The Experts below are selected from a list of 8871 Experts worldwide ranked by ideXlab platform
Jean Lang - One of the best experts on this subject based on the ideXlab platform.
-
development of the sanofi pasteur tetravalent Dengue Vaccine one more step forward
Vaccine, 2015Co-Authors: Bruno Guy, Melanie Saville, Jean Lang, Olivier Briand, Nicholas JacksonAbstract:Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent Dengue Vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this Dengue Vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four Vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naive and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four Dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.
-
broad neutralization of wild type Dengue virus isolates following immunization in monkeys with a tetravalent Dengue Vaccine based on chimeric yellow fever 17d Dengue viruses
Virology, 2012Co-Authors: Veronique Barban, Nathalie Mantel, Sunil Gulia, Jorge L Munozjordan, Gilberto A Santiago, Yves Girerd, Jeanbaptiste Claude, Jean LangAbstract:The objective of the study was to evaluate if the antibodies elicited after immunization with a tetravalent Dengue Vaccine, based on chimeric yellow fever 17D/Dengue viruses, can neutralize a large range of Dengue viruses (DENV). A panel of 82 DENVs was developed from viruses collected primarily during the last decade in 30 countries and included the four serotypes and the majority of existing genotypes. Viruses were isolated and minimally amplified before evaluation against a tetravalent polyclonal serum generated during Vaccine preclinical evaluation in monkey, a model in which protection efficacy of this Vaccine has been previously demonstrated (Guirakhoo et al., 2004). Neutralization was observed across all the DENV serotypes, genotypes, geographical origins and isolation years. These data indicate that antibodies elicited after immunization with this Dengue Vaccine candidate should widely protect against infection with contemporary DENV lineages circulating in endemic countries.
-
Development of Sanofi Pasteur tetravalent Dengue Vaccine
Revista do Instituto de Medicina Tropical de São Paulo, 2012Co-Authors: Jean LangAbstract:With almost 50% of the world population at risk and an estimated annual burden that includes 230M infections, 2M severe cases and 25000 deaths, Dengue is a major public health concern. Brazil is a priority country for Dengue vaccination as it accounts for 70% of all reported cases in Americas (1998-2009) and > 1 million clinical cases reported in 2010. After decades of research by different groups around the world, Dengue Vaccine development reached a major milestone in 2010 with the initiation of the first phase III clinical trial to investigate a candidate Vaccine. This Vaccine is the Sanofi Pasteur CYD tetravalent Dengue Vaccine (TDV) which is now being evaluated for protective efficacy in large scale trials in Latin America and south-east Asia as part of an extensive clinical development program in both regions. The CYD TDV candidate comprises four recombinant, live, attenuated Vaccines (CYD-1–4) based on a yellow fever Vaccine 17D (YF17D) backbone, each expressing the pre-membrane and envelope genes of one of the four Dengue virus serotypes. The Vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YF17D, and does not infect mosquitoes by the oral route.
-
priming effect of Dengue and yellow fever vaccination on the immunogenicity infectivity and safety of a tetravalent Dengue Vaccine in humans
American Journal of Tropical Medicine and Hygiene, 2011Co-Authors: Ming Qiao, David Shaw, Remi Forrat, Anh Warteltram, Jean LangAbstract:A Dengue Vaccine effective against all four serotypes is urgently needed. However, safety and immunogenicity could be affected by prior exposure to flaviviruses. This open, controlled, phase IIa study was conducted in 35 healthy adults who had received monovalent, live attenuated Vero cell-derived Dengue Vaccine against Dengue virus 1 (VDV1) or 2 (VDV2) or yellow fever (YF) Vaccine 1 year before or who were flavivirus-naive. All participants received one subcutaneous injection of tetravalent Dengue Vaccine (TDV) and were followed for 180 days. Previous vaccination did not increase reactogenicity, laboratory abnormalities, or incidence of Vaccine viremia, but it did increase the neutralizing antibody response to Dengue virus that persisted at day 180. There was no increase in YF antibodies in participants previously immunized with YF Vaccine. Prior exposure to YF or monovalent Dengue Vaccines had no adverse effects on the safety or incidence of viremia associated with this TDV, but it increased immunogenicity.
-
from research to phase iii preclinical industrial and clinical development of the sanofi pasteur tetravalent Dengue Vaccine
Vaccine, 2011Co-Authors: Beatrice Barrere, Melanie Saville, Claire Malinowski, Remy Teyssou, Jean LangAbstract:Dengue Vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent Dengue Vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated Vaccines (CYD-1–4) based on a yellow fever Vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four Dengue virus serotypes. The Vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to Vaccine in the countries where the Dengue disease burden makes it an urgent public health priority. The Vaccine has now been administered to more than 6000 children and adults from Dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of Vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing Vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the Vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a Dengue Vaccine into immunization programs.
