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

Men, Ruhe; Wyatt, Linda S.; Tokimatsu, Issei; Arakaki, Shingo; Shameem, Golam Masud Mohammad; Elkins, Randy; Chanock, Robert M.; Moss, Bernard; Lai, Ching-Juh

doi:10.1016/s0264-410x(00)00121-3

Cited by 88 publications

(47 citation statements)

References 30 publications

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“…Infected animals demonstrate measurable viremia yet fail to show clinical signs of infection. [23][24][25][26][27][28] In this study, we show that tetravalent formulations of the DENVax recombinants are safe, immunogenic, and have protective efficacy in cynomolgus macaques. (DENV-1 16007, DENV-2 16681, DEN-3 16562, and DENV-4 1036).…”

Section: Introductionmentioning

confidence: 99%

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

Osorio¹,

Brewoo²,

Silengo³

et al. 2011

The American Journal of Tropical Medicine and Hygiene

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Abstract. 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.*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. PROTECTION BY A DENGUE VACCINE IN MACAQUESderived (DENV-1 16007, DENV-2 16681, DEN-3 16562, and DENV-4 1036). 21 Virus plaque titration was performed under double agarose overlay in six-well plates of confluent Vero cells as described. 20,22 The second agarose overlay containing neutral red vital stain was added four or seven days after infection, depending on the virus plaque phenotypes. Plaques were counted for three consecutive days after the second agarose overlay.Tetravalent DENVax vaccine formulations. The construction and characterization of the four DENVax viruses has been reported. 21 To complete preclinical development of DENVax, new viral stocks were generated by introducing RNAs transcribed from infectious cDNA clones (pD2-PDK53 and chimeric pD2/1, /3, and /4 plasmids) into the certified vaccine production Vero cells by electroporation as described 21 under Good Manufacturing Practice (GMP) conditions at Shantha Biotechnics. The viruses were amplified, plaque purified, characterized, and sequenced for each of the four DENVax serotypes. On the basis of these analyses, a formal pre-master virus seed was chosen for each DENVax serotype and was then amplified to generate the master virus seed for each serotype (Huang, C. and others, unpublished data).For this study, individual pre-master seed viruses were used to make non-GMP surrogate master seeds in serum-free media as follows. Viruses diluted in DMEM to achieve a multiplicity of infection of 0.001 were adsorbed for 1.5 hours onto rinsed Vero cell monolayers at 37°C. After adsorption, the monolayers were rinsed three times with phosphate-buffered saline, and then fresh serum-free DMEM medium was added. The viruses were grown for 8-12 days in an atmosphere of 5% CO...

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Section: Introductionmentioning

confidence: 99%

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

Osorio¹,

Brewoo²,

Silengo³

et al. 2011

The American Journal of Tropical Medicine and Hygiene

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“…The E ectodomain, which constitutes approximately 80% of the protein (80E), contains three distinct domains that have been identified immunologically (11,12) and by X-ray crystallography (13). E domain I (EI) is the central domain, and E domain II (EII) is the dimerization domain and contains the flavivirus conserved fusion peptide.…”

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confidence: 99%

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confidence: 99%

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Liu

Song

Putnak

et al. 2015

Clin. Vaccine Immunol.

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The envelope (E) protein of flaviviruses includes three domains, EI, EII, and EIII, and is the major protective antigen. Because EIII is rich in type-specific and subcomplex-specific neutralizing epitopes and is easy to express, it is particularly attractive as a recombinant vaccine antigen. VaxInnate has developed a vaccine platform that genetically links vaccine antigens to bacterial flagellin, a Toll-like receptor 5 ligand. Here we report that tetravalent dengue vaccines (TDVs) consisting of four constructs, each containing two copies of EIII fused to flagellin (R3.2x format), elicited robust and long-lived neutralizing antibodies (geometric mean titers of 200 to 3,000), as measured with a 50% focus reduction neutralization test (FRNT 50 ). In an immunogenicity study, rhesus macaques (n ‫؍‬ 2) immunized subcutaneously with 10 g or 90 g of TDV three or four times, at 4-to 6-week intervals, developed neutralizing antibodies to four dengue virus (DENV) serotypes (mean post-dose 3 FRNT 50 titers of 102 to 601). In an efficacy study, rhesus macaques (n ‫؍‬ 4) were immunized intramuscularly with 16 g or 48 g of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-g doses of TDV developed neutralizing antibodies against the four serotypes (geometric mean titers of 49 to 258) and exhibited reduced viremia after DENV-2 challenge, with a group mean viremia duration of 1.25 days and 2 of 4 animals being completely protected, compared to the placebo-treated animals, which all developed viremia, with a mean duration of 4 days. In conclusion, flagellin-EIII fusion vaccines are immunogenic and partially protective in a nonhuman primate model. Dengue disease poses a significant health threat to almost onehalf of the world's population residing in the Asian-Pacific region and Latin America, where the disease is endemic, as well as to travelers and military personnel. Currently, no licensed dengue vaccine is available. Several vaccine candidates based on live attenuated dengue viruses (DENVs) or dengue virus-flavivirus chimeras are currently being evaluated in phase II or III clinical trials (for reviews, see references 1-3). However, some of these vaccines require lengthy immunization regimens of up to 1 year for the development of immunity to all four serotypes, which seems to make them less well suited for travelers and military personnel. In a series of recently published phase IIb/III trials conducted in five Asian countries in which dengue is endemic, the Sanofi-Aventis chimeric yellow fever (YF) 17D-DENV-1 to -4 CYD tetravalent dengue vaccine (TDV) showed an acceptable safety profile and 56% overall efficacy (4); however, the vaccine failed to confer significant protection against DENV-2 (5). These findings underscore the need for the development of alternative vaccine platforms, such as those based on purified inactivated virus (6), DNA (7), and recombinant subunit truncated envelope (E) proteins (e.g., 80% envelope protein [80E]) (8). Some of these alternative vaccine candidates hav...

