Immunogenicity and protective efficacy of a recombinant fusion protein containing the domain III of the dengue 1 envelope protein in non-human primates

Bernardo, Lídice; Izquierdo, Alienys; Álvarez, Mayling; Rosario, Delfina; Prado, Irina; López, Carlos; Martínez, Rafael; Castro, Jorge; Santana, Emidalys; Hermida, Lisset; Guillén, Gerardo; Guzmán, María G.

doi:10.1016/j.antiviral.2008.06.005

Cited by 57 publications

(36 citation statements)

References 49 publications

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“…Similar to other NHP studies, one limitation of this work was the small group sizes (n ϭ 2 to 4), which limited the power of statistical analyses. Overall, our results with the flagellin-EIII fusion candidates are consistent with previously published results obtained with high doses (50 to 500 g) of EIII fusion proteins formulated in an exogenous adjuvant (31,35,36). Utilizing a similar DENV-2/NHP model, Simmons et al observed relatively poor durability of antibody responses and lack of protection from viremia in rhesus macaques (n ϭ 4) following three immunizations (days 0, 30, and 60) with Freund's adjuvanted EIII (amino acids 298 to 400)-maltose-binding pro- TDVs.…”

Section: Discussionsupporting

confidence: 82%

“…Envelope-specific IgG levels were measured by ELISA as described in Materials and Methods and are expressed as GMTs and 95% CIs. (35,36). It is noteworthy that these chimeric antigens included a longer EIII sequence (amino acids 286 to 426) than was used for our studies, suggesting that additional C-terminal residues may contribute to protective immunogenicity of DENV EIII.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

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 role of anamnestic responses for reducing viremia after challenge has been supported by previous studies (54)(55)(56)(57)(58)(59)(60). We also found that monkeys immunized with ChinDENV and challenged s.c. with wt DENV-2 had dramatic increases in serum neutralizing antibodies, suggesting a good memory component in ChinDENV immunity.…”

Section: Discussionsupporting

confidence: 57%

A Chimeric Dengue Virus Vaccine using Japanese Encephalitis Virus Vaccine Strain SA14-14-2 as Backbone Is Immunogenic and Protective against Either Parental Virus in Mice and Nonhuman Primates

Deng

Yang

et al. 2013

J Virol

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The development of a safe and efficient dengue vaccine represents a global challenge in public health. Chimeric dengue viruses (DENV) based on an attenuated flavivirus have been well developed as vaccine candidates by using reverse genetics. In this study, based on the full-length infectious cDNA clone of the well-known Japanese encephalitis virus live vaccine strain SA14-14-2 as a backbone, a novel chimeric dengue virus (named ChinDENV) was rationally designed and constructed by replacement with the premembrane and envelope genes of dengue 2 virus. The recovered chimeric virus showed growth and plaque properties similar to those of the parental DENV in mammalian and mosquito cells. ChinDENV was highly attenuated in mice, and no viremia was induced in rhesus monkeys upon subcutaneous inoculation. ChinDENV retained its genetic stability and attenuation phenotype after serial 15 passages in cultured cells. A single immunization with various doses of ChinDENV elicited strong neutralizing antibodies in a dose-dependent manner. When vaccinated monkeys were challenged with wild-type DENV, all animals except one that received the lower dose were protected against the development of viremia. Furthermore, immunization with Chin-DENV conferred efficient cross protection against lethal JEV challenge in mice in association with robust cellular immunity induced by the replicating nonstructural proteins. Taken together, the results of this preclinical study well demonstrate the great potential of ChinDENV for further development as a dengue vaccine candidate, and this kind of chimeric flavivirus based on JE vaccine virus represents a powerful tool to deliver foreign antigens.

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“…NHP studies of monovalent preparations have demonstrated moderate immunogenicity and protection from wild-type DENV challenge. 112,122,144 NHPs immunized with monovalent DENV-1 or DENV-2 candidates using an emulsified Freund's adjuvant developed NAb and were protected against homologous challenge.…”

Section: Candidates In Clinical Developmentmentioning

confidence: 99%

Vaccines for the prevention of dengue: Development update

Thomas

Endy²

2011

Human Vaccines

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Immunogenicity and protective efficacy of a recombinant fusion protein containing the domain III of the dengue 1 envelope protein in non-human primates

Cited by 57 publications

References 49 publications

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

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

A Chimeric Dengue Virus Vaccine using Japanese Encephalitis Virus Vaccine Strain SA14-14-2 as Backbone Is Immunogenic and Protective against Either Parental Virus in Mice and Nonhuman Primates

Vaccines for the prevention of dengue: Development update

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