Bruno Guy - One of the best experts on this subject based on the ideXlab platform.
-
characterization of recombinant yellow fever Dengue Vaccine viruses with human monoclonal antibodies targeting key conformational epitopes
Vaccine, 2019Co-Authors: Valerie Lecouturier, Nicholas Jackson, Catherine Berry, Aure Saulnier, Sophie Naville, Catherine Manin, Yves Girerdchambaz, James E Crowe, Bruno GuyAbstract:Abstract The recombinant yellow fever-17D–Dengue virus, live, attenuated, tetravalent Dengue Vaccine (CYD-TDV) is licensed in several Dengue-endemic countries. Although the Vaccine provides protection against Dengue, the level of protection differs by serotype and warrants further investigation. We characterized the antigenic properties of each Vaccine virus serotype using highly neutralizing human monoclonal antibodies (hmAbs) that bind quaternary structure-dependent epitopes. Specifically, we monitored the binding of Dengue virus-1 (DENV-1; 1F4), DENV-2 (2D22) or DENV-3 (5J7) serotype-specific or DENV-1–4 cross-reactive (1C19) hmAbs to the four chimeric yellow fever-Dengue Vaccine viruses (CYD-1–4) included in phase III Vaccine formulations using a range of biochemical and functional assays (dot blot, ELISA, surface plasmon resonance and plaque reduction neutralization assays). In addition, we used the “classic” live, attenuated DENV-2 Vaccine serotype, immature CYD-2 viruses and DENV-2 virus-like particles as control antigens for anti-serotype-2 reactivity. The CYD Vaccine serotypes were recognized by each hmAbs with the expected specificity, moreover, surface plasmon resonance indicated a high functional affinity interaction with the CYD serotypes. In addition, the hmAbs provided similar protection against CYD and wild-type Dengue viruses in the in vitro neutralization assay. Overall, these findings demonstrate that the four CYD viruses used in clinical trials display key conformational and functional epitopes targeted by serotype-specific and/or cross-reactive neutralizing human antibodies. More specifically, we showed that CYD-2 displays serotype- specific epitopes present only on the mature virus. This indicates that the CYD-TDV has the ability to elicit antibody specificities which are similar to those induced by the wild type DENV. Future investigations will be needed to address the nature of CYD-TDV-induced responses after Vaccine administration, and how these laboratory markers relate to Vaccine efficacy and safety.
-
Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? Questions Raised by the Development and Implementation of Dengue Vaccines: Example of the Sanofi Pasteur Tetravalent Dengue Vacc
Cold Spring Harbor perspectives in biology, 2018Co-Authors: Bruno GuyAbstract:Dengue is a still-growing public health concern in many tropical and subtropical regions of the world. The development and implementation of an effective Dengue Vaccine in these regions is a high priority. This insight focuses on the expected characteristics of a safe and efficacious Vaccine, referring to the clinical experience obtained during the development of the first tetravalent Dengue Vaccine from Sanofi Pasteur, now licensed in several endemic countries. Safety and efficacy data from both short- and long-term follow-up of large-scale efficacy studies will be discussed, as well as the next steps following Vaccine introduction.
-
development of the sanofi pasteur tetravalent Dengue Vaccine one more step forward
Vaccine, 2015Co-Authors: Bruno Guy, Melanie Saville, Jean Lang, Olivier Briand, Nicholas JacksonAbstract:Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent Dengue Vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this Dengue Vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four Vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naive and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four Dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.
-
modelling the immunological response to a tetravalent Dengue Vaccine from multiple phase 2 trials in latin america and south east asia
Vaccine, 2015Co-Authors: Ilaria Dorigatti, Bruno Guy, Nicholas Jackson, Melanie Saville, Ricardo Aguas, Christl A Donnelly, Laurent Coudeville, Neil M. FergusonAbstract:Background The most advanced Dengue Vaccine candidate is a live-attenuated recombinant Vaccine containing the four Dengue viruses on the yellow fever Vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV Vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the Vaccine.
-
Dengue Vaccine: Hypotheses to understand CYD-TDV-induced protection
Nature Reviews Microbiology, 2015Co-Authors: Bruno Guy, Nicholas JacksonAbstract:Dengue virus (DENV) is a human pathogen with a large impact on public health. Although no Vaccine against DENV is currently licensed, a recombinant Vaccine - chimeric yellow fever virus-DENV tetravalent Dengue Vaccine (CYD-TDV) - has shown efficacy against symptomatic Dengue disease in two recent Phase III clinical trials. Safety observations were also recently reported for these trials. In this Opinion article, we review the data from recent Vaccine clinical trials and discuss the putative mechanisms behind the observed efficacy of the Vaccine against different forms of the disease, focusing on the interactions between the infecting virus, pre-existing host immunity and Vaccine-induced immune responses.
