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Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003).

ABSTRACT: The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.

SUBMITTER: White LJ

PROVIDER: S-EPMC7990299 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Clinical Safety Experience of TAK-003 for Dengue Fever: A New Tetravalent Live Attenuated Vaccine Candidate.

Project description:BackgroundAn unmet medical need remains for an effective dengue tetravalent vaccine that can be administered irrespective of previous dengue exposure. TAK-003, a dengue tetravalent vaccine, has demonstrated efficacy in an ongoing phase 3 trial in children and adolescents living in dengue-endemic areas, with an acceptable safety profile in both dengue-naive and dengue-exposed individuals.MethodsSafety findings are presented herein from an integrated analysis of data for healthy 4-60-year-olds from two phase 2 and three phase 3 double-blind, placebo-controlled clinical trials of TAK-003 (TAK-003, n = 14 627; placebo, n = 7167). Safety evaluation included analyses of postinjection reactogenicity, unsolicited adverse events (AEs), serious AEs (SAEs), and deaths. Subgroup analyses were performed by age group, baseline serostatus, and gender.ResultsThe most common local and systemic AEs were injection site pain (43% for TAK-003 and 26% for placebo) and headache (34% and 30%, respectively). Injection site AEs were mostly mild and resolved within 1-3 days. Unsolicited AEs and AEs leading to discontinuation occurred with similar frequency across both groups, while SAEs were fewer for TAK-003 recipients (6% vs 8% for placebo). Four of the 5 vaccine-related SAEs (which included hypersensitivity, dengue fever, and dengue hemorrhagic fever) occurred in the placebo group. No deaths were considered vaccine-related. Subgroup analyses showed no differences in safety by baseline serostatus or by gender, albeit analysis by age indicated greater local reactogenicity rates for adolescents (46% for TAK-003 and 28% for placebo) and adults (56% and 19%, respectively) than for children (37% and 25%, respectively).ConclusionsNo important safety risks were identified, and TAK-003 was well tolerated irrespective of age, gender, or baseline dengue serostatus in recipients aged 4-60 years.

| S-EPMC9907483 | biostudies-literature

Live Attenuated Tetravalent Dengue Vaccination in Non-Human Primates

Project description:We measured genome-wide transcript abundance patterns in 246 whole blood samples collected from 35 cynomolgus macaques before and after vaccination with a live attenuated tetravalent dengue vaccine (TDV) or PBS (placebo). Animal work was conducted at the Charmany Instructional Facility of the School of Veterinary Medicine, University of Wisconsin-Madison, and all animal procedures were approved by the University of Wisconsin-Madison's Animal Care and Use Committee. Thirty-five adult male, DENV-seronegative cynomolgus macaques from Vietnam were placed in quarantine for 30 days prior to the start of the study. Five groups of animals (n=6 animals per group) received TDV either subcutaneously (SC) in 0.5 mL inocula or intradermally (ID) in 0.1 mL inocula using a needle-free injector (PharmaJet' device) or needle and syringe (N&S). Animals received two doses (same route) of TDV either on the same day (Day 0) or sixty days apart. One group (n=5) received PBS by ID route and needle-free injector. On day 90 after primary vaccination, 3 animals from each group were challenged with 105 PFU wt DENV-2 (New Guinea C strain) or 105 PFU wt DENV-4 (Dominica/81 strain) by SC route using N&S. Whole blood samples were collected for transcriptional profiling from all animals on days -11, -2, 1, 3, 5, and 7 before and after immunization, and for placebo animals on days 88, 91, 93, 95, and 97 before and after wt DENV challenge. Blood samples were drawn into PAXgene Blood RNA tubes and stored at -80'C prior to RNA extraction and processing.

2016-05-10 | GSE72430 | GEO

Assessing the Diversity and Stability of Cellular Immunity Generated in Response to the Candidate Live-Attenuated Dengue Virus Vaccine TAK-003.

Project description:The development of an efficacious DENV vaccine has been a long-standing public health priority. However, this effort has been complicated significantly due to the hazard presented by incomplete humoral immunity in mediating immune enhancement of infection and disease severity. Therefore, there is a significant need for DENV vaccine platforms capable of generating broad immune responses including durable cellular immunity, as well as novel analytical tools to assess the magnitude, diversity, and persistence of vaccine-elicited immunity. In this study, we demonstrate that a single dose of the recombinant, tetravalent, live-attenuated DENV vaccine TAK-003 elicits potent and durable cellular immunity against both the structural and non-structural proteins of all four DENV serotypes, which is maintained for at least 4 months post-immunization. Although not contained within the vaccine formulation, significant reactivity against the non-structural (NS) proteins of DENV-1,-3, and-4 is observed following vaccination, to an extent directly proportional to the magnitude of responses to the corresponding vaccine (DENV-2) components. Distinct, quantifiable, and durable patterns of DENV antigen reactivity can be observed in individuals following vaccination. Detailed epitope mapping of T cell reactivity against the DENV-2 proteome using a matrix of overlapping peptide pools demonstrated that TAK-003 elicits a broad response directed across the DENV-2 proteome, with focused reactivity against NS1 and NS3. We conclude that, as measured by an IFN-γ ELISPOT assay, a single dose of TAK-003 generates potent T cell-mediated immunity which is durable in magnitude and breadth through 4 months post-vaccination.

| S-EPMC6684763 | biostudies-literature

Influence of Fc?RIIa-Expressing Cells on the Assessment of Neutralizing and Enhancing Serum Antibodies Elicited by a Live-Attenuated Tetravalent Dengue Vaccine.

