% in West Nile neuroinvasive disease (WNND), which causes encephalitis, meningitis, or flaccid paralysis. The elderly are at particular risk for WNND, with more than half the cases occurring in persons older than sixty years of age. There is no licensed treatment for WNND, nor is there any licensed Vaccine for humans for the prevention of WNV infection. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a recombinant live attenuated WNV Vaccine based on chimerization of the wild-type WNV NY99 genome with that of the live attenuated DENV-4 candidate Vaccine rDEN4Δ30. The genes encoding the prM and envelope proteins of DENV-4 were replaced with those of WNV NY99 and the resultant virus was designated rWN/DEN4Δ30. The Vaccine was evaluated in healthy flavivirus-naive adult volunteers age 18–50 years in two separate studies, both of which are reported here. The first study evaluated 10 3 or 10 4 PFU of the Vaccine given as a single dose; the second study evaluated 10 5 PFU of the Vaccine given as two doses 6 months apart. The Vaccine was well-tolerated and immunogenic at all three doses, inducing seroconversion to WNV NY99 in 74% (10 3 PFU), 75% (10 4 PFU), and 55% (10 5 PFU) of subjects after a single dose. A second 10 5 PFU dose of rWN/DEN4Δ30 given 6 months after the first dose increased the seroconversion rate 89%. Based on the encouraging results from these studies, further evaluation of the candidate Vaccine in adults older than 50 years of age is planned.
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The live attenuated Chimeric Vaccine rWN/DEN4Δ30 is well-tolerated and immunogenic in healthy flavivirus-naïve adult volunteers.
Vaccine, 2013Co-Authors: Anna P Durbin, Stephen S Whitehead, Peter F. Wright, Amber Bickford Cox, Wangeci Kagucia, Daniel Elwood, Susan Henderson, Kimberli Wanionek, Jim Speicher, Alexander G. PletnevAbstract:Abstract WNV has become the leading vector-borne cause of meningoencephalitis in the United States. Although the majority of WNV infections result in asymptomatic illness, approximately 20% of infections result in West Nile fever and 1% in West Nile neuroinvasive disease (WNND), which causes encephalitis, meningitis, or flaccid paralysis. The elderly are at particular risk for WNND, with more than half the cases occurring in persons older than sixty years of age. There is no licensed treatment for WNND, nor is there any licensed Vaccine for humans for the prevention of WNV infection. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a recombinant live attenuated WNV Vaccine based on chimerization of the wild-type WNV NY99 genome with that of the live attenuated DENV-4 candidate Vaccine rDEN4Δ30. The genes encoding the prM and envelope proteins of DENV-4 were replaced with those of WNV NY99 and the resultant virus was designated rWN/DEN4Δ30. The Vaccine was evaluated in healthy flavivirus-naive adult volunteers age 18–50 years in two separate studies, both of which are reported here. The first study evaluated 10 3 or 10 4 PFU of the Vaccine given as a single dose; the second study evaluated 10 5 PFU of the Vaccine given as two doses 6 months apart. The Vaccine was well-tolerated and immunogenic at all three doses, inducing seroconversion to WNV NY99 in 74% (10 3 PFU), 75% (10 4 PFU), and 55% (10 5 PFU) of subjects after a single dose. A second 10 5 PFU dose of rWN/DEN4Δ30 given 6 months after the first dose increased the seroconversion rate 89%. Based on the encouraging results from these studies, further evaluation of the candidate Vaccine in adults older than 50 years of age is planned.
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substitution of the structural genes of dengue virus type 4 with those of type 2 results in Chimeric Vaccine candidates which are attenuated for mosquitoes mice and rhesus monkeys
Vaccine, 2003Co-Authors: Stephen S Whitehead, Joseph E Blaney, Kathryn A Hanley, Lara E Gilmore, William R Elkins, Brian R MurphyAbstract:Antigenic Chimeric viruses in which the structural genes of dengue virus type 4 (DEN4) have been replaced with those derived from dengue virus type 2 (DEN2) have been created and evaluated as a first step in generating a live attenuated tetravalent dengue virus Vaccine. Specifically, the capsid, membrane precursor, and envelope (CME) or the membrane precursor and envelope (ME) gene regions of DEN2 were substituted for the corresponding genes of wild-type rDEN4 or Vaccine candidate rDEN4delta30 which contains a 30 nucleotide deletion in the 3' untranslated region. The two DEN2/4 Chimeric viruses lacking the delta 30 mutation were highly attenuated in tumor-bearing SCID-HuH-7 mice, mosquitoes, and rhesus monkeys, indicating chimerization with either the CME or ME regions lead to attenuation. In mosquitoes and SCID-HuH-7 mice, addition of the delta 30 mutation to the Chimeric viruses resulted in comparable or only slightly increased levels of attenuation. In rhesus monkeys, addition of the delta 30 mutation rendered the CME Chimeric virus non-infectious, indicating that the attenuation resulting from chimerization and the delta 30 mutation were additive for these animals. In contrast, the attenuation in rhesus monkeys of ME Chimeric virus was not significantly modified by the addition of the delta 30 mutation. The satisfactory level of attenuation and immunogenicity achieved by the ME containing DEN2/4delta 30 Chimeric virus, as well as its very low infectivity for mosquitoes, make it a Vaccine candidate suitable for evaluation in phase I clinical trials.
