Efficacy of a Tetravalent Chimeric Dengue Vaccine (DENVax) in Cynomolgus Macaques

Jorge E. Osorio Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Joseph N. Brewoo Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Shawn J. Silengo Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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John Arguello Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Ioana R. Moldovan Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Magdalena Tary-Lehmann Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Tim D. Powell Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Jill A. Livengood Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Richard M. Kinney Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Claire Y.-H. Huang Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Dan T. Stinchcomb Inviragen, Inc., Madison, Wisconsin and Fort Collins, Colorado; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Cellular Technology Limited, Shaker Heights, Ohio; Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado

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Three tetravalent formulations of chimeric dengue (DENVax) viruses containing the pre-membrane and envelope genes of serotypes 1–4 expressed by the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity, and efficacy in cynomolgus macaques (Macaca fascicularis). Subcutaneous injection of the DENVax formulations was well-tolerated. Low levels of viremia of only one of the four vaccine viruses were detected yet virus neutralizing antibody titers were induced against all four dengue virus serotypes after one or two administrations of vaccine. All animals immunized with the high-dose formulation were protected from viremia, and all immunized animals were completely protected from DENV-3 and DENV-4 challenge. A lower dose of DENVax formulation partially protected animals from DENV-1 or DENV-2 challenge. In contrast, all control animals developed high levels of viremia for multiple days after challenge with DENV 1–4. This study highlights the immunogenicity and efficacy of the tetravalent DENVax formulations in nonhuman primates.

Author Notes

*Address correspondence to Jorge E. Osorio, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706. E-mail: osorio@svm.vetmed.wisc.edu
†These authors contributed equally to this article.

Financial support: This study was partially supported by National Institutes of Health grant 5-U01-AI070443.

Authors' addresses: Jorge E. Osorio and Joseph N. Brewoo, Inviragen, Inc., Madison, WI and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, E-mails: Osorio@svm.vetmed.wisc.edu and jbrewoo@inviragen.com. Shawn J. Silengo, Tim D. Powell, Jill A. Livengood, and Dan T. Stinchcomb, Inviragen, Inc., Fort Collins, CO. John Arguello and Richard M. Kinney, Inviragen, Inc., Ft. Collins, CO and Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, CO. E-mails: ssilengo@inviragen.com, tpowell@inviragen.com, jlivengood@inviragen.com, dstinchcomb@inviragen.com, jarguello@inviragen.com, and zzkinney@msn.com. Ioana R. Moldovan and Magdalena Tary-Lehmann, Cellular Technology Limited, Shaker Heights, OH. Claire Y.-H. Huang, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, CO. E-mails: ioana.moldovan@immunospot.com, magda.tary-lehmann@immunospot.com, and yxh0@cdc.gov.

  • 1.

    Guzman MG, Kouri G, 2002. Dengue: an update. Lancet Infect Dis 2: 3342.

  • 2.

    Wilder-Smith A, Gubler DJ, 2008. Geographic expansion of dengue: the impact of international travel. Med Clin North Am 92: 13771390.

  • 3.

    Gubler DJ, 2006. Dengue/dengue haemorrhagic fever: history and current status. Novartis Found Symp 277: 316; discussion 16–22, 71–73, 251–253.

  • 4.

    Kyle JL, Harris E, 2008. Global spread and persistence of dengue. Annu Rev Microbiol 62: 7192.

  • 5.

    Henchal EA, Putnak JR, 1990. The dengue viruses. Clin Microbiol Rev 3: 376396.

  • 6.

    Halstead SB, 1970. Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med 42: 350362.

  • 7.

    Halstead SB, 1988. Pathogenesis of dengue: challenges to molecular biology. Science 239: 476481.

  • 8.

    Halstead SB, 2002. Vaccines aplenty. Curr Opin Infect Dis 15: 461463.

  • 9.

    Gubler DJ, 1998. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11: 480496.

  • 10.

    Halstead SB, Deen J, 2002. The future of dengue vaccines. Lancet 360: 12431245.

  • 11.

    Kinney RM, Huang CY, 2001. Development of new vaccines against dengue fever and Japanese encephalitis. Intervirology 44: 176197.

  • 12.

