Efficacy and Safety of a Tetravalent Dengue Vaccine (TAK-003) in Children With Prior Japanese Encephalitis or Yellow Fever Vaccination.

BACKGROUND: We explored the impact of prior Yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003 (NCT02747927). METHODS: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific RT-PCR. YF and JE vaccination history was recorded. RESULTS: Of the 20,071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy was 55.7% (95% CI, 39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups. CONCLUSIONS: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings.

Long-term Safety and Immunogenicity of a Tetravalent Dengue Vaccine Candidate in Children and Adults: A Randomized, Placebo-Controlled, Phase 2 Study.

BACKGROUND: We report long-term safety and immunogenicity of Takeda's tetravalent dengue vaccine candidate (TAK-003) in healthy children and adults living in dengue-endemic areas in Puerto Rico, Columbia, Singapore, and Thailand. METHODS: In part 1 of this phase 2, randomized, placebo-controlled trial we sequentially enrolled 1.5-45 year olds (n = 148) into 4 age-descending groups, randomized 2:1 to receive 2 doses of TAK-003 or placebo 90 days apart. In part 2, 1-11 year olds (n = 212) were enrolled and randomized 3:1 to TAK-003 or placebo groups. We assessed neutralizing antibody titers for the 4 dengue serotypes (DENV) up to month 36 in part 1, and symptomatic dengue and serious adverse events (SAEs) up to month 36 in both parts. RESULTS: At month 36, seropositivity rates were 97.3%, 98.7%, 88.0% and 56.0% for DENV-1, -2, -3 and -4, respectively. Seropositivity rates varied significantly for DENV-4 according to serostatus at baseline (89.5% in seropositives versus 21.6% in seronegatives). No vaccine-related SAEs were reported. CONCLUSIONS: The trial demonstrated persistence of neutralizing antibody titers against TAK-003 over 3 years in children and adults living in dengue-endemic countries, with limited contribution from natural infection. TAK-003 was well tolerated. CLINICAL TRIALS REGISTRATION: NCT01511250.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents.

BACKGROUND: Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019. METHODS: We present primary efficacy data from part 1 of an ongoing phase 3 randomized trial of a tetravalent dengue vaccine candidate (TAK-003) in regions of Asia and Latin America in which the disease is endemic. Healthy children and adolescents 4 to 16 years of age were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. Participants presenting with febrile illness were tested for virologically confirmed dengue by serotype-specific reverse-transcriptase polymerase chain reaction. The primary end point was overall vaccine efficacy in preventing virologically confirmed dengue caused by any dengue virus serotype. RESULTS: Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). Efficacy trends varied according to serotype. The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively). CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927.).

Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2-17 years: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries. METHODS: We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2-17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066. FINDINGS: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226-632) in two-dose, 421 (285-622) in one-dose, 719 (538-960) in one-dose plus 1-year booster, and 100 (50-201) in placebo recipients against DENV 1; 1052 (732-1511), 1319 (970-1794), 1200 (927-1553), and 208 (99-437) against DENV 2; 183 (113-298), 201 (135-298), 288 (211-392), and 71 (37-139) against DENV 3; and 152 (97-239), 164 (114-236), 219 (165-290), and 46 (26-82) against DENV 4; and tetravalent seropositivity rate was 89% (79-96), 86% (80-92), 97% (93-99), and 60% (47-72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19-0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported. INTERPRETATION: TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study. FUNDING: Takeda Vaccines.

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.

Immunogenicity and safety of a tetravalent dengue vaccine in dengue-naïve adolescents in Mexico City.