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mutations which enhance the replication of dengue virus type 4 and an antigenic Chimeric dengue virus type 2 4 Vaccine candidate in vero cells
Vaccine, 2003Co-Authors: Joseph E Blaney, Brian R Murphy, Gracielle G Manipon, Cai Yen Firestone, Daniel H Johnson, Christopher T Hanson, Stephen S WhiteheadAbstract:Mutations which increase the replication of dengue viruses in cell culture would greatly facilitate the manufacture of both a live attenuated or inactivated dengue virus Vaccine. We have identified eight missense mutations in dengue virus type 4 (DEN4) that increase the plaque size and kinetics of replication of recombinant DEN4 virus in Vero cells. DEN4 viruses bearing these Vero cell adaptation mutations were also evaluated for the level of replication in the brains of mice. Two of these eight recombinant viruses expressing distinct mutations in NS3 were both restricted in replication in the brains of suckling mice. In contrast, six recombinant viruses, each encoding individual mutations in NS4B (five) or in NS5 (one), were not attenuated in mouse brain. Recombinant viruses encoding various combinations of these Vero cell adaptation mutations did not demonstrate enhanced replication in Vero cells over that exhibited by the single mutations. Finally, addition of a subset of the above non-attenuating, adaptation mutations to a DEN2/4 Chimeric Vaccine candidate was found to increase the virus yield in Vero cells by up to 500-fold. The importance of these Vero cell adaptation mutations in flavivirus Vaccine design and development is discussed.
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attenuation and immunogenicity in humans of a live dengue virus type 4 Vaccine candidate with a 30 nucleotide deletion in its 3 untranslated region
American Journal of Tropical Medicine and Hygiene, 2001Co-Authors: Anna P Durbin, Brian R Murphy, William R Elkins, Ruth A Karron, David W Vaughn, Mary J Reynolds, John Perreault, Bhavin Thumar, Robert M Chanock, Stephen S WhiteheadAbstract:The recombinant dengue virus type-4 Vaccine candidate 2AA30 was attenuated in rhesus monkeys due to an engineered 30-nucleotide deletion in the 3'-untranslated region of the viral genome. A clinical trial to evaluate the safety and immunogenicity of a single dose of 2Adelta30 was conducted with 20 adult human volunteers. The Vaccine candidate was well tolerated and did not cause systemic illness in any of the 20 volunteers. Viremia was detectable in 14 volunteers at a mean level of 1.6 log10 plaque-forming units/ml of serum, although all 20 volunteers seroconverted with a seven-fold or greater increase in serum neutralizing antibody titer on day 28 post-vaccination (mean titer = 1:580). A mild, asymptomatic, macular rash developed in 10 volunteers, and a transient elevation in the serum level of alanine aminotransferase was noted in five volunteers. The low level of reactogenicity and high degree of immunogenicity of this Vaccine candidate warrant its further evaluation and its use to create Chimeric Vaccine viruses expressing the structural genes of dengue virus types 1, 2, and 3.
Konstantin V. Pugachev - One of the best experts on this subject based on the ideXlab platform.
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Preclinical and Clinical Development of a YFV 17 D-Based Chimeric Vaccine against West Nile Virus
Viruses, 2013Co-Authors: Gustavo H. Dayan, Konstantin V. Pugachev, Joan Bevilacqua, Jean Lang, Thomas P. MonathAbstract:Substantial success has been achieved in the development and implementation of West Nile (WN) Vaccines for horses; however, no human WN Vaccines are approved. This review focuses on the construction, pre-clinical and clinical characterization of ChimeriVax-WN02 for humans, a live Chimeric Vaccine composed of a yellow fever (YF) 17D virus in which the prM-E envelope protein genes are replaced with the corresponding genes of the WN NY99 virus. Pre-clinical studies demonstrated that ChimeriVax-WN02 was significantly less neurovirulent than YF 17D in mice and rhesus and cynomolgus monkeys. The Vaccine elicited neutralizing antibody titers after inoculation in hamsters and monkeys and protected immunized animals from lethal challenge including intracerebral inoculation of high dose of WN NY99 virus. Safety, viremia and immunogenicity of ChimeriVax-WN02 were assessed in one phase I study and in two phase II clinical trials. No safety signals were detected in the three clinical trials with no remarkable differences in incidence of adverse events (AEs) between Vaccine and placebo recipients. Viremia was transient and the mean viremia levels were low. The Vaccine elicited strong and durable neutralizing antibody and cytotoxic T cell responses. WN epidemiology impedes a classical licensure pathway; therefore, innovative licensure strategies should be explored.
