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.

Immunogenicity and tolerability of a bivalent virus-like particle norovirus vaccine candidate in children from 6 months up to 4 years of age: A phase 2 randomized, double-blind trial.

We conducted a dose-finding phase 2 study of the HilleVax bivalent virus-like particle (VLP) vaccine candidate (HIL-214) in two cohorts of children, 6-≤12 months and 1-≤4 years of age (N = 120 per cohort), in Panama and Colombia (ClinicalTrials.gov, identifier NCT02153112). On Day 1, children randomized to one of the four equal groups received intramuscular injections of four different HIL-214 formulations containing 15/15, 15/50, 50/50, or 50/150 µg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3. On Day 29, half the children in each group received a second vaccination (N = 60), while the other half received saline placebo injections to maintain the blind. VLP-specific ELISA Pan-Ig and histo-blood group binding antigen-blocking antibodies (HBGA) were measured on Days 1, 29, 57 and 210. On Day 29, after one dose, there were large Pan-Ig and HBGA responses in both age cohorts with some indication of dose-dependence, and higher geometric mean titers (GMT) in the older children. A further increase in titers was observed 28 days after a second dose in the 6-≤12-month-old groups, but less so in the 1-≤4-year-old groups; GMTs at Day 57 were broadly similar across doses and in both age groups. GMTs of Pan-Ig and HBGA persisted above baseline up to Day 210. All formulations were well tolerated with mostly mild-to-moderate transient solicited adverse events reported by parents/guardians, and no vaccine-related serious adverse events occurred. Further development of HIL-214 is warranted to protect the most susceptible young children against norovirus.

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.

Immunogenicity of a bivalent virus-like particle norovirus vaccine in children from 1 to 8 years of age: A phase 2 randomized, double-blind study.

BACKGROUND: Young children can suffer severe consequences of norovirus gastroenteritis. We performed a dose-finding study of a bivalent virus-like particle (VLP) vaccine candidate (TAK-214) in healthy 1-8-year-old children. METHODS: In this phase 2 study two age cohorts (1-3 and 4-8 years of age inclusive, N = 120 per cohort) of children enrolled from Finland, Panama and Colombia were initially randomized 1:1:1:1 to four groups which were further split into two equal subgroups, to receive one or two intramuscular doses of four TAK-214 formulations containing 15/15, 15/50, 50/50 or 50/150 µg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3 at 28 days interval. ELISA Pan-Ig and histoblood group antigen-blocking (HBGA) antibodies against each VLP were measured on days 1, 29, 57 and 210. Parents/guardians recorded solicited local and systemic adverse events (AE) and any unsolicited or serious AEs (SAE). RESULTS: All formulations were well-tolerated across both age cohorts and dosage groups with no vaccine-related SAEs reported. Solicited AEs were mostly mild-to-moderate, resolved quickly, and did not increase after the second dose. Pan-Ig and HBGA responses induced after one dose were only slightly increased by the second dose. Across dose groups at Day 29 after one dose GI.1 Pan Ig seroresponse rates (SRR) were 82-97% and 81-96% and GII.4c SRR were 79-97% and 80-91% in 1-3 and 4-8 year-olds, respectively. Respective rates were to 92-93% and 73-92% for GI.1, and 77-100% and 62-83% for GII.4c at Day 57 following two doses. HBGA responses had similar profiles. Both Pan Ig and HBGA geometric mean titers persisted above baseline up to Day 210. CONCLUSIONS: All dosages of TAK-214 displayed acceptable reactogenicity in 1-8-year-old children and induced robust, durable immune responses after one dose which are further increased after two doses.

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.

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.

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.

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.

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

[ABSTRACT]. 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.

