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Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial.

ABSTRACT: New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

SUBMITTER: Durbin AP

PROVIDER: S-EPMC7410446 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A recombinant live attenuated tetravalent dengue vaccine (CYD-TDV) has been shown to be efficacious in preventing virologically-confirmed dengue disease, severe dengue disease and dengue hospitalization in children aged 2-16 years in Asia and Latin America. We analyzed pooled safety data from 18 phase I, II and III clinical trials in which the dengue vaccine was administered to participants aged 2-60 years, including long-term safety follow-up in three efficacy trials. The participants were analyzed according to their age at enrollment. The percentage of participants aged 2-60 years reporting ?1 solicited injection-site or systemic reactions was slightly higher in the CYD-TDV group than in the placebo group. The most common solicited injection-site reactions were pain. Headache and malaise were the most common solicited systemic reactions. In both groups 0.3% of participants discontinued for safety reasons. The most common unsolicited adverse events were injection-site reactions, gastrointestinal disorders, and infections. Reactogenicity did not increase with successive doses of CYD-TDV. The frequency and nature of SAEs occurring within 28 days of any dose were similar in the CYD-TDV and placebo groups and were common medical conditions that could be expected as a function of age. Baseline dengue virus serostatus did not appear to influence the safety profile. No vaccine-related anaphylactic reactions, neurotropic events or viscerotropic events were reported. In year 3 after dose 1, an imbalance for dengue hospitalization, including for severe dengue, observed in participants aged <9 years in the CYD-TDV group compared with the placebo group was not observed for participants aged ?9 years. In Year 4, this imbalance in participants aged <9 years was less marked, giving an overall lower risk of dengue hospitalization or severe dengue from dose 1 to Year 4 in the CYD-TDV group. These results have contributed to the definition of the target population for vaccination (?9 years old) for which CYD-TDV has a satisfactory safety profile. Long-term safety will continue to be monitored in the ongoing follow-up of efficacy trials. Safety and effectiveness in real-life settings will be assessed through post-licensure studies.

Project description:Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations.We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18-45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov, number NCT01224639.We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group.Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted.Takeda Vaccines.

Project description:BackgroundDengue hemorrhagic fever is the leading cause of hospitalization and death in children living in Asia and Latin America. There is an urgent need for an effective and safe dengue vaccine to reduce morbidity and mortality in this high-risk population given the lack of dengue specific treatment at present. This review aims to determine the efficacy, safety, and immunogenicity of CYD-TDV vaccine in children.MethodsThis is a systematic review including meta-analysis of randomized controlled clinical trial data from Embase, Medline, the Cochrane Library, Web of Science, and ClinicalTrials.gov. Studies that assessed CYD-TDV vaccine efficacy [(1 - RR)*100], safety (RR), and immunogenicity (weighted mean difference) in children were included in this study. Random effects model was employed to analyze patient-level data extracted from primary studies.ResultsThe overall efficacy of CYD-TDV vaccine was 54% (40-64), while serotype-specific efficacy was 77% (66-85) for DENV4, 75% (65-82) for DENV3, 50% (36-61) for DENV1, and 34% (14-49) for DENV2. 15% (-174-74) vaccine efficacy was obtained for the unknown serotype. Meta-analysis of included studies with longer follow-up time (25 months) revealed that CYD-TDV vaccine significantly increased the risk of injection site reactions (RR = 1.1: 1.04-1.17; p-value = 0.001). Immunogenicity (expressed as geometric mean titers) in descending order was 439.7 (331.7-547.7), 323 (247 - 398.7), 144.1 (117.9-170.2), and 105 (88.7-122.8) for DENV3, DENV2, DENV1, and DENV4, respectively.ConclusionCYD-TDV vaccine is effective and immunogenic in children overall. Reduced efficacy of CYD-TDV vaccine against DENV2 notoriously known for causing severe dengue infection and dengue outbreaks cause for serious concern. Post hoc meta-analysis of long-term follow-up data (≥25 months) from children previously vaccinated with CYD-TDV vaccine is needed to make a conclusion regarding CYD-TDV vaccine safety in children. However, CYD-TDV vaccine should be considered for use in regions where DENV2 is not endemic as currently there is no specific treatment for dengue infection.

Dataset Information

Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial.

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