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Clinical Infectious Diseases : An... Aug 2022Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously,... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Antibodies, Viral; Dengue; Dengue Vaccines; Dengue Virus; Humans; Serogroup; Treatment Outcome; Vaccines, Attenuated; Vaccines, Combined
PubMed: 34606595
DOI: 10.1093/cid/ciab864 -
The Lancet. Global Health Feb 2024About 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... (Randomized Controlled Trial)
Randomized 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.
Topics: Adolescent; Child; Female; Humans; Male; Dengue; Dengue Vaccines; Dengue Virus; Double-Blind Method; Hypersensitivity; Vaccination; Child, Preschool
PubMed: 38245116
DOI: 10.1016/S2214-109X(23)00522-3 -
The Journal of Infectious Diseases May 2022Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adolescent; Antibodies, Neutralizing; Antibodies, Viral; Child; Child, Preschool; Dengue; Dengue Vaccines; Dengue Virus; Double-Blind Method; Humans; Vaccination; Vaccines, Attenuated
PubMed: 33319249
DOI: 10.1093/infdis/jiaa761 -
PLoS Neglected Tropical Diseases Mar 2023Yellow 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Humans; Yellow Fever Vaccine; Dengue Vaccines; Dengue; Yellow Fever; Vaccines, Combined; Antibodies, Viral; Immunogenicity, Vaccine; Vaccines, Attenuated
PubMed: 36888687
DOI: 10.1371/journal.pntd.0011124 -
Vaccine Oct 2023Individuals with human papillomavirus (HPV)-related disease remain at risk for subsequent HPV infection and related disease after treatment of specific lesions.... (Review)
Review
Individuals with human papillomavirus (HPV)-related disease remain at risk for subsequent HPV infection and related disease after treatment of specific lesions. Prophylactic HPV vaccines have shown benefits in preventing subsequent HPV-related disease when administered before or soon after treatment. Based on our understanding of the HPV life cycle and vaccine mechanism of action, prophylactic HPV vaccination is not expected to clear active persistent HPV infection or unresected HPV-associated dysplastic tissue remaining after surgery. However, vaccination may reasonably be expected to prevent new HPV infections caused by a different HPV type as well as re-infection with the same HPV type, whether from a new exposure to an infected partner or through autoinoculation from an adjacent or distant productively infected site. In this review, we describe the evidence for using prophylactic HPV vaccines in patients with HPV-associated disease before, during, or after treatment and discuss potential mechanisms by which individuals with HPV-associated disease may or may not benefit from prophylactic vaccines. We also consider how precise terminology relating to the use of prophylactic vaccines in this population is critical to avoid the incorrect implication that prophylactic vaccines have direct therapeutic potential, which would be counter to the vaccine's mechanism of action, as well as considered off-label. In other words, the observed effects occur through the known mechanism of action of prophylactic HPV vaccines, namely by preventing virus of the same or a different HPV type from infecting the patient after the procedure.
Topics: Female; Humans; Papillomavirus Vaccines; Papillomavirus Infections; Uterine Cervical Neoplasms; Human Papillomavirus Viruses; Vaccination
PubMed: 37704498
DOI: 10.1016/j.vaccine.2023.08.047 -
Clinical Infectious Diseases : An... Feb 2023
Topics: Humans; Dengue Vaccines; Dengue; Dengue Virus; Vaccines, Attenuated; Antibodies, Viral
PubMed: 36196620
DOI: 10.1093/cid/ciac808 -
The Biochemical Journal Oct 19701. Free and membrane-bound polyribosomes and ribosomal monomers were isolated from normal and Rauscher-virus-infected mouse spleens by means of discontinuous sucrose...
1. Free and membrane-bound polyribosomes and ribosomal monomers were isolated from normal and Rauscher-virus-infected mouse spleens by means of discontinuous sucrose density gradients. 2. The addition of ribonuclease inhibitor from rat liver was essential to protect these polyribosomes from degradation. To separate the smooth and rough membranes from ribosomal monomers an additional centrifugation step through a continuous sucrose density gradient was necessary. 3. After infection a marked increase in rRNA from both membrane-bound and free polyribosomes was observed. Treatment of the membrane-bound polyribosomes with sodium deoxycholate yielded only 80S particles even when ribonuclease inhibitor was added. 4. A striking feature of the infected spleen was the occurrence of large polyribosomes. Up to 40 monomers per polyribosome could be counted on electron micrographs.