[RESUMEN]. Objetivo. Describir la inmunogenicidad y la seguridad de una vacuna tetravalente contra el dengue (TAK-003) en adolescentes sanos residentes en Ciudad de México, considerada un área no endémica de dengue (NCT03341637). Métodos. Se asignó de manera aleatoria a un grupo de participantes de 12 a 17 años en una proporción 3:1 para que recibieran dos dosis (en el mes 0 y en el mes 3) de la vacuna TAK-003 o de un placebo. Se evaluó la inmunogenicidad mediante un análisis de microneutralización de anticuerpos neutralizantes del virus del dengue al inicio del estudio y en los meses 4 y 9. Se registraron los eventos adversos de notificación solicitada y los referidos por iniciativa propia después de cada vacunación. A lo largo del estudio se registraron los eventos adversos graves y los que requirieron atención médica. Resultados. Participaron 400 adolescentes y 391 (97,8%) finalizaron el estudio. 36 adolescentes (9%) fueron seropositivos a ≥1 serotipos (título recíproco ≥10) al inicio del estudio. La media geométrica de los títulos en las personas seronegativas vacunadas con TAK-003 al inicio del estudio fue de 328, 1743, 120 y 143 en el mes 4 y 135, 741, 46 y 38 en el mes 9 en relación con DENV-1, -2, -3 y -4, respectivamente. La media geométrica de los títulos de las personas que recibieron un placebo se mantuvo en <10. Las tasas de seropositividad tetravalente en los vacunados fueron 99,6% y 85,8% a los meses 4 y 9, respectivamente. Se consideró relacionado con el tratamiento un evento adverso con atención médica que tuvo lugar en cada grupo (TAK-003: eritema en el lugar de la inyección; placebo: faringitis). Conclusiones. TAK-003 fue inmunogénica ante los cuatro serotipos y bien tolerada en los adolescentes sin exposición previa al dengue que vivían en Ciudad de México.

[RESUMO]. Objetivo. Descrever a imunogenicidade e a segurança de uma vacina tetravalente contra dengue (TAK-003) em adolescentes saudáveis residentes da Cidade do México, área considerada não endêmica para dengue (ClinicalTrials.gov: NCT03341637). Métodos. Participantes com idade entre 12 e 17 anos foram randomizados a uma proporção de 3:1 para receber duas doses da vacina TAK-003 ou placebo (no mês 0 e no mês 3). A imunogenicidade foi avaliada pelos títulos de anticorpos neutralizantes contra dengue determinados em ensaio de microneutralização ao início do estudo, no mês 4 e no mês 9. A ocorrência de eventos adversos solicitados ou espontâneos foi registrada após cada rodada de vacinação. Eventos adversos graves e eventos adversos que exigiram atendimento médico foram monitorados ao longo de todo o estudo. Resultados. De 400 adolescentes incluídos na amostra estudada, 391 (97,8%) completaram o estudo. Trinta e seis (9%) apresentaram positividade basal a um ou mais sorotipos virais da dengue (título recíproco ≥10). A média geométrica dos títulos de anticorpos nos vacinados com TAK-003 que eram soronegativos ao início do estudo foi de 328, 1743, 120 e 143 no mês 4 e 135, 741, 46 e 38 no mês 9, contra os sorotipos virais DENV-1, DENV-2, DENV-3 e DENV-4, respectivamente. A média geométrica dos títulos de anticorpos no grupo placebo se manteve abaixo de 10. A taxa de soropositividade tetravalente nos vacinados foi de 99,6% no mês 4 e 85,8% no mês 9. Um único evento adverso que exigiu atendimento médico em cada grupo foi considerado relacionado ao tratamento (eritema no local de aplicação no grupo TAK-003 e faringite no grupo placebo). Conclusão. A vacina TAK-003 demonstrou ser imunogênica contra os quatro sorotipos virais da dengue e foi bem tolerada em adolescentes residentes da Cidade do México sem história pregressa de infecção pela dengue.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial.

BACKGROUND: Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults. METHODS: This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18-49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 µg, 5 µg, or 10 µg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626). FINDINGS: Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749-1703) in the 2 µg TAK-426 group, 1992 (1401-2833) in the 5 µg TAK-426 group, and 3690 (2677-5086) in the 10 µg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 µg group were significantly greater than in the 2 µg group (GMT ratio 3·27 [95% CI 1·98-5·39], p<0·0001) and the 5 µg group (GMT ratio 1·85 [1·15-2·98], p=0·012). INTERPRETATION: TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 µg TAK-426 dose was selected for further clinical development. FUNDING: Takeda Vaccines and the US Biomedical Advanced Research and Development Authority. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Efficacy of an intramuscular bivalent norovirus GI.1/GII.4 virus-like particle vaccine candidate in healthy US adults.