    Yoksan S, Bhamarapravati N, Halstead S, 1986. Dengue virus vaccine development: study on biological markers of cloned dengue 1–4 viruses serially passaged in primary kidney cells. George TD St., Kay BH, Blok J, eds. Arbovirus Research in Australia. Proceedings of the Fourth Symposium. Brisbane, Australia: Commonwealth Scientific and Industrial Research Organisation/Queensland Institute of Medical Research, 3538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Vaughn DW, Hoke CH Jr, Yoksan S, LaChance R, Innis BL, Rice RM, Bhamarapravati N, 1996. Testing of a dengue 2 live-attenuated vaccine (strain 16681 PDK 53) in ten American volunteers. Vaccine 14: 329336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Sabchareon A, Lang J, Chanthavanich P, Yoksan S, Forrat R, Attanath P, Sirivichayakul C, Pengsaa K, Pojjaroen-Anant C, Chokejindachai W, Jagsudee A, Saluzzo JF, Bhamarapravati N, 2002. Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses. Am J Trop Med Hyg 66: 264272.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Kanesa-thasan N, Sun W, Kim-Ahn G, Van Albert S, Putnak JR, King A, Raengsakulsrach B, Christ-Schmidt H, Gilson K, Zahradnik JM, Vaughn DW, Innis BL, Saluzzo JF, Hoke CH Jr, 2001. Safety and immunogenicity of attenuated dengue virus vaccines (Aventis Pasteur) in human volunteers. Vaccine 19: 31793188.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Bhamarapravati N, Yoksan S, Chayaniyayothin T, Angsubphakorn S, Bunyaratvej A, 1987. Immunization with a live attenuated dengue-2-virus candidate vaccine (16681-PDK 53): clinical, immunological and biological responses in adult volunteers. Bull World Health Organ 65: 189195.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Dharakul T, Kurane I, Bhamarapravati N, Yoksan S, Vaughn DW, Hoke CH, Ennis FA, 1994. Dengue virus-specific memory T cell responses in human volunteers receiving a live attenuated dengue virus type 2 candidate vaccine. J Infect Dis 170: 2733.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Rothman AL, Kanesa-thasan N, West K, Janus J, Saluzzo JF, Ennis FA, 2001. Induction of T lymphocyte responses to dengue virus by a candidate tetravalent live attenuated dengue virus vaccine. Vaccine 19: 46944699.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Kinney RM, Butrapet S, Chang GJ, Tsuchiya KR, Roehrig JT, Bhamarapravati N, Gubler DJ, 1997. Construction of infectious cDNA clones for dengue 2 virus: strain 16681 and its attenuated vaccine derivative, strain PDK-53. Virology 230: 300308.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Butrapet S, Huang CY, Pierro DJ, Bhamarapravati N, Gubler DJ, Kinney RM, 2000. Attenuation markers of a candidate dengue type 2 vaccine virus, strain 16681 (PDK-53), are defined by mutations in the 5¢ noncoding region and nonstructural proteins 1 and 3. J Virol 74: 30113019.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Huang CY, Butrapet S, Tsuchiya KR, Bhamarapravati N, Gubler DJ, Kinney RM, 2003. Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine development. J Virol 77: 1143611447.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Huang CY, Butrapet S, Pierro DJ, Chang GJ, Hunt AR, Bhamarapravati N, Gubler DJ, Kinney RM, 2000. Chimeric dengue type 2 (vaccine strain PDK-53)/dengue type 1 virus as a potential candidate dengue type 1 virus vaccine. J Virol 74: 30203028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Men R, Wyatt LS, Tokimatsu I, Arakaki S, Shameem G, Elkins R, Chanock R, Moss B, Lai CJ, 2000. Immunization of rhesus monkeys with a recombinant of modified vaccinia virus Ankara expressing a truncated envelope glycoprotein of dengue type 2 virus induced resistance to dengue type 2 virus challenge. Vaccine 18: 31133122.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Halstead SB, Palumbo NE, 1973. Studies on the immunization of monkeys against dengue. II. Protection following inoculation of combinations of viruses. Am J Trop Med Hyg 22: 375381.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Halstead SB, Shotwell H, Casals J, 1973. Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection. J Infect Dis 128: 1522.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Halstead SB, Shotwell H, Casals J, 1973. Studies on the pathogenesis of dengue infection in monkeys. I. Clinical laboratory responses to primary infection. J Infect Dis 128: 714.