OBJECTIVE: To describe the immunogenicity and safety of a tetravalent dengue vaccine (TAK-003) in healthy adolescents living in Mexico City, an area considered non-endemic for dengue (NCT03341637). METHODS: Participants aged 12-17 years were randomized 3:1 to receive two doses (Month 0 and Month 3) of TAK-003 or placebo. Immunogenicity was assessed by microneutralization assay of dengue neutralizing antibodies at baseline, Months 4 and 9. Solicited and unsolicited adverse events (AEs) were recorded after each vaccination. Serious (SAEs) and medically-attended AEs (MAAEs) were recorded throughout the study. RESULTS: 400 adolescents were enrolled, 391 (97.8%) completed the study. Thirty-six (9%) were baseline seropositive to ≥1 serotypes (reciprocal titer ≥10). Geometric mean titers (GMTs) in baseline seronegative TAK-003 recipients were 328, 1743, 120, and 143 at Month 4, and 135, 741, 46, and 38 at Month 9 against DENV-1, -2, -3, and -4, respectively. Placebo GMTs remained <10. Tetravalent seropositivity rates in vaccine recipients were 99.6% and 85.8% at Months 4 and 9, respectively. One MAAE in each group was considered treatment-related (TAK-003: injection-site erythema, and placebo: pharyngitis). CONCLUSION: TAK-003 was immunogenic against all four serotypes and was well tolerated in dengue-naïve adolescents living in Mexico City.

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology.

BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.

Safety and Immunogenicity of a Tetravalent Dengue Vaccine Candidate in Healthy Children and Adults in Dengue-Endemic Regions: A Randomized, Placebo-Controlled Phase 2 Study.

BACKGROUND: A safe, effective tetravalent dengue vaccine is a global health priority. The safety and immunogenicity of a live attenuated, recombinant tetravalent dengue vaccine candidate (TDV) were evaluated in healthy volunteers from dengue-endemic countries. METHODS: This multicenter, double-blind, phase 2 study was conducted in Puerto Rico, Colombia, Singapore, and Thailand. During stage I, 148 volunteers aged 1.5-45 years were sequentially enrolled into 4 age-descending groups and randomized at a ratio of 2:1 to receive TDV or placebo. In stage II (group 5), 212 children aged 1.5-11 years were randomized at a ratio of 3:1 to receive TDV or placebo. Participants received a subcutaneous injection of TDV or placebo on days 0 and 90 and were followed for analysis of safety, seropositivity, and neutralizing antibodies to DENV-1-4. RESULTS: Injection site pain, itching, and erythema (mostly mild) were the only solicited adverse events more frequently reported with TDV than with placebo in all age groups. After 2 TDV doses, seropositivity was >95% in all 5 groups for DENV-1-3 and 72.7%-100% for DENV-4; geometric mean titers ranged from 582 to 1187 for DENV-1, from 582 to 1187 for DENV-2, from 196 to 630 for DENV-3, and from 41 to 210 for DENV-4 among the 5 groups. CONCLUSIONS: TDV was well tolerated and immunogenic in volunteers aged 1.5-45 years, irrespective of prevaccination dengue exposure.

Role of the dengue vaccine TAK-003 in an outbreak response: Modeling the Sri Lanka experience.

BACKGROUND: Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. METHODOLOGY/PRINCIPAL FINDINGS: Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. CONCLUSIONS/SIGNIFICANCE: Overall, the study and modeling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.

Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents. METHODS: In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related. INTERPRETATION: TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals. FUNDING: Takeda Vaccines. TRANSLATIONS: For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section.

Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial.

BACKGROUND: Roughly half the world's population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. METHODS: In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4-11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. FINDINGS: 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI -13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. INTERPRETATION: These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. FUNDING: Sanofi Pasteur.

A randomized phase 3 trial of the immunogenicity and safety of coadministration of a live-attenuated tetravalent dengue vaccine (TAK-003) and an inactivated hepatitis a (HAV) virus vaccine in a dengue non-endemic country.