Project description:Background. ?Recent trials of recombinant, live-attenuated chimeric yellow fever-dengue tetravalent dengue vaccine (CYD-TDV) demonstrated efficacy against symptomatic, virologically confirmed dengue disease with higher point estimates of efficacy toward dengue virus (DENV)3 and DENV4 and moderate levels toward DENV1 and DENV2. It is interesting to note that serotype-specific efficacy did not correlate with absolute neutralizing antibody (nAb) geometric mean titer (GMT) values measured in a Vero-based plaque reduction neutralization test assay. The absence of Fc? receptors on Vero cells may explain this observation. Methods. ?We performed parallel seroneutralization assays in Vero cells and CV-1 cells that express Fc?RIIa (CV-1-Fc) to determine the neutralizing and enhancing capacity of serotype-specific DENV Abs present in CYD-TDV clinical trial sera. Results. ?Enhancement of DENV infection was observed in CV-1-Fc cells in naturally exposed nonvaccine sera, mostly for DENV3 and DENV4, at high dilutions. The CYD-TDV-vaccinated sera showed similar enhancement patterns. The CV-1-Fc nAb GMT values were 2- to 9-fold lower than Vero for all serotypes in both naturally infected individuals and CYD-TDV-vaccinated subjects with and without previous dengue immunity. The relative (CV-1-Fc/Vero) GMT decrease for anti-DENV1 and anti-DENV2 responses was not greater than for the other serotypes. Conclusions. ?In vitro neutralization assays utilizing Fc?RIIa-expressing cells provide evidence that serotype-specific Ab enhancement may not be a primary factor in the serotype-specific efficacy differences exhibited in the CYD-TDV trials.

| S-EPMC4689971 | biostudies-literature

Dissecting Antibodies Induced by a Chimeric Yellow Fever-Dengue, Live-Attenuated, Tetravalent Dengue Vaccine (CYD-TDV) in Naive and Dengue-Exposed Individuals.

Project description:Sanofi Pasteur has developed a chimeric yellow fever-dengue, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is currently approved for use in several countries. In clinical trials, CYD-TDV was efficacious at reducing laboratory-confirmed cases of dengue disease. Efficacy varied by dengue virus (DENV) serotype and prevaccination dengue immune status. We compared the properties of antibodies in naive and DENV-exposed individuals who received CYD-TDV. We depleted specific populations of DENV-reactive antibodies from immune serum samples to estimate the contribution of serotype-cross-reactive and type-specific antibodies to neutralization. Subjects with no preexisting immunity to DENV developed neutralizing antibodies to all 4 serotypes of DENV. Further analysis demonstrated that DENV4 was mainly neutralized by type-specific antibodies whereas DENV1, DENV2, and DENV3 were mainly neutralized by serotype cross-reactive antibodies. When subjects with preexisting immunity to DENV were vaccinated, they developed higher levels of neutralizing antibodies than naive subjects who were vaccinated. In preimmune subjects, CYD-TDV boosted cross-reactive neutralizing antibodies while maintaining type-specific neutralizing antibodies acquired before vaccination. Our results demonstrate that the quality of neutralizing antibodies induced by CYD-TDV varies depending on DENV serotype and previous immune status. We discuss the implications of these results for understanding vaccine efficacy.

| S-EPMC6392503 | biostudies-literature

An open-label, Phase 3 trial of TAK-003, a live attenuated dengue tetravalent vaccine, in healthy US adults: immunogenicity and safety when administered during the second half of a 24-month shelf-life.

Project description:Dengue is caused by a mosquito-transmitted flavivirus. The disease is now endemic to many tropical and subtropical regions, manifesting as approximately 96 million symptomatic cases of dengue each year. Clinical trials have shown TAK-003 (Qdenga®), a live attenuated dengue tetravalent vaccine, to be well-tolerated, immunogenic, and efficacious in adults with no prior exposure to dengue virus infection living in non-endemic regions, as well as in adults and children living in dengue-endemic areas. This open-label, single-arm phase 3 trial (NCT03771963) was conducted in two dengue non-endemic areas of the USA, and it evaluated the immunogenicity and safety of naturally-aged TAK-003 administered to adult participants. Overall, the immunogenicity data from this trial are consistent with those reported from other TAK-003 phase 2 and 3 trials, and the safety data are consistent with the broader integrated safety data analysis. The data show that naturally-aged TAK-003 had a well-tolerated reactogenicity and adverse events profile when administered in the second half of its clinical 24-month shelf-life and that it still elicited an immune response that persisted up to 6 months after the second dose against all four dengue serotypes, with no important safety risks identified during the trial.

| S-EPMC10583633 | biostudies-literature

Long-term safety assessment of live attenuated tetravalent dengue vaccines: deliberations from a WHO technical consultation.

