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We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine c...
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We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine can protect against dengue challenge. The dengue vaccine (EDIII-E2) is composed of both a protein particle and a DNA-expression plasmid delivered simultaneously via intramuscular injection (protein) and gene gun (DNA) into rhesus macaques. The protein component can contain a maximum of 60 copies of EDIII presented on a multimeric scaffold of Geobacillus stearothermophilus E2 proteins. The DNA component is composed of the EDIII portion of the envelope gene cloned into an expression plasmid. The EDIII-E2 vaccine elicited robust antibody responses to DENV2, with neutralizing antibody responses detectable following the first boost and reaching titers of greater than 1:100,000 following the second and final boost. Vaccinated and naive groups of macaques were challenged with DENV2. All vaccinated macaques were protected from detectable viremia by infectious assay, while naive animals had detectable viremia for 2-7 days post-challenge. All naive macaques had detectable viral RNA from day 2-10 post-challenge. In the EDIII-E2 group, three macaques were negative for viral RNA and three were found to have detectable viral RNA post challenge. Viremia onset was delayed and the duration was shortened relative to naive controls. The presence of viral RNA post-challenge corresponded to a 10-30-fold boost in neutralization titers 28 days post challenge, whereas no boost was observed in the fully protected animals. Based on these results, we determine that pre-challenge 50% neutralization titers of >1:6000 correlated with sterilizing protection against DENV2 challenge in EDIII-E2 vaccinated macaques. Identification of the critical correlate of protection-for the EDIII-E2 platform in the robust non-human primate model lays the groundwork for further development of a tetravalent EDIII-E2 dengue vaccine. (C) 2016 The Authors. Published by Elsevier Ltd.
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More than one third of the world's population living in tropical and subtropical areas of the world is at risk of dengue infections and as many as 100[NON-BREAKING SPACE]million people are yearly infected. This disease has reemerg...
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More than one third of the world's population living in tropical and subtropical areas of the world is at risk of dengue infections and as many as 100[NON-BREAKING SPACE]million people are yearly infected. This disease has reemerged during the past 20[NON-BREAKING SPACE]years in the form of an epidemic. Dengue is caused by one of four related serotypes of dengue virus and often leads to severe forms of the disease, resulting commonly from secondary infections. Dengue virus is a mosquito borne virus, belongs to the family Flaviviridae and consists of a single stranded positive sense RNA genome. Like other RNA viruses it escapes defense mechanisms and neutralization attempts by mutations, which make it more resistant and adaptable to its environment. Antiviral strategies and vaccine development is thus impaired and hence to date there is no licensed vaccine available for dengue virus. Here we discuss various efforts made towards the identification of potential vaccine targets for dengue as well as various strategies employed by research groups/pharmaceutical companies towards the development of a successful dengue vaccine.
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Background: The first dengue vaccine (DV) has been licensed in some countries, but an assessment of the public's acceptance of DV is widely lacking. This study aimed to explore and understand DV acceptance and its associated expla...
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Background: The first dengue vaccine (DV) has been licensed in some countries, but an assessment of the public's acceptance of DV is widely lacking. This study aimed to explore and understand DV acceptance and its associated explanatory variables among healthy inhabitants of Aceh, Indonesia.
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Background: The dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of d...
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Background: The dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of dengue vaccines may be possible in the near future. Advancing on the recent WHO-SAGE recommendations for the safe and effective use of CYD-TDV at the regional level on average, this study investigates the vaccination impacts and cost-effectiveness of CYD-TDV and of a hypothetical new vaccine candidate (NVC) in a country-specific manner for three endemic countries: Vietnam, Thailand, and Colombia.
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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...
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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 lib (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. (C) 2015 The Authors. Published by Elsevier Ltd.
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To explore and understand the attitude towards dengue vaccination and its modifiable determinants among inhabitants of Aceh (northern Sumatra Island, Indonesia), the region that was most severely affected by the earthquake and tsu...
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To explore and understand the attitude towards dengue vaccination and its modifiable determinants among inhabitants of Aceh (northern Sumatra Island, Indonesia), the region that was most severely affected by the earthquake and tsunami of 26 December 2004. A community-based, cross-sectional study was conducted among 535 healthy inhabitants in nine regencies (Kabupaten or Kotamadya) of Aceh that were selected randomly from November 2014 to March 2015. A set of validated, pre-tested, structured questionnaires was used to guide the interviews. The questionnaires covered a range of explanatory variables and one outcome variable (attitude to dengue vaccination). Multi-step logistic regression analysis and Spearman's rank correlation were used to test the role of explanatory variables for the outcome variable. More than 70% of the participants had a poor attitude towards dengue vaccination. Modifiable determinants associated with poor attitude to dengue vaccination were low education level, working as farmers and traditional market traders, low socioeconomic status and poor knowledge, attitude and practice regarding dengue fever (P?<?0.05). The KAP domain scores were correlated strongly with attitude to dengue vaccination, rs?=?0.25, rs?=?0.67 and rs?=?0.20, respectively (P?<?0.001). Multivariate analysis found that independent predictors associated with attitude towards dengue vaccination among study participants were only sex and attitude towards dengue fever (P?<?0.001). This study reveals that low KAP regarding dengue fever, low education level and low socioeconomic status are associated with a poor attitude towards dengue vaccination. Therefore, inhabitants of suburbs who are working as farmers or traditional market traders with low socioeconomic status are the most appropriate target group for a dengue vaccine introduction program. Copyright ?? 2016 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.