BACKGROUND: Vaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for travelers to countries where both diseases are endemic. This randomized, observer-blind, phase 3 trial evaluated coadministration of HAV vaccine with tetravalent dengue vaccine (TAK-003) in healthy adults aged 18-60 years living in the UK. METHODS: Participants were randomized (1:1:1) to receive HAV vaccine and placebo on Day 1, and placebo on Day 90 (Group 1), TAK-003 and placebo on Day 1, and TAK-003 on Day 90 (Group 2), or TAK-003 and HAV vaccine on Day 1, and TAK-003 on Day 90 (Group 3). The primary objective was non-inferiority of HAV seroprotection rate (anti-HAV ≥ 12.5 mIU/mL) in Group 3 versus Group 1, one month post-first vaccination (Day 30) in HAV-naïve and dengue-naïve participants. Sensitivity analyses were performed on combinations of baseline HAV and dengue serostatus. Secondary objectives included dengue seropositivity one month post-second vaccination (Day 120), HAV geometric mean concentrations (GMCs), and safety. RESULTS: 900 participants were randomized. On Day 30, HAV seroprotection rates were non-inferior following coadministration of HAV and TAK-003 (Group 3: 98.7 %) to HAV administration alone (Group 1: 97.1 %; difference: -1.68, 95 % CI: -8.91 to 4.28). Sensitivity analyses including participants who were neither HAV-naïve nor DENV-naïve at baseline supported this finding. Anti-HAV GMCs on Day 30 were 82.1 (95 % CI: 62.9-107.1) mIU/mL in Group 1 and 93.0 (76.1-113.6) mIU/mL in Group 3. By Day 120, 90.9-96.8 % of TAK-003 recipients were seropositive (neutralizing antibody titer > 10) to all four dengue serotypes. Coadministration of HAV vaccine and TAK-003 was well tolerated, with no important safety risks identified. CONCLUSION: Immune responses following coadministration of HAV vaccine and TAK-003 were non-inferior to administration of HAV vaccine alone. The results support the coadministration of HAV vaccine and TAK-003 with no adverse impact on immunogenicity, safety, and reactogenicity of either vaccine. CLINICALTRIALS: gov registration: NCT03525119.

Effect of the Tetravalent Dengue Vaccine TAK-003 on Sequential Episodes of Symptomatic Dengue.

In the pivotal phase 3 efficacy trial (NCT02747927) of the TAK-003 dengue vaccine, 5 of 13,380 TAK-003 recipients and 13 of 6,687 placebo recipients experienced two episodes of symptomatic dengue between the first dose and the end of the study, ∼57 months later (patients received the second dose 3 months after the first dose). Two of these participants experienced repeat infection with the same serotype (i.e., homotypic reinfection). In comparison with placebo, the relative risk of a subsequent episode of symptomatic dengue was 0.19 (95% CI, 0.07-0.54) in TAK-003 recipients. Based on the small number of subsequent episodes, these data suggest a potential incremental effect of TAK-003 beyond prevention of the first episode of symptomatic dengue after vaccination.

Immunogenicity and safety of concomitant and sequential administration of yellow fever YF-17D vaccine and tetravalent dengue vaccine candidate TAK-003: A phase 3 randomized, controlled study.

BACKGROUND: Yellow fever (YF) vaccination is often mandatory for travelers to YF-endemic areas. The areas with risk of YF partially overlap with those of dengue, for which there is currently no recommended vaccine available for dengue-naïve individuals. This phase 3 study assessed the immunogenicity and safety of concomitant and sequential administration of YF (YF-17D) and tetravalent dengue (TAK-003) vaccines in healthy adults aged 18-60 years living in areas of the US non-endemic for either virus. METHODS: Participants were randomized 1:1:1 to receive the following vaccinations at Months 0, 3, and 6, respectively: YF-17D+placebo, TAK-003, and TAK-003 (Group 1); TAK-003+placebo, TAK-003, and YF-17D (Group 2); or YF-17D+TAK-003, TAK-003, and placebo (Group 3). The primary objective was to demonstrate non-inferiority (upper bound of 95% confidence interval [UB95%CI] of difference <5%) of YF seroprotection rate one month following concomitant administration of YF-17D and TAK-003 (Group 3) compared with YF-17D plus placebo (Group 1). The secondary objectives included demonstration of non-inferiority of YF and dengue geometric mean titers (GMTs) (UB95%CI for GMT ratio <2.0), and safety. RESULTS: 900 adults were randomized. YF seroprotection rates one month post-YF-17D (Month 1) were 99.5% and 99.1% in Group 1 and 3, respectively, and non-inferiority was demonstrated (UB95%CI = 2.69% i.e. <5%). Non-inferiority was also demonstrated for GMTs against YF one month post-YF-17D, and against DENV-2, -3, and -4 (UB95%CI <2), but not DENV-1 (UB95%CI: 2.22), one month post-second TAK-003 vaccination. Adverse event rates following TAK-003 were consistent with previous results, and no important safety risks were identified. CONCLUSIONS: In this study, YF-17D vaccine and TAK-003 were immunogenic and well tolerated when sequentially or concomitantly administered. The non-inferiority of immune responses to YF-17D and TAK-003 was demonstrated for concomitant administration of the 2 vaccines compared to separate vaccination, except against DENV-1 but with GMTs similar to those observed in other TAK-003 trials. TRIAL REGISTRATION: ClinicalTrials.gov identified: NCT03342898.

