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1.
Paediatr Drugs ; 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38649595

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children aged ≤ 5 years and adults aged ≥ 60 years worldwide. Despite this, RSV-specific therapeutic options are limited. Rilematovir is an investigational, orally administered inhibitor of RSV fusion protein-mediated viral entry. OBJECTIVE: To establish the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir (low or high dose) in children aged ≥ 28 days and ≤ 3 years with RSV disease. METHODS: CROCuS was a multicenter, international, double-blind, placebo-controlled, randomized, adaptive phase II study, wherein children aged ≥ 28 days and ≤ 3 years with confirmed RSV infection who were either hospitalized (Cohort 1) or treated as outpatients (Cohort 2) were randomized (1:1:1) to receive rilematovir (low or high dose) or placebo. Study treatment was administered daily as an oral suspension from days 1 to 7, with dosing based on weight and age groups. The primary objective was to establish antiviral activity of rilematovir by evaluating the area under the plasma concentration-time curve of RSV viral load in nasal secretions from baseline through day 5. Severity and duration of RSV signs and symptoms and the safety and tolerability of rilematovir were also assessed through day 28 (± 3). RESULTS: In total, 246 patients were randomized, treated, and included in the safety analysis population (Cohort 1: 147; Cohort 2: 99). Of these, 231 were included in the intent-to-treat-infected analysis population (Cohort 1: 138; Cohort 2: 93). In both cohorts, demographics were generally similar across treatment groups. In both cohorts combined, the difference (95% confidence interval) in the mean area under the plasma concentration-time curve of RSV RNA viral load through day 5 was - 1.25 (- 2.672, 0.164) and - 1.23 (- 2.679, 0.227) log10 copies∙days/mL for the rilematovir low-dose group and the rilematovir high-dose group, respectively, when compared with placebo. The estimated Kaplan-Meier median (95% confidence interval) time to resolution of key RSV symptoms in the rilematovir low-dose, rilematovir high-dose, and placebo groups of Cohort 1 was 6.01 (4.24, 7.25), 5.82 (4.03, 8.18), and 7.05 (5.34, 8.97) days, respectively; in Cohort 2, estimates were 6.45 (4.81, 9.70), 6.26 (5.41, 7.84), and 5.85 (3.90, 8.27) days, respectively. A similar incidence of adverse events was reported in patients treated with rilematovir and placebo in Cohort 1 (rilematovir: 61.9%; placebo: 58.0%) and Cohort 2 (rilematovir: 50.8%; placebo: 47.1%), with most reported as grade 1 or 2 and none leading to study discontinuation. The study was terminated prematurely, as the sponsor made a non-safety-related strategic decision to discontinue rilematovir development prior to full recruitment of Cohort 2. CONCLUSIONS: Data from the combined cohort suggest that rilematovir has a small but favorable antiviral effect of indeterminate clinical relevance compared with placebo, as well as a favorable safety profile. Safe and effective therapeutic options for RSV in infants and young children remain an unmet need. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2016-003642-93; ClinicalTrials.gov Identifier: NCT03656510. First posted date: 4 September, 2018.

2.
J Infect Dis ; 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38682569

ABSTRACT

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.

3.
Acta Med Port ; 37(2): 126-135, 2024 Feb 01.
Article in Portuguese | MEDLINE | ID: mdl-38309298

ABSTRACT

Dengue is a vector-borne disease that has a significant impact on global public health. The vector mosquito belongs to the genus Aedes. Two species play a key role in human transmission: Ae. aegypti, which has adapted to the urban environment of highly populated areas in tropical and subtropical countries, leading to a dramatic increase in dengue cases over the years, and Ae. albopictus, which poses a potential threat to temperate climate countries due to its ability to adapt to colder climates. The disease is widespread across the world, posing a risk to nearly half of the world's population. Although most cases are asymptomatic, dengue causes a burden on healthcare systems and mainly affects the younger population. The disease is also spreading to temperate climate countries, thus becoming a global threat. Vector control measures and vaccine development have been the main prevention strategies, as there is still no effective treatment for the disease.


A dengue é uma doença transmitida por um vetor hematófago (mosquito) que possui um impacto significativo na saúde pública mundial. O mosquito transmissor pertence ao género Aedes. São duas as espécies responsáveis pela transmissão humana: o Ae. aegypti, que se adaptou ao ambiente urbano de áreas altamente populosas de países tropicais e subtropicais, resultando num aumento dramático dos casos de dengue ao longo dos anos; e o Ae. Albopictus, que representa uma potencial ameaça para os países de clima temperado pela sua capacidade de adaptação aos climas mais frios. A doença está presente em grande parte do mundo, colocando cerca de metade da população do planeta em risco. Embora a maioria dos casos seja assintomática, a dengue causa uma sobrecarga nos sistemas de saúde e impacta principalmente os jovens. A doença também tem vindo a alastrar-se a países de clima temperado, tornando-se uma ameaça global. As medidas de controlo vetorial e o desenvolvimento de vacinas têm sido as principais estratégias de prevenção, uma vez que não existe ainda um tratamento eficaz para a doença.