BACKGROUND: We performed this first-in-human efficacy trial of Takeda's bivalent norovirus vaccine candidate (TAK-214) against moderate or severe acute gastroenteritis (AGE) in healthy adults. METHODS: This double-blind, randomized, placebo-controlled phase 2b trial was conducted over two winter seasons in 18-49 year-old US Navy recruits. Participants were randomized (1:1) to receive intramuscular injections of saline placebo (N = 2,357) or TAK-214 [15 µg GI.1 and 50 µg GII.4c VLPs, 0.5 mg Al(OH)3] (N = 2,355), and monitored for 45 days post-vaccination for AGE. Norovirus genotypes were identified by RT-PCR and sequencing of stool/vomitus samples. Sera from AGE cases were used to assess immune responses as genotype-specific histo-blood group antigen (HBGA)-blocking antibodies. FINDINGS: With low rates of homotypic norovirus AGE detected the statistical analysis was proactively modified to account for AGE due to any norovirus genotype. Of the 48 norovirus AGE cases of "any severity", 29 in placebo and 19 in vaccinees, causative genotypes were GI.1 (n = 1), G1.7a (n = 1), GII.2 (n = 39) and GII.4 (n = 7). Applying predefined definitions of moderate or severe AGE gave 26 vs. 10 cases due to any norovirus genotype in placebo vs. vaccine groups, a vaccine efficacy (VE) of 61.8% (95.01% CI, 20.8 to 81.6; p = 0.0097). Five vs. one moderate or severe cases due to vaccine GI.1/GII.4 homotypic genotypes in placebo vs. vaccine arms gave a primary endpoint vaccine efficacy of 80.0% (99.99% CI, -1318.1 to 99.7; p = 0.142). Levels of GI.1 and GII.4 HBGA-blocking antibodies were increased in vaccinees and in some placebo AGE cases infected with GII.2, indicating cross-reactivity in the immune responses to different genotypes. INTERPRETATION: Despite limited cases of homotypic norovirus AGE meaning the primary endpoint was not fully evaluable, we showed TAK-214 provided statistically significant efficacy against "any moderate/severe norovirus AGE" principally caused by the heterotypic GII.2 genotype, demonstrating induction of cross-genotype protection.

A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose.

INTRODUCTION: Acute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population. METHODS: In this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18-49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 µg GI.1 and 50 µg GII.4c VLP antigens and 500 µg Al(OH)3, with or without 15 µg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection. RESULTS: After one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18-49, 60-74, 75-84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue. CONCLUSIONS: Adults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.

Safety and immunogenicity of experimental stand-alone trivalent, inactivated Sabin-strain polio vaccine formulations in healthy infants: A randomized, observer-blind, controlled phase 1/2 trial.

BACKGROUND: To increase the global supply of affordable IPV vaccine, preferably using Sabin viruses to comply with GAPIII requirements, Takeda has assessed three dosages of a stand-alone sIPV. METHODS: In this phase I/II study two cohorts of 40 adults and 60 toddlers, respectively, were initially assessed for safety after receiving high-dosage sIPV compared with placebo (adults) or Salk IPV (toddlers). A cohort of 240 infants was then enrolled and randomized (1:1:1:1) to receive low-, medium- or high-dosage sIPV, or a reference Salk IPV in a three-dose primary schedule at 6, 10 and 14 weeks of age. Parents completed safety diaries for 4 weeks after each dose, and immunogenicity was measured as neutralization antibody titers at baseline and four weeks after vaccination. RESULTS: All vaccinations were generally well-tolerated and sIPV had a comparable safety profile to the control arm in adults or the reference Salk IPV vaccine in toddlers and infants. Infants displayed dosage-dependent immune responses to sIPV when assayed using Sabin strains, which were equivalent to the reference IPV in the high-dosage sIPV group for serotypes 1 and 2, but not for Sabin and Salk serotype 3. Seroconversion rates (SCR) of the low- and medium-dosage groups were significantly lower than the Salk IPV group for both Sabin and Salk serotypes 1 and type 2 (p < 0.05), with no significant differences for Salk or Sabin serotypes 3. Responses to sIPV, particularly to Sabin types 1 and 2, were higher in initially seronegative infants, indicating possible interference by maternally-derived antibodies. CONCLUSIONS: A novel stand-alone Sabin-based IPV vaccine was well tolerated with an acceptable safety profile, but less immunogenic than reference Salk IPV at 6, 10 and 14 weeks of age for Salk serotypes 1 and 2, with apparent interference by maternal antibodies. Additional preclinical assessments will be made before any further clinical development.

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.

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.

Immunogenicity and safety of lyophilized and liquid dengue tetravalent vaccine candidate formulations in healthy adults: a randomized, phase 2 clinical trial.