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Direct random insertion of an influenza virus immunologic determinant into the NS1 glycoprotein of a Vaccine flavivirus.
Virology, 2009Co-Authors: Alexander A. Rumyantsev, Zhenxi Zhang, Qing-sheng Gao, Nicolas Moretti, Nathan Brown, Harold Kleanthous, Simon Delagrave, Farshad Guirakhoo, Marc S. Collett, Konstantin V. PugachevAbstract:A live Chimeric Vaccine virus against Japanese encephalitis (JE), ChimeriVax-JE, was used to define methods for optimal, random insertion of foreign immunologic determinants into flavivirus glycoproteins. The conserved M2e peptide of influenza A virus was randomly inserted into the yellow fever-specific NS1 glycoprotein of ChimeriVax-JE. A technique combining plaque purification with immunostaining yielded a recombinant virus that stably expressed M2e at NS1-236 site. The site was found permissive for other inserts. The insertion inhibited NS1 dimerization in vitro, which had no significant effect on virus replication in vitro and immunogenicity in vivo. Two different NS1-specific monoclonal antibodies and a polyclonal antibody efficiently recognized only the NS1 protein dimer, but not monomer. Adaptation of the virus to Vero cells resulted in two amino acid changes upstream from the insert which restored NS1 dimerization. Immunized mice developed high-titer M2e-specific antibodies predominantly of the IgG2A isotype indicative of a Th1-biased response.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Abstract Chimeric yellow fever (YF)–dengue (DEN) viruses (ChimeriVax–DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290–7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [∼7 to 8 log 10 , plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log 10 PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax–DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Chimeric yellow fever (YF)-dengue (DEN) viruses (ChimeriVax-DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290-7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [ approximately 7 to 8 log(10), plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log(10) PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax-DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.
Yunfeng Zhu - One of the best experts on this subject based on the ideXlab platform.
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A promising new approach of VEGFR2-based DNA Vaccine for tumor immunotherapy.
Immunology letters, 2009Co-Authors: Jinqi Yan, Rui Jia, Hongbin Song, Ying Liu, Liang Zhang, Wei Zhang, Yu Wang, Yunfeng ZhuAbstract:To develop new approach for tumor immunotherapy with VEGFR2-based DNA Vaccine. VEGFR2 derived from different species were prepared by RT-PCR and subjected to recombinant constructs. The Chimeric gene of VEGFR2 was prepared by integrating different epitopes in different species. By transfecting into cells, the immunological effect was evaluated with the approaches of ELISA, ELISPOT, and animal experiments. (1) All these constructs, in particular Chimeric construct, can result in both humoral- and cellular-immune response in BALB/c mice after immunization evaluated by the ratio of CD4+/CD8+ and release of IFN-gamma and IL-4 respectively. (2) Mice were vaccinated with these constructs and challenged with renal carcinoma cells subsequently. It manifested that tumor growth was suppressed significantly in the mice vaccinated by Chimeric VEGFR2 construct. Our results manifested that VEGFR2-based DNA Chimeric Vaccine could be developed as a promising approach for tumor immunotherapy.
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A promising new approach of VEGFR2-based DNA Vaccine for tumor immunotherapy
Immunology Letters, 2009Co-Authors: Jinqi Yan, Rui Jia, Hongbin Song, Ying Liu, Liang Zhang, Yu Wang, Zhang Wei, Yunfeng ZhuAbstract:Abstract Aim To develop new approach for tumor immunotherapy with VEGFR2-based DNA Vaccine. Methods VEGFR2 derived from different species were prepared by RT-PCR and subjected to recombinant constructs. The Chimeric gene of VEGFR2 was prepared by integrating different epitopes in different species. By transfecting into cells, the immunological effect was evaluated with the approaches of ELISA, ELISPOT, and animal experiments. Results (1) All these constructs, in particular Chimeric construct, can result in both humoral- and cellular-immune response in balb/c mice after immunization evaluated by the ratio of CD4 + /CD8+ and release of IFN-γ and IL-4 respectively. (2) Mice were vaccinated with these constructs and challenged with renal carcinoma cells subsequently. It manifested that tumor growth was suppressed significantly in the mice vaccinated by Chimeric VEGFR2 construct. Conclusion Our results manifested that VEGFR2-based DNA Chimeric Vaccine could be developed as a promising approach for tumor immunotherapy.