Topics: Animals; Binding Sites; Carbon Isotopes; Cell Membrane; Centrifugation, Density Gradient; DNA; Leukemia, Experimental; Mice; Microscopy, Electron; Organ Size; Proteins; RNA; Rauscher Virus; Ribosomes; Spleen; Virus Cultivation
PubMed: 5493508
DOI: 10.1042/bj1190749 -
Vaccine Feb 2023Vaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Humans; Dengue Vaccines; Dengue Virus; Viral Vaccines; Vaccines, Combined; Hepatitis A; Hepatitis A Antibodies; Vaccines, Attenuated; Double-Blind Method; Hepatitis A Vaccines; Hepatitis A virus; Dengue; Immunogenicity, Vaccine; Antibodies, Viral
PubMed: 36681529
DOI: 10.1016/j.vaccine.2023.01.007 -
Clinical and Vaccine Immunology : CVI Jun 2015The cheetah population in Namibia is the largest free-ranging population in the world and a key population for research regarding the health status of this species. We...
The cheetah population in Namibia is the largest free-ranging population in the world and a key population for research regarding the health status of this species. We used serological methods and quantitative real-time PCR to test free-ranging and captive Namibian cheetahs for the presence of feline leukemia virus (FeLV), a gammaretrovirus that can be highly aggressive in populations with low genetic diversity, such as cheetahs. We also assessed the presence of antibodies to other gammaretroviruses and the responses to a FeLV vaccine developed for domestic cats. Up to 19% of the free-ranging cheetahs, 27% of the captive nonvaccinated cheetahs, and 86% of the captive vaccinated cheetahs tested positive for FeLV antibodies. FeLV-antibody-positive free-ranging cheetahs also tested positive for Rauscher murine leukemia virus antibodies. Nevertheless, FeLV was not detectable by quantitative real-time PCR and no reverse transcriptase activity was detectable by product-enhanced reverse transcriptase assay in the plasma of cheetahs or the supernatants from cultures of peripheral blood mononuclear cells. The presence of antibodies to gammaretroviruses in clinically healthy specimens may be caused either by infection with a low-pathogenic retrovirus or by the expression of endogenous retroviral sequences. The strong humoral immune responses to FeLV vaccination demonstrate that cheetahs can respond to the vaccine and that vaccination against FeLV infection may be beneficial should FeLV infection ever become a threat, as was seen in Iberian lynx and Florida panthers.
Topics: Acinonyx; Animals; Antibodies, Viral; Blood; Leukemia Virus, Feline; Male; Namibia; Real-Time Polymerase Chain Reaction; Retrospective Studies; Retroviridae Infections; Serologic Tests; Tumor Virus Infections; Viral Vaccines
PubMed: 25809630
DOI: 10.1128/CVI.00705-14 -
Journal of Virology Feb 1969A random bred strain of mice (CD-1) was shown to develop resistance to Rauscher leukemia virus (RLV) as the animals matured. Resistant adult mice developed relatively...
A random bred strain of mice (CD-1) was shown to develop resistance to Rauscher leukemia virus (RLV) as the animals matured. Resistant adult mice developed relatively high-serum levels of interferon (150 to 2,000 units per ml) in contrast to susceptible 21-day-old animals in which interferon levels were undetectable or low (less than 20 to 200 units per ml). A similar correlation between resistance and interferon levels was observed in comparisons between resistant CD-1 and susceptible BALB/c mice. The F(1) hybrids of CD-1 x BALB/c and BALB/c x CD-1 matings manifested an intermediate degree of susceptibility and interferon production. The difference in interferon production by CD-1 and BALB/c mice was specific for the RLV-host interaction, since both strains produced equal serum levels of interferon in response to Sindbis and Newcastle disease viruses. The mortality of CD-1 suckling mice infected with Rauscher leukemia virus was decreased by treatment with interferon. These data demonstrate an association between interferon production by the host and the observed relative resistance of the CD-1 strain of adult mice to the subsequent malignant transformation. This virus-host relationship provides an excellent model for further study of factors affecting the development of virus-induced leukemia.
Topics: Age Factors; Animals; Arboviruses; Hybridization, Genetic; Interferons; Leukemia, Experimental; Mice; Newcastle disease virus; Phenotype; Rauscher Virus
PubMed: 5774143
DOI: 10.1128/JVI.3.2.99-105.1969