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“…Several laboratories worldwide are exploring multiple approaches towards developing dengue virus vaccines based on live attenuated viruses (1,21,36), inactivated viruses (35), infectious clone-derived intertypic (18,26) and chimeric (5,13,14,43) viruses, antigen-encoding plasmids (23,24), recombinant proteins expressed in heterologous systems (2,22,38,40), and live vaccinia virus vectors encoding antigen genes (9,31,32). However, the major focus is on the live, empirically attenuated (1,21,36), and infectious clone-derived ChimeriVax vaccines based on the attenuated YF17D yellow fever vaccine vector (13,14).…”

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Replication-Defective Adenoviral Vaccine Vector for the Induction of Immune Responses to Dengue Virus Type 2

Jaiswal

Khanna

Swaminathan

2003

J Virol

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A recombinant replication-defective adenovirus vector that can overexpress the ectodomain of the envelope protein of dengue virus type 2 (NGC strain) has been constructed. This virus was immunogenic in mice and elicited dengue virus type 2 specific B-and T-cell responses. Sera from immunized mice contained neutralizing antibodies that could specifically recognize dengue virus type 2 and neutralize its infectivity in vitro, indicating that this approach has the potential to confer protective immunity. In vitro stimulation of splenocytes (from immunized mice) with dengue virus type 2 resulted in a significant proliferative response accompanied by the production of high levels of gamma interferon but did not show significant changes in interleukin-4 levels. This is suggestive of a Th1-like response (considered to be important in the maturation of cytotoxic T lymphocytes that are essential for the elimination of virus-infected cells). The data show that adenovirus vectors offer a promising alternative strategy for the development of dengue virus vaccines.Dengue viruses, which are members of the Flaviviridae family, are mosquito-borne human pathogens with a worldwide prevalence (12). There are four antigenically distinct serotypes of dengue viruses (28). There is neither an effective antiviral therapy for the treatment of dengue virus infections nor a licensed vaccine for their prevention (12,27). Infection with any one dengue virus serotype provides lifelong homologous immunity with only transient cross-protection against the remaining three serotypes (19). Sequential infection in areas of hyperendemicity (where multiple serotypes cocirculate) has the potential to trigger life-threatening disease widely believed to be mediated by an antibody-dependent enhancement mechanism (33). This has prompted the view that a dengue vaccine must be tetravalent; that is, it must afford solid and long-lasting protection against all four dengue virus serotypes.Several laboratories worldwide are exploring multiple approaches towards developing dengue virus vaccines based on live attenuated viruses (1, 21, 36), inactivated viruses (35), infectious clone-derived intertypic (18, 26) and chimeric (5, 13, 14, 43) viruses, antigen-encoding plasmids (23, 24), recombinant proteins expressed in heterologous systems (2,22,38,40), and live vaccinia virus vectors encoding antigen genes (9, 31, 32). However, the major focus is on the live, empirically attenuated (1, 21, 36), and infectious clone-derived ChimeriVax vaccines based on the attenuated YF17D yellow fever vaccine vector (13,14). Alternative attenuated vector backbones based on dengue type 1 (DEN-1) (29, 45), DEN-2 (18), and DEN-4 (8) viruses are being developed in parallel. All these strategies rely on the creation of monovalent vaccine viruses, which are mixed together to generate tetravalent formulations.Recent studies in which the tetravalent live attenuated (21) and ChimeriVax (13) vaccines were tested in humans and nonhuman primates, respectively, revealed that the tetravalent form...

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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

Cited by 88 publications

References 30 publications

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

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

Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

Replication-Defective Adenoviral Vaccine Vector for the Induction of Immune Responses to Dengue Virus Type 2

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