Farshad Guirakhoo - One of the best experts on this subject based on the ideXlab platform.
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Direct random insertion of an influenza virus immunologic determinant into the NS1 glycoprotein of a Vaccine flavivirus.
Virology, 2009Co-Authors: Alexander A. Rumyantsev, Zhenxi Zhang, Qing-sheng Gao, Nicolas Moretti, Nathan Brown, Harold Kleanthous, Simon Delagrave, Farshad Guirakhoo, Marc S. Collett, Konstantin V. PugachevAbstract:A live Chimeric Vaccine virus against Japanese encephalitis (JE), ChimeriVax-JE, was used to define methods for optimal, random insertion of foreign immunologic determinants into flavivirus glycoproteins. The conserved M2e peptide of influenza A virus was randomly inserted into the yellow fever-specific NS1 glycoprotein of ChimeriVax-JE. A technique combining plaque purification with immunostaining yielded a recombinant virus that stably expressed M2e at NS1-236 site. The site was found permissive for other inserts. The insertion inhibited NS1 dimerization in vitro, which had no significant effect on virus replication in vitro and immunogenicity in vivo. Two different NS1-specific monoclonal antibodies and a polyclonal antibody efficiently recognized only the NS1 protein dimer, but not monomer. Adaptation of the virus to Vero cells resulted in two amino acid changes upstream from the insert which restored NS1 dimerization. Immunized mice developed high-titer M2e-specific antibodies predominantly of the IgG2A isotype indicative of a Th1-biased response.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Abstract Chimeric yellow fever (YF)–dengue (DEN) viruses (ChimeriVax–DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290–7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [∼7 to 8 log 10 , plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log 10 PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax–DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Chimeric yellow fever (YF)-dengue (DEN) viruses (ChimeriVax-DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290-7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [ approximately 7 to 8 log(10), plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log(10) PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax-DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.
Ken Draper - One of the best experts on this subject based on the ideXlab platform.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Abstract Chimeric yellow fever (YF)–dengue (DEN) viruses (ChimeriVax–DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290–7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [∼7 to 8 log 10 , plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log 10 PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax–DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.
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viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever dengue Chimeric Vaccine genetic reconstructions dose adjustment and antibody responses against wild type dengue virus isolates
Virology, 2002Co-Authors: Farshad Guirakhoo, Konstantin V. Pugachev, Zhenxi Zhang, John Catalan, J Arroyo, Chuck Miller, R Weltzin, K Georgakopoulos, Simeon W Ocran, Ken DraperAbstract:Chimeric yellow fever (YF)-dengue (DEN) viruses (ChimeriVax-DEN) were reconstructed to correct amino acid substitutions within the envelope genes of original constructs described by Guirakhoo et al. (2001, J. Virol. 75, 7290-7304). Viruses were analyzed and compared to the previous constructs containing mutations in terms of their growth kinetics in Vero cells, neurovirulence in mice, and immunogenicity in monkeys as monovalent or tetravalent formulations. All chimeras grew to high titers [ approximately 7 to 8 log(10), plaque-forming units (PFU)/ml] in Vero cells and were less neurovirulent than YF 17D Vaccine in mice. For monkey experiments, the dose of DEN2 chimera was lowered to 3 log(10) PFU in the tetravalent mixture in an effort to reduce its dominant immunogenicity. The magnitude of viremia in ChimeriVax-DEN immunized monkeys was similar to that of YF-VAX, but significantly lower than those induced by wild-type DEN viruses. All monkeys developed high levels of neutralizing antibodies against homologous (chimeras) or heterologous (wild-type DEN viruses isolated from different geographical regions) viruses after a single dose of monovalent or tetravalent Vaccine. Administration of a second dose of tetravalent Vaccine 2 months later increased titers to both homologous and heterologous viruses. A dose adjustment for dengue 2 chimera resulted in a more balanced response against dengue 1, 2, and 3 viruses, but a somewhat higher response against Chimeric dengue 4 virus. This indicates that further formulations for dose adjustments need to be tested in monkeys to identify an optimal formulation for humans.