Jorge E Osorio - One of the best experts on this subject based on the ideXlab platform.
-
a recombinant chimeric tetravalent Dengue Vaccine candidate based on a Dengue virus serotype 2 backbone
Expert Review of Vaccines, 2016Co-Authors: Jorge E Osorio, Derek Wallace, Dan T StinchcombAbstract:Dengue fever is caused by infection with one of four Dengue virus (DENV) serotypes (DENV-1-4), necessitating tetravalent Dengue Vaccines that can induce protection against all four DENV. Takeda's live attenuated tetravalent Dengue Vaccine candidate (TDV) comprises an attenuated DENV-2 strain plus chimeric viruses containing the prM and E genes of DENV-1, -3 and -4 cloned into the attenuated DENV-2 'backbone'. In Phase 1 and 2 studies, TDV was well tolerated by children and adults aged 1.5-45 years, irrespective of prior Dengue exposure; mild injection-site symptoms were the most common adverse events. TDV induced neutralizing antibody responses and seroconversion to all four DENV as well as cross-reactive T cell-mediated responses that may be necessary for broad protection against Dengue fever.
-
development of a recombinant chimeric tetravalent Dengue Vaccine candidate
Vaccine, 2015Co-Authors: Jorge E Osorio, Derek Wallace, Charalambos D Partidos, Dan T StinchcombAbstract:Dengue is a significant threat to public health worldwide. Currently, there are no licensed Vaccines available for Dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent Dengue Vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the Vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naive adults. TDV administration was generally well-tolerated independent of dose and route. The Vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24-67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8(+) T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in Dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study.
-
safety and immunogenicity of different doses and schedules of a live attenuated tetravalent Dengue Vaccine tdv in healthy adults a phase 1b randomized study
Vaccine, 2015Co-Authors: Richard E Rupp, Derek Wallace, Jorge E Osorio, Marsha Raanan, Mary Kathryn Smith, Gary J Luckasen, Judith Lee Kirstein, Joseph D Santangelo, Gilad GordonAbstract:Abstract Introduction A safe, effective Dengue Vaccine that can simultaneously induce immunity to all four Dengue virus serotypes (DENV-1–4) is a public health priority. A chimeric tetravalent Dengue Vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. Methods In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18–45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a Vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1–4 at Day 120. Results The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84–100%; DEN-2: 96–100%; DEN-3: 83–100%; and DEN-4: 33–77%. More than 80% of participants in each group seroconverted to at least three Dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1–3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. Conclusions All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250 ).
-
immunogenicity and efficacy of chimeric Dengue Vaccine denvax formulations in interferon deficient ag129 mice
Vaccine, 2012Co-Authors: Joseph N Brewoo, Richard M Kinney, Tim D Powell, John J Arguello, Shawn J Silengo, Charalambos D Partidos, Claire Y H Huang, Dan T Stinchcomb, Jorge E OsorioAbstract:Formulations of chimeric Dengue Vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1–4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 Vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent Dengue Vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent Vaccines that confer protection against homologous or heterologous virus challenge.
Nicholas Jackson - One of the best experts on this subject based on the ideXlab platform.
-
characterization of recombinant yellow fever Dengue Vaccine viruses with human monoclonal antibodies targeting key conformational epitopes
Vaccine, 2019Co-Authors: Valerie Lecouturier, Nicholas Jackson, Catherine Berry, Aure Saulnier, Sophie Naville, Catherine Manin, Yves Girerdchambaz, James E Crowe, Bruno GuyAbstract:Abstract The recombinant yellow fever-17D–Dengue virus, live, attenuated, tetravalent Dengue Vaccine (CYD-TDV) is licensed in several Dengue-endemic countries. Although the Vaccine provides protection against Dengue, the level of protection differs by serotype and warrants further investigation. We characterized the antigenic properties of each Vaccine virus serotype using highly neutralizing human monoclonal antibodies (hmAbs) that bind quaternary structure-dependent epitopes. Specifically, we monitored the binding of Dengue virus-1 (DENV-1; 1F4), DENV-2 (2D22) or DENV-3 (5J7) serotype-specific or DENV-1–4 cross-reactive (1C19) hmAbs to the four chimeric yellow fever-Dengue Vaccine viruses (CYD-1–4) included in phase III Vaccine formulations using a range of biochemical and functional assays (dot blot, ELISA, surface plasmon resonance and plaque reduction neutralization assays). In addition, we used the “classic” live, attenuated DENV-2 Vaccine serotype, immature CYD-2 viruses and DENV-2 virus-like particles as control antigens for anti-serotype-2 reactivity. The CYD Vaccine serotypes were recognized by each hmAbs with the expected specificity, moreover, surface plasmon resonance indicated a high functional affinity interaction with the CYD serotypes. In addition, the hmAbs provided similar protection against CYD and wild-type Dengue viruses in the in vitro neutralization assay. Overall, these findings demonstrate that the four CYD viruses used in clinical trials display key conformational and functional epitopes targeted by serotype-specific and/or cross-reactive neutralizing human antibodies. More specifically, we showed that CYD-2 displays serotype- specific epitopes present only on the mature virus. This indicates that the CYD-TDV has the ability to elicit antibody specificities which are similar to those induced by the wild type DENV. Future investigations will be needed to address the nature of CYD-TDV-induced responses after Vaccine administration, and how these laboratory markers relate to Vaccine efficacy and safety.