Subject(s)
Aedes , Dengue Virus , Dengue , Animals , Humans , Dengue/diagnosis , Dengue/prevention & control , Mosquito Vectors
4.
Lancet Glob Health ; 12(2): e257-e270, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38245116

ABSTRACT

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.


Subject(s)
Dengue Vaccines , Dengue , Adolescent , Child , Female , Humans , Male , Dengue/prevention & control , Dengue Vaccines/adverse effects , Dengue Virus , Double-Blind Method , Hypersensitivity , Vaccination/methods , Child, Preschool
5.
Clin Microbiol Infect ; 29(10): 1320-1327, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37422079

ABSTRACT

OBJECTIVES: To assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults. METHODS: This phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes. RESULTS: RSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (-0.837; 1.011), -0.10 (-2.171; 1.963), and -1.03 (-4.746; 2.682) log10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively. DISCUSSION: Rilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (NCT03379675).


Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Adult , Humans , Antiviral Agents/adverse effects , Double-Blind Method , Respiratory Syncytial Virus Infections/drug therapy , RNA
6.
Eur Respir Rev ; 32(168)2023 Jun 30.
Article in English | MEDLINE | ID: mdl-37343960

ABSTRACT

AIMS: To summarise the evidence on barriers to and facilitators of population adherence to prevention and control measures for coronavirus disease 2019 (COVID-19) and other respiratory infectious diseases. METHODS: A qualitative synthesis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis and the Cochrane Effective Practice and Organization of Care: Qualitative Evidence Synthesis. We performed an electronic search on MEDLINE, Embase and PsycINFO from their inception to March 2023. RESULTS: We included 71 studies regarding COVID-19, pneumonia, tuberculosis, influenza, pertussis and H1N1, representing 5966 participants. The measures reported were vaccinations, physical distancing, stay-at-home policy, quarantine, self-isolation, facemasks, hand hygiene, contact investigation, lockdown, infection prevention and control guidelines, and treatment. Tuberculosis-related measures were access to care, diagnosis and treatment completion. Analysis of the included studies yielded 37 barriers and 23 facilitators. CONCLUSIONS: This review suggests that financial and social support, assertive communication, trust in political authorities and greater regulation of social media enhance adherence to prevention and control measures for COVID-19 and infectious respiratory diseases. Designing and implementing effective educational public health interventions targeting the findings of barriers and facilitators highlighted in this review are key to reducing the impact of infectious respiratory diseases at the population level.


Subject(s)
COVID-19 , Communicable Diseases , Influenza A Virus, H1N1 Subtype , Influenza, Human , Humans , COVID-19/prevention & control , COVID-19/epidemiology , Communicable Disease Control
7.
Viruses ; 16(1)2023 12 22.
Article in English | MEDLINE | ID: mdl-38257724

ABSTRACT

The emergence and continued geographic expansion of arboviruses and the growing number of infected people have highlighted the need to develop and improve multiplex methods for rapid and specific detection of pathogens. Sequencing technologies are promising tools that can help in the laboratory diagnosis of conditions that share common symptoms, such as pathologies caused by emerging arboviruses. In this study, we integrated nanopore sequencing and the advantages of reverse transcription polymerase chain reaction (RT-PCR) to develop a multiplex RT-PCR protocol for the detection of Chikungunya virus (CHIKV) and several orthoflaviviruses (such as dengue (Orthoflavivirus dengue), Zika (Orthoflavivirus zikaense), yellow fever (Orthoflavivirus flavi), and West Nile (Orthoflavivirus nilense) viruses) in a single reaction, which provides data for sequence-based differentiation of arbovirus lineages.


Subject(s)
Arboviruses , Chikungunya virus , Dengue , Nanopore Sequencing , Zika Virus Infection , Zika Virus , Humans , Arboviruses/genetics , Chikungunya virus/genetics , Multiplex Polymerase Chain Reaction , Zika Virus/genetics
8.
N Engl J Med ; 386(24): 2283-2294, 2022 06 16.
Article in English | MEDLINE | ID: mdl-35704480

ABSTRACT

BACKGROUND: In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown. METHODS: We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase-polymerase-chain-reaction assays, next-generation sequencing, and virus isolation. RESULTS: Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus, or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats (Oligoryzomys microtis). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset. CONCLUSIONS: M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis. (Funded by the Bolivian Ministry of Health and others.).


