Recombinant Chimeric Yellow Fever-Dengue Type 2 Virus Is Immunogenic and Protective in Nonhuman Primates

doi:10.1128/JVI.74.12.5477-5485.2000

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Journal of Virology, June 2000, p. 5477-5485, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Recombinant Chimeric Yellow Fever-Dengue Type 2 Virus Is Immunogenic and Protective in Nonhuman Primates

F. Guirakhoo,¹^,^* R. Weltzin,¹ T. J. Chambers,² Z.-X. Zhang,¹ K. Soike,³ M. Ratterree,³ J. Arroyo,¹ K. Georgakopoulos,¹ J. Catalan,¹ and T. P. Monath¹

OraVax, Inc., Cambridge, Massachusetts 02139¹; Department of Molecular Microbiology and Immunology, St. Louis University Medical School, St. Louis, Missouri 63104²; and Tulane Regional Primate Research Center, Covington, Louisiana 70433³

Received 24 January 2000/Accepted 20 March 2000

A chimeric yellow fever (YF)-dengue type 2 (dengue-2) virus (ChimeriVax-D2) was constructed using a recombinant cDNA infectiousclone of a YF vaccine strain (YF 17D) as a backbone into whichwe inserted the premembrane (prM) and envelope (E) genes of dengue-2virus (strain PUO-218 from a case of dengue fever in Bangkok,Thailand). The chimeric virus was recovered from the supernatantof Vero cells transfected with RNA transcripts and amplified oncein these cells to yield a titer of 6.3 log₁₀ PFU/ml. The ChimeriVax-D2was not neurovirulent for 4-week-old outbred mice inoculated intracerebrally.This virus was evaluated in rhesus monkeys for its safety (inductionof viremia) and protective efficacy (induction of anti-dengue-2neutralizing antibodies and protection against challenge). Inone experiment, groups of non-YF-immune monkeys received gradeddoses of ChimeriVax-D2; a control group received only the vaccinediluents. All monkeys (except the control group) developed a briefviremia and showed no signs of illness. Sixty-two days postimmunization,animals were challenged with 5.0 log₁₀ focus forming units (FFU)of a wild-type dengue-2 virus. No viremia (<1.7 log₁₀ FFU/ml)was detected in any vaccinated group, whereas all animals in theplacebo control group developed viremia. All vaccinated monkeysdeveloped neutralizing antibodies in a dose-dependent response.In another experiment, viremia and production of neutralizingantibodies were determined in YF-immune monkeys that receivedeither ChimeriVax-D2 or a wild-type dengue-2 virus. Low viremiawas detected in ChimeriVax-D2-inoculated monkeys, whereas alldengue-2-immunized animals became viremic. All of these animalswere protected against challenge with a wild-type dengue-2 virus,whereas all YF-immune monkeys and nonimmune controls became viremicupon challenge. Genetic stability of ChimeriVax-D2 was assessedby continuous in vitro passage in VeroPM cells. The titer of ChimeriVax-D2,the attenuated phenotype for 4-week-old mice, and the sequenceof the inserted prME genes were unchanged after 18 passages inVero cells. The high replication efficiency, attenuation phenotypein mice and monkeys, immunogenicity and protective efficacy, andgenomic stability of ChimeriVax-D2 justify it as a novel vaccinecandidate to be evaluated inhumans.

^* Corresponding author. Mailing address: OraVex, Inc., 38 Sidney St., Cambridge, MA 02139. Phone: (617) 494-1339. Fax: (617)494-0927. E-mail: fguirakhoo{at}oravax.com.

Journal of Virology, June 2000, p. 5477-5485, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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