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Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical developme...
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Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines. (C) 2018 The Authors. Published by Elsevier Ltd.
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Background: Dengue fever is the most prevalent mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year. There is an unmet medical need to develop a safe, effective and affordable dengue v...
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Background: Dengue fever is the most prevalent mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year. There is an unmet medical need to develop a safe, effective and affordable dengue vaccine against all four Dengue serotype viruses-DENV1, DENV-2, DENV-3 and DENV-4. Panacea Biotec Ltd (PBL) has developed a cell culture-derived, live-attenuated, lyophilized Tetravalent Dengue Vaccine (TDV). Here, in phase I/II study we assessed the safety and immunogenicity of single dose ‘Dengue Tetravalent Vaccine’ in healthy Indian adults. Methods: In the study, 100 healthy adult volunteers aged 18–60 years were enrolled. The participants were allocated to TDV and placebo groups in 3:1 ratio, i.e. 75 participants to TDV group and 25 participants to the placebo group. Enrolled participants were administered a single dose of 0.5 ml of the test vaccine / placebo by subcutaneous route. Primary outcome for safety included all solicited AEs up to 21 days, unsolicited AEs up to 28 days and all AEs/serious adverse events (SAEs) till day 90 postvaccination. For immunogenicity assessment the primary outcome was seroconversion & seropositivity rate by PRNT50 to all four serotype till 90 days. Results: Overall, 100 subjects were vaccinated out of which 8 subjects (5 subjects in vaccine group and 3 subjects in placebo group) dropped out from the study. The most commonly reported solicited local AE was pain and most common solicited systemic AE was headache and fever. No SAE was reported during the study. There was no statistically significant difference between TDV and placebo groups in terms of AEs. Of the 92 subjects who completed all scheduled visits in the study, 59 (81.9%) achieved seroconversion for DENV-1, 56 (77.8%) for DENV-2; 59 (81.9%) for DENV-3 and 57 (79.2%) for DENV-4 in TDV group. The seroconversion rate in the TDV group was statistically significant (p < 0.001) compared to placebo.
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Summary Dengue is an emerging mosquito-borne viral infection with increasing reports of outbreaks. The clinical picture ranges from a benign febrile illness through to severe and potentially fatal manifestations. No specific anti-...
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Summary Dengue is an emerging mosquito-borne viral infection with increasing reports of outbreaks. The clinical picture ranges from a benign febrile illness through to severe and potentially fatal manifestations. No specific anti-viral treatment exists, and therapy only consists of supportive care. During the last three decades, several attempts to develop an effective vaccine have been made. The first dengue vaccine to obtain licensure was Dengvaxia, which was authorized in 2015 and is currently available in over 20 countries. Its use has been approved with strict limitations regarding age and serostatus of the recipients, highlighting the necessity for a more safe and efficacious vaccine. At present several vaccine, candidates are undergoing clinical and pre-clinical trials. The most advanced candidates are TDV and TDV 003/005, two live-attenuated vaccines, but another 15 vaccines are under development, introducing novel immunization strategies to the traditional dengue vaccine scenario. This work reviews the current research status on dengue vaccines.
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Background: Dengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine-to fourteen-year-old children in thre...
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Background: Dengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine-to fourteen-year-old children in three regions with the highest number of dengue cases using CYD-TDV (Dengvaxia, Sanofi Pasteur). In July 2017, a community-based dengue vaccination program was implemented in Cebu province. The program was discontinued in December 2017 amidst public controversy, after the first dose had been administered. We assessed the effectiveness of a single dose of CYD-TDV against hospitalized virologically confirmed dengue (VCD). Methods: We conducted a case-control study in Cebu province following the dengue mass vaccination. Children who were nine to fourteen years of age during the mass vaccination and subsequently admitted to any of four participating public hospitals with suspected dengue were enrolled in the study as cases. Blood for RT-PCR and clinical and socio-demographic information were obtained. To estimate the level of vaccine protection, vaccination status was compared between children with hospitalized virologically confirmed dengue and controls of the same six-year age-group as the cases, matched on sex, neighborhood and time of occurrence of cases. Findings: We enrolled 490 cases and 980 controls. Receipt of one dose of CYD-TDV was associated with 26% (95 % CI,-2 to 47%; p = 0 0675) overall protection against hospitalized virologically confirmed dengue and 51% (95 % CI, 23 to 68; p = 0 0016) protection against dengue with warning signs. Interpretation: A single dose of CYD-TDV given to nine to fourteen-year-old children through a community-based mass vaccination program conferred protection against dengue with warning signs and severe dengue but we were unable to conclude on protection against milder illness. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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