Subject(s)
Arenaviruses, New World , Hemorrhagic Fever, American , RNA, Viral , Rodentia , Animals , Arenaviruses, New World/genetics , Arenaviruses, New World/isolation & purification , Bolivia/epidemiology , Cross Infection/transmission , Cross Infection/virology , Disease Transmission, Infectious , Hemorrhagic Fever, American/complications , Hemorrhagic Fever, American/genetics , Hemorrhagic Fever, American/transmission , Hemorrhagic Fever, American/virology , Hemorrhagic Fevers, Viral/genetics , Hemorrhagic Fevers, Viral/transmission , Hemorrhagic Fevers, Viral/virology , High-Throughput Nucleotide Sequencing , Humans , Polymerase Chain Reaction , RNA, Viral/genetics , RNA, Viral/isolation & purification , Rats/virology , Rodentia/virology , Viral Zoonoses/transmission , Viral Zoonoses/virology
9.
Front Psychiatry ; 13: 823218, 2022.
Article in English | MEDLINE | ID: mdl-35449568

ABSTRACT

Background: Chikungunya fever is a disabling articular disease caused by chikungunya virus (CHIKV). In the past decade it has affected millions of people across America, Africa, Asia, and Europe, turning this infection into a public health concern. The acute phase of chikungunya infection is usually self-limiting, characterized by severe arthralgia, fever, chills, myalgia, headache, and rash. CHIKV neurovirulence is evident and seems to be higher among elders. Considering their susceptibility to cognitive decline and dementia, the aim of our study was to investigate whether CHIKV infection might cause long-term cognitive impairment in aged people. Methods: A cross-sectional study was conducted with volunteers aged from 60 to 90 who had been affected by chikungunya and also with healthy controls. A structured questionnaire was used to record demographic and clinical data, functional status, and depression. Global cognitive function was assessed through MoCA. A comprehensive neuropsychological battery was performed to assess specific cognitive functions. Results: Subjective memory complaints were present in 70% of subjects with previous chikungunya. This group had a poorer performance in MoCA (p = 0.000) and specific cognitive tests: Semantic (p = 0.05) and Phonemic Verbal Fluency (p = 0.003), 5-Digit (choice, reading, counting and alternance, p = 0.003, p = 0.014, p = 0.021, and p = 0.021, respectively), Stroop test (time, errors and interference, p = 0.000, p = 0.027 and p = 0.015, respectively), and RAVLT (word total session p = 0.05). These tests reflect performance on general executive functions, cognitive flexibility, inhibitory control, processing speed, semantic memory and episodic memory. Conclusion: Our data suggest that CHIKV infection may cause long-term cognitive decline in aged people and might be a risk factor for future dementia in this population.

10.
Lancet ; 399(10323): 461-472, 2022 01 29.
Article in English | MEDLINE | ID: mdl-35065705

ABSTRACT

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/therapeutic use , Adolescent , Adult , Aged , Alum Compounds/therapeutic use , Belgium , Brazil , Colombia , Double-Blind Method , Female , Humans , Male , Middle Aged , Oligodeoxyribonucleotides/therapeutic use , Philippines , Protein Multimerization , Recombinant Proteins/therapeutic use , Risk , SARS-CoV-2 , South Africa , Vaccine Efficacy , Young Adult
11.
J Infect Dis ; 225(9): 1521-1532, 2022 05 04.
Article in English | MEDLINE | ID: mdl-33319249

ABSTRACT

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.


Subject(s)
Dengue Vaccines , Dengue Virus , Dengue , Adolescent , Antibodies, Neutralizing , Antibodies, Viral , Child , Child, Preschool , Dengue Virus/genetics , Double-Blind Method , Humans , Vaccination , Vaccines, Attenuated
12.
Clin Infect Dis ; 75(1): 107-117, 2022 08 24.
Article in English | MEDLINE | ID: mdl-34606595

ABSTRACT

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.


Subject(s)
Dengue Vaccines , Dengue Virus , Dengue , Antibodies, Viral , Humans , Serogroup , Treatment Outcome , Vaccines, Attenuated/adverse effects , Vaccines, Combined
13.
Hum Vaccin Immunother ; 18(1): 1981085, 2022 12 31.
Article in English | MEDLINE | ID: mdl-34614379

ABSTRACT

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.


