Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen

Doris Apt; Kanakatte Raviprakash; Alice Brinkman; Andrey Semyonov; Shumin Yang; Craig Skinner; Lori Diehl; Richard Lyons; Kevin Porter; Juha Punnonen

doi:10.1016/j.vaccine.2005.07.100

Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen

Doris Apt^*, Kanakatte Raviprakash, Alice Brinkman, Andrey Semyonov, Shumin Yang, Craig Skinner, Lori Diehl, Richard Lyons, Kevin Porter, Juha Punnonen

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

We employed DNA shuffling and screening technologies to develop a single recombinant dengue envelope (E) antigen capable of inducing neutralizing antibodies against all four antigenically distinct dengue serotypes. By DNA shuffling of codon-optimized dengue 1-4 E genes, we created a panel of novel chimeric clones expressing C-terminal truncated E antigens that combined epitopes from all four dengue serotypes. DNA vaccines encoding these novel chimeras induced multivalent T cell and neutralizing antibody responses against all four dengue serotypes in mice. By contrast, a mixture of four unshuffled, parental DNA vaccines failed to produce tetravalent neutralizing antibodies in mice. The neutralizing antibody titers for some of these antigens could be further improved by extending the sequences to express full-length pre-membrane and envelope proteins. The chimeric antigens also protected mice against a lethal dengue-2 virus challenge. These data demonstrate that DNA shuffling and associated screening can lead to the selection of multi-epitope antigens against closely related dengue virus serotypes and suggest a broad utility for these technologies in optimizing vaccine antigens.

Original language	English
Pages (from-to)	335-344
Number of pages	10
Journal	Vaccine
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.vaccine.2005.07.100
State	Published - 16 Jan 2006
Externally published	Yes

Keywords

Antigen
Cross-neutralizing antibodies
DNA shuffling
Dengue virus
Multivalent antigen
Tetravalent

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10.1016/j.vaccine.2005.07.100

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title = "Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen",

abstract = "We employed DNA shuffling and screening technologies to develop a single recombinant dengue envelope (E) antigen capable of inducing neutralizing antibodies against all four antigenically distinct dengue serotypes. By DNA shuffling of codon-optimized dengue 1-4 E genes, we created a panel of novel chimeric clones expressing C-terminal truncated E antigens that combined epitopes from all four dengue serotypes. DNA vaccines encoding these novel chimeras induced multivalent T cell and neutralizing antibody responses against all four dengue serotypes in mice. By contrast, a mixture of four unshuffled, parental DNA vaccines failed to produce tetravalent neutralizing antibodies in mice. The neutralizing antibody titers for some of these antigens could be further improved by extending the sequences to express full-length pre-membrane and envelope proteins. The chimeric antigens also protected mice against a lethal dengue-2 virus challenge. These data demonstrate that DNA shuffling and associated screening can lead to the selection of multi-epitope antigens against closely related dengue virus serotypes and suggest a broad utility for these technologies in optimizing vaccine antigens.",

keywords = "Antigen, Cross-neutralizing antibodies, DNA shuffling, Dengue virus, Multivalent antigen, Tetravalent",

author = "Doris Apt and Kanakatte Raviprakash and Alice Brinkman and Andrey Semyonov and Shumin Yang and Craig Skinner and Lori Diehl and Richard Lyons and Kevin Porter and Juha Punnonen",

note = "Funding Information: We would like to thank Ms. Heather Kelly for excellent technical assistance. We would also like to thank Dr. Robert Shope at University of Texas Medical Branch at Galveston for support and expert advice. Part of this work was performed under a Cooperative Research and Development Agreement between Maxygen, Inc. and the Naval Medical Research Center. The opinions and assertions contained herein are not to be considered official or to reflect the views of the U.S. Navy or the Naval Service at large. This study was supported in part by a grant from Defense Advanced Research Projects Agency (DARPA). All animal experiments were conducted at Maxygen under a protocol approved by Maxygen's Institutional Animal Care and Use Committee, and were in accordance with the principles set forth in the “Guide for the Care and Use of Laboratory Animals”, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Academy Press, Washington, DC, 1996.",

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AU - Apt, Doris

AU - Raviprakash, Kanakatte

AU - Brinkman, Alice

AU - Semyonov, Andrey

AU - Yang, Shumin

AU - Skinner, Craig

AU - Diehl, Lori

AU - Lyons, Richard

AU - Porter, Kevin

AU - Punnonen, Juha

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AB - We employed DNA shuffling and screening technologies to develop a single recombinant dengue envelope (E) antigen capable of inducing neutralizing antibodies against all four antigenically distinct dengue serotypes. By DNA shuffling of codon-optimized dengue 1-4 E genes, we created a panel of novel chimeric clones expressing C-terminal truncated E antigens that combined epitopes from all four dengue serotypes. DNA vaccines encoding these novel chimeras induced multivalent T cell and neutralizing antibody responses against all four dengue serotypes in mice. By contrast, a mixture of four unshuffled, parental DNA vaccines failed to produce tetravalent neutralizing antibodies in mice. The neutralizing antibody titers for some of these antigens could be further improved by extending the sequences to express full-length pre-membrane and envelope proteins. The chimeric antigens also protected mice against a lethal dengue-2 virus challenge. These data demonstrate that DNA shuffling and associated screening can lead to the selection of multi-epitope antigens against closely related dengue virus serotypes and suggest a broad utility for these technologies in optimizing vaccine antigens.

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JF - Vaccine

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ER -

Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen

Abstract

Keywords

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