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, 2007. Efficacy of a live attenuated tetravalent candidate dengue vaccine in naive and previously infected cynomolgus macaques. Vaccine 25: 54095416.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, 2007. Characterization of humoral and cellular immune responses in cynomolgus macaques upon primary and subsequent heterologous infections with dengue viruses. Microbes Infect 9: 940946.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Blaney JE Jr, Johnson DH, Firestone CY, Hanson CT, Murphy BR, Whitehead SS, 2001. Chemical mutagenesis of dengue virus type 4 yields mutant viruses which are temperature sensitive in Vero cells or human liver cells and attenuated in mice. J Virol 75: 97319740.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Guy B, Barban V, Mantel N, Aguirre M, Gulia S, Pontvianne J, Jourdier TM, Ramirez L, Gregoire V, Charnay C, Burdin N, Dumas R, Lang J, 2009. Evaluation of interferences between dengue vaccine serotypes in a monkey model. Am J Trop Med Hyg 80: 302311.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Guirakhoo F, Pugachev K, Arroyo J, Miller C, Zhang ZX, Weltzin R, Georgakopoulos K, Catalan J, Ocran S, Draper K, Monath TP, 2002. 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 298: 146159.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Guirakhoo F, Pugachev K, Zhang Z, Myers G, Levenbook I, Draper K, Lang J, Ocran S, Mitchell F, Parsons M, Brown N, Brandler S, Fournier C, Barrere B, Rizvi F, Travassos A, Nichols R, Trent D, Monath T, 2004. Safety and efficacy of chimeric yellow fever-dengue virus tetravalent vaccine formulations in nonhuman primates. J Virol 78: 47614775.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Butrapet S, Kinney RM, Huang CY, 2006. Determining genetic stabilities of chimeric dengue vaccine candidates based on dengue 2 PDK-53 virus by sequencing and quantitative TaqMAMA. J Virol Methods 131: 19.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Houng HS, Chung-Ming Chen R, Vaughn DW, Kanesa-thasan N, 2001. Development of a fluorogenic RT-PCR system for quantitative identification of dengue virus serotypes 1–4 using conserved and serotype-specific 3¢ noncoding sequences. J Virol Methods 95: 1932.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Huang CY, Butrapet S, Moss KJ, Childers T, Erb SM, Calvert AE, Silengo SJ, Kinney RM, Blair CD, Roehrig JT, 2010. The dengue virus type 2 envelope protein fusion peptide is essential for membrane fusion. Virology 396: 305315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Kreher CR, Dittrich MT, Guerkov R, Boehm BO, Tary-Lehmann M, 2003. CD4+ and CD8+ cells in cryopreserved human PBMC maintain full functionality in cytokine ELISPOT assays. J Immunol Methods 278: 7993.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Yip HC, Karulin AY, Tary-Lehmann M, Hesse MD, Radeke H, Heeger PS, Trezza RP, Heinzel FP, Forsthuber T, Lehmann PV, 1999. Adjuvant-guided type-1 and type-2 immunity: infectious/noninfectious dichotomy defines the class of response. J Immunol 162: 39423949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Halstead SB, 2008. Dengue virus-mosquito interactions. Annu Rev Entomol 53: 273291.

  • 39.

    Brault A, Kinney R, Maharaj P, Green E, Reisen W, Huang CY, 2011. Replication of the primary dog kidney-53 dengue 2 virus vaccine candidate in Aedes aegypti is modulated by a mutation in the 5′ untranslated region and amino acid substitutions in nonstructural proteins 1 and 3. Vector Borne Zoonotic Dis [E pub ahead of print].

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Clements DE, Coller BA, Lieberman MM, Ogata S, Wang G, Harada KE, Putnak JR, Ivy JM, McDonell M, Bignami GS, Peters ID, Leung J, Weeks-Levy C, Nakano ET, Humphreys T, 2010. Development of a recombinant tetravalent dengue virus vaccine: immunogenicity and efficacy studies in mice and monkeys. Vaccine 28: 27052715.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Blaney JE Jr, Matro JM, Murphy BR, Whitehead SS, 2005. Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys. J Virol 79: 55165528.

    • PubMed
    • Search Google Scholar
    • Export Citation
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