-
development of the sanofi pasteur tetravalent Dengue Vaccine one more step forward
Vaccine, 2015Co-Authors: Bruno Guy, Melanie Saville, Jean Lang, Olivier Briand, Nicholas JacksonAbstract:Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent Dengue Vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this Dengue Vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four Vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naive and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four Dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.
-
modelling the immunological response to a tetravalent Dengue Vaccine from multiple phase 2 trials in latin america and south east asia
Vaccine, 2015Co-Authors: Ilaria Dorigatti, Bruno Guy, Nicholas Jackson, Melanie Saville, Ricardo Aguas, Christl A Donnelly, Laurent Coudeville, Neil M. FergusonAbstract:Background The most advanced Dengue Vaccine candidate is a live-attenuated recombinant Vaccine containing the four Dengue viruses on the yellow fever Vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV Vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the Vaccine.
-
Dengue Vaccine: Hypotheses to understand CYD-TDV-induced protection
Nature Reviews Microbiology, 2015Co-Authors: Bruno Guy, Nicholas JacksonAbstract:Dengue virus (DENV) is a human pathogen with a large impact on public health. Although no Vaccine against DENV is currently licensed, a recombinant Vaccine - chimeric yellow fever virus-DENV tetravalent Dengue Vaccine (CYD-TDV) - has shown efficacy against symptomatic Dengue disease in two recent Phase III clinical trials. Safety observations were also recently reported for these trials. In this Opinion article, we review the data from recent Vaccine clinical trials and discuss the putative mechanisms behind the observed efficacy of the Vaccine against different forms of the disease, focusing on the interactions between the infecting virus, pre-existing host immunity and Vaccine-induced immune responses.
Dan T Stinchcomb - One of the best experts on this subject based on the ideXlab platform.
-
a recombinant chimeric tetravalent Dengue Vaccine candidate based on a Dengue virus serotype 2 backbone
Expert Review of Vaccines, 2016Co-Authors: Jorge E Osorio, Derek Wallace, Dan T StinchcombAbstract:Dengue fever is caused by infection with one of four Dengue virus (DENV) serotypes (DENV-1-4), necessitating tetravalent Dengue Vaccines that can induce protection against all four DENV. Takeda's live attenuated tetravalent Dengue Vaccine candidate (TDV) comprises an attenuated DENV-2 strain plus chimeric viruses containing the prM and E genes of DENV-1, -3 and -4 cloned into the attenuated DENV-2 'backbone'. In Phase 1 and 2 studies, TDV was well tolerated by children and adults aged 1.5-45 years, irrespective of prior Dengue exposure; mild injection-site symptoms were the most common adverse events. TDV induced neutralizing antibody responses and seroconversion to all four DENV as well as cross-reactive T cell-mediated responses that may be necessary for broad protection against Dengue fever.
-
development of a recombinant chimeric tetravalent Dengue Vaccine candidate
Vaccine, 2015Co-Authors: Jorge E Osorio, Derek Wallace, Charalambos D Partidos, Dan T StinchcombAbstract:Dengue is a significant threat to public health worldwide. Currently, there are no licensed Vaccines available for Dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent Dengue Vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the Vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naive adults. TDV administration was generally well-tolerated independent of dose and route. The Vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24-67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8(+) T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in Dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study.
-
immunogenicity and efficacy of chimeric Dengue Vaccine denvax formulations in interferon deficient ag129 mice
Vaccine, 2012Co-Authors: Joseph N Brewoo, Richard M Kinney, Tim D Powell, John J Arguello, Shawn J Silengo, Charalambos D Partidos, Claire Y H Huang, Dan T Stinchcomb, Jorge E OsorioAbstract:Formulations of chimeric Dengue Vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1–4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 Vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent Dengue Vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent Vaccines that confer protection against homologous or heterologous virus challenge.