Project description:Dengue is a rapidly growing public health threat with approximately 2.5 billion people estimated to be at risk. Several vaccine candidates are at various stages of pre-clinical and clinical development. Thus far, live dengue vaccine candidates have been administered to several thousands of volunteers and were well-tolerated, with minimal short-term safety effects reported in Phase I and Phase II clinical trials. Based on the natural history of dengue, a theoretical possibility of an increased risk of severe dengue as a consequence of vaccination has been hypothesized but not yet observed. In October 2011, the World Health Organization (WHO) convened a consultation of experts in dengue, vaccine regulation and vaccine safety to review the current scientific evidence regarding safety concerns associated with live attenuated dengue vaccines and, in particular, to consider methodological approaches for their long-term evaluation. In this paper we summarize the scientific background and methodological considerations relevant to the safety assessment of these vaccines. Careful planning and a coordinated approach to safety assessment are recommended to ensure adequate long-term evaluation of dengue vaccines that will support their introduction and continued use.

| S-EPMC5355209 | biostudies-other

Analyzing the Human Serum Antibody Responses to a Live Attenuated Tetravalent Dengue Vaccine Candidate.

Project description:Background:Dengue virus serotypes 1-4 (DENV-1-4) are the most common vector-borne viral pathogens of humans and the etiological agents of dengue fever and dengue hemorrhagic syndrome. A live-attenuated tetravalent dengue vaccine (TDV) developed by Takeda Vaccines has recently progressed to phase 3 safety and efficacy evaluation. Methods:We analyzed the qualitative features of the neutralizing antibody (nAb) response induced in naive and DENV-immune individuals after TDV administration. Using DENV-specific human monoclonal antibodies (mAbs) and recombinant DENV displaying different serotype-specific Ab epitopes, we mapped the specificity of TDV-induced nAbs against DENV-1-3. Results:Nearly all subjects had high levels of DENV-2-specific nAbs directed to epitopes centered on domain III of the envelope protein. In some individuals, the vaccine induced nAbs that tracked with a DENV-1-specific neutralizing epitope centered on domain I of the envelope protein. The vaccine induced binding Abs directed to a DENV-3 type-specific neutralizing epitope, but findings of mapping of DENV-3 type-specific nAbs were inconclusive. Conclusion:Here we provide qualitative measures of the magnitude and epitope specificity of the nAb responses to TDV. This information will be useful for understanding the performance of TDV in clinical trials and for identifying correlates of protective immunity.

| S-EPMC5972589 | biostudies-literature

Induction of neutralizing antibodies against four serotypes of dengue viruses by MixBiEDIII, a tetravalent dengue vaccine.

Project description:The worldwide expansion of four serotypes of dengue virus (DENV) poses great risk to global public health. Several vaccine candidates are under development. However, none is yet available for humans. In the present study, a novel strategy to produce tetravalent DENV vaccine based on envelope protein domain III (EDIII) was proposed. Tandem EDIIIs of two serotypes (type 1-2 and type 3-4) of DENV connected by a Gly-Ser linker ((Gly4Ser)3) were expressed in E. coli, respectively. Then, the two bivalent recombinant EDIIIs were equally mixed to form the tetravalent vaccine candidate MixBiEDIII, and used to immunize BALB/c mice. The results showed that specific IgG and neutralizing antibodies against all four serotypes of DENV were successfully induced in the MixBiEDIII employing Freund adjuvant immunized mice. Furthermore, in the suckling mouse model, sera from mice immunized with MixBiEDIII provided significant protection against four serotypes of DENV challenge. Our data demonstrated that MixBiEDIII, as a novel form of subunit vaccine candidates, might have the potential to be further developed as a tetravalent dengue vaccine in the near future.

| S-EPMC3897746 | biostudies-literature

Historical discourse on the development of the live attenuated tetravalent dengue vaccine candidate TV003/TV005.

Project description:Dengue is the most important arboviral disease world-wide with an estimated 400 million annual infections. Dengvaxia™ is a live attenuated tetravalent vaccine recently licensed for dengue seropositive individuals aged 9-45 years. There is great need for a dengue vaccine that could be given to dengue-naïve individuals and very young children. To that end, the U.S. NIH developed a live attenuated tetravalent dengue vaccine using an iterative approach evaluating the safety, infectivity, and immunogenicity of different candidates. This approach identified poor candidates who were then discarded from further evaluation. Each of the components of the tetravalent vaccine formulation is able to replicate to very low titer, inducing a homotypic immune response to each. The immune response elicited by the tetravalent vaccine is balanced, without immunodominance of one component. The vaccine was licensed by several manufacturers for development, including the Instituto Butantan which initiated a Phase 3 efficacy trial.

| S-EPMC7685199 | biostudies-literature

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