Takeda has developed a live-attenuated dengue tetravalent vaccine candidate (TAK-003) which has been shown to be immunogenic with acceptable reactogenicity in phase 1 trials. In agreement with World Health Organization prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2°C to +8°C. This randomized, double-blind, phase 2 study (NCT02193087) was performed in 1002 healthy dengue-naïve adults, 18-49 years of age, across seven centers in the USA to compare the safety and immunogenicity of one or two doses of a lyophilized TAK-003 formulation with the liquid TAK-003 formulation used in previous phase 1 studies. The primary objective was to show immunologic equivalence in terms of geometric mean titers (GMT) of neutralizing antibodies to the four dengue serotypes one month after one dose of the lyophilized and liquid formulations. Secondary assessments were of safety and seropositivity rates, including after a second dose. The primary endpoint was not met, because immunologic equivalence after one dose was only shown for the DENV-2 serotype. Nonetheless, GMTs and seropositivity rates to all four serotypes were achieved with all formulations after two doses and are in line with what was observed in previous studies. Additionally, in view of the acceptable reactogenicity, with no vaccine-related serious adverse events reported, these data support continuing further clinical development of the lyophilized TAK-003 formulation.

Safety and immunogenicity of a single dose of a tetravalent dengue vaccine with two different serotype-2 potencies in adults in Singapore: A phase 2, double-blind, randomised, controlled trial.

BACKGROUND: Early formulations of Takeda's tetravalent dengue vaccine candidate (TAK-003) have demonstrated notably higher neutralizing antibody responses against serotype 2 than other serotypes. Here, we assessed the immunogenicity and tolerability in adults living in Singapore of two TAK-003 formulations: an early formulation, referred to as HD-TDV, and a new formulation with 10-fold lower serotype 2 potency, referred to as TDV (NCT02425098). METHODS: Subjects aged 21-45 years were stratified by baseline dengue serostatus and randomised 1:1 to receive a single dose of either HD-TDV or TDV. Immunogenicity was evaluated at Days 15, 30, 90, 180, and 365 post-vaccination as geometric mean titres (GMTs) of neutralising antibodies and seropositivity rates. Viremia was assessed per vaccine strain. Solicited and unsolicited adverse events (AEs) were assessed by severity and causality. RESULTS: Of 351 subjects randomised, 176 received HD-TDV and 175 received TDV. Peak GMTs against all serotypes were observed at Day 30, with highest GMTs against DENV-2 in both groups. In subjects seronegative at baseline, the response to DENV-2 was less dominant with TDV (Day 30 GMTs: 813 for TDV, 10,966 for HD-TDV). In these subjects, DENV-4 seropositivity rates and GMTs were higher with TDV (Day 30 GMTs: 58 for TDV, 21 for HD-TDV; seropositivity rates: 76% for TDV, 60% for HD-TDV). Viremia mainly occurred for TDV-2 in both vaccine groups, with a lower incidence in TDV recipients, and mostly resolved by Day 30. Both vaccine formulations showed an acceptable safety profile with similar overall rates of solicited and unsolicited AEs across vaccine groups. CONCLUSIONS: These results suggest a more balanced immune response with the new formulation TDV compared with the early formulation HD-TDV, particularly in subjects who were seronegative prior to vaccination, and support the choice of the new formulation for the phase 3 efficacy assessment.

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.).

Persistence of Antibodies to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: 1-Year Follow-up With Memory Probe Vaccination.

BACKGROUND: We previously reported the tolerability and immunogenicity 1 month after intramuscular administration of 2 bivalent virus-like particle (VLP)-based candidate norovirus vaccine formulations in adults. We now describe the persistence of immunity and responses to a memory probe vaccination 1 year later. METHODS: A total of 454 healthy men and women aged 18-49 years in 3 equal groups received placebo (saline) or 15/50 or 50/50 vaccine formulations (ie, 15 or 50 µg of GI.1 genotype VLPs, respectively, and 50 µg of GII.4c VLPs) with MPL and Al(OH)3. Immunogenicity and safety were assessed up to day 365, when 351 participants received a memory probe vaccination of 15 µg each of GI.1 and GII.4c VLPs with Al(OH)3. RESULTS: No safety signals were detected up to 1 year after the first vaccination. Pan-immunoglobulin, immunoglobulin A, and histo-blood group antigen-blocking (HBGA) antibody levels among vaccinees waned but remained higher than levels before vaccination and levels in placebo recipients on days 180 and 365. Memory probe vaccination increased all antibody titers. Levels of HBGA antibodies to GI.1 but not GII.4c were higher after the first vaccination in candidate vaccine groups, compared with those in the placebo group. CONCLUSION: Levels of antibodies to both candidate norovirus VLP formulations persisted above baseline levels for at least 1 year after primary vaccination. HBGA-blocking responses to the memory probe for GI.1 but not GII.4c displayed characteristics of immune memory. CLINICAL TRIALS REGISTRATION: NCT02142504.