Consistency of immunogenicity in three consecutive lots of a tetravalent dengue vaccine candidate (TAK-003): A randomized placebo-controlled trial in US adults.

BACKGROUND: We conducted a trial to demonstrate immunogenic equivalence of three consecutive manufacturing lots of Takeda's tetravalent dengue vaccine candidate, TAK-003, and further assessed its safety and reactogenicity. METHODS: Healthy US adults (n = 923) randomized 2:2:2:1 to four groups received two doses of one of three TAK-003 lots or placebo on Days 0 and 90, with follow-up to Day 270. Primary endpoint evaluated lot-to-lot equivalence of geometric mean neutralizing titers at Day 120 against each of 4 dengue serotypes in baseline seronegative participants. Solicited local and systemic, and unsolicited adverse events (AEs) were assessed for 7, 14 and 28 days after each dose, respectively. Serious AEs (SAE) were monitored throughout the study. RESULTS: Eight of 12 prespecified equivalence comparisons were met in the per-protocol set but failed marginally in the other 4 mainly due to loss of statistical power following higher than anticipated baseline seropositivity and drop-out rates. All three TAK-003 lots elicited high rates of tetravalent dengue seropositivity (96.7 %, 93.0 % and 97.5 % at Day 120; 91.0 %, 80.5 % and 85.7 % at Day 270) and had similar reactogenicity profiles with no vaccine-related SAEs. CONCLUSIONS: The three lots of TAK-003 were immunogenic for all four dengue serotypes and well tolerated in healthy adults. Despite not meeting all equivalence comparisons, no major differences were observed between lots and the data support acceptable consistency of the manufacturing process. Trial registrationClinicalTrials.gov identifier: NCT03423173.

p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway.

Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75(NTR)), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75(NTR) to enhance cAMP degradation. The p75(NTR)-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75(NTR)-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75(NTR) regulates degradation of cAMP and perpetuates scar formation after injury.

Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation.

cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein ß-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.

Characterization of the cell-mediated immune response to Takeda's live-attenuated tetravalent dengue vaccine in adolescents participating in a phase 2 randomized controlled trial conducted in a dengue-endemic setting.

BACKGROUND: As robust dengue-specific CD4+ and CD8+ T cell responses are essential for protective immunity, we assessed cell-mediated immune (CMI) responses to a DENV-2-based dengue tetravalent vaccine candidate (TAK-003) in adolescents living in Panama, a dengue-endemic country. METHODS: Peripheral blood mononuclear cells were collected from a subset of 67 participants ≥ 10 years old included in a phase 2 clinical trial of TAK-003 (Clinicaltrials.gov: NCT02302066). Following stimulation with dengue peptides, the frequency, magnitude, and cross-reactivity of the CD8+ and CD4+ T cell IFN-γ, TNF-α and IL-2 responses were assessed by flow cytometry. RESULTS: Intracellular cytokine staining identified NS1, NS3, and NS5 as the most common non-structural (NS) targets of the CD4+ T-cell response (IFN-γ+); NS3 and NS5 were the main NS targets of the CD8+ T cell response (IFN-γ+). Both CD4+ and CD8+ T-cell responses were multi-functional (IFN-γ + TNF-α + IL-2+) and cross-reactive against DENV-1, -3, and -4 serotypes. Similar responses were seen in all CMI assessments irrespective of participant baseline status for dengue neutralizing antibodies and T cells. CONCLUSIONS: TAK-003 elicited cross-reactive, multi-functional CD4+ and CD8+ T-cell responses, irrespective of dengue pre-exposure.