Subject(s)
Meningococcal Infections , Meningococcal Vaccines , Neisseria meningitidis , Adolescent , Adult , Aged , Antibodies, Bacterial , Child , Humans , Meningococcal Infections/prevention & control , Serogroup , Vaccines, Conjugate , Young Adult
14.
Int J Infect Dis ; 108: 443-453, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33894353

ABSTRACT

OBJECTIVES: To estimate the incidence of dengue infection across geographically distinct areas of Brazil. METHODS: This prospective, household-based, cohort study enrolled participants in five areas and followed them up for up to 4 years (2014-2018). Dengue seroprevalence was assessed at each scheduled visit. Suspected dengue cases were identified through enhanced passive and active surveillance. Acute symptomatic dengue infection was confirmed through reverse-transcriptase quantitative polymerase chain reaction in combination with an antigenic assay (non-structural protein 1) and serology. RESULTS: Among 3300 participants enrolled, baseline seroprevalence was 76.2%, although only 23.3% of participants reported a history of dengue. Of 1284 suspected symptomatic dengue cases detected, 50 (3.9%) were laboratory-confirmed. Based on 8166.5 person-years (PY) of follow-up, the incidence of laboratory-confirmed symptomatic infection (primary endpoint) was 6.1 per 1000 PY (95% confidence interval [CI]: 4.5, 8.1). Incidence varied substantially in different years (1.8-7.4 per 1000 PY). The incidence of inapparent primary dengue infection was substantially higher: 41.7 per 1000 PY (95% CI: 31.1, 54.6). CONCLUSIONS: Our findings, highlighting that the incidence of dengue infection is underestimated in Brazil, will inform the design and implementation of future dengue vaccine trials. CLINICAL TRIAL REGISTRATION: NCT01751139.


Subject(s)
Dengue/epidemiology , Adolescent , Adult , Asymptomatic Infections/epidemiology , Brazil/epidemiology , Child , Child, Preschool , Cohort Studies , Dengue Virus/immunology , Family Characteristics , Female , Humans , Incidence , Male , Middle Aged , Prospective Studies , Seroepidemiologic Studies , Young Adult
15.
BMJ Open ; 11(1): e045529, 2021 01 29.
Article in English | MEDLINE | ID: mdl-33514584

ABSTRACT

INTRODUCTION: The current COVID-19 pandemic has increased the need for populational adherence to measures for the prevention and control of respiratory infectious diseases. However, their effectiveness depends on the population's preventive behaviour, which may be divergent from public policies. Therefore, this study aims to summarise and evaluate the evidence on barriers and facilitators to populational adherence to prevention and control measures in COVID-19 and other respiratory infectious diseases. METHODS AND ANALYSIS: We will search on MEDLINE, Embase and PsycINFO for studies focusing on adults receiving protective behaviour recommendations to combat COVID-19 and other respiratory infectious diseases. The searches will be carried out from database's inception to the present. We will include studies that use qualitative methods in their data collection and analysis and studies that use mixed methods if they include any qualitative methods of analysis. Studies published in English, Portuguese and Spanish will be included. Two review authors will independently screen the studies for inclusion and extract data. We will assess the quality of the included studies using the Critical Skills Appraisal Programme tool. For the assessment of the confidence in the synthesised findings, we will use the GRADE-Confidence in the Evidence from Reviews of Qualitative research. Data analysis will be conducted using the best-fit framework approach based on adapted dimensions from the Health Belief Model and the Behaviour Change Wheel. ETHICS AND DISSEMINATION: This study will be conducted on published evidence, and thus, no ethical approval is required. The findings of this rapid qualitative evidence synthesis will be disseminated to academic audiences, health policy-makers and the general population. We will publish the results in peer-reviewed journals, present our findings in conferences, and disseminate results via social media. We also aim to present the research findings in plain language and disseminate the knowledge to the general population to increase public interest. PROSPERO REGISTRATION NUMBER: CRD42020205750.


Subject(s)
COVID-19 , Communicable Disease Control/methods , Communication Barriers , Disease Transmission, Infectious/prevention & control , Health Knowledge, Attitudes, Practice , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/psychology , Health Behavior , Health Risk Behaviors , Humans , Qualitative Research , Research Design , SARS-CoV-2 , Social Perception
16.
Int J Infect Dis ; 105: 120-123, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33476757

ABSTRACT

The Northeast region of Brazil registered the second-highest incidence proportion of Chikungunya fever in 2019. In that year, an outbreak consisting of patients presenting with febrile disease associated with joint pain was reported by the public primary health care service in the city of Natal, in the state of Rio Grande do Norte, in March 2019. At first, the aetiological agent of the disease was undetermined. Since much is still unknown about chikungunya virus' (CHIKV) genomic diversity and evolutionary history in this northeasternmost state, we used a combination of portable whole-genome sequencing, molecular clock, and epidemiological analyses that revealed the reintroduction of the CHIKV East-Central-South-African (ECSA) lineage into Rio Grande do Norte. We estimated that the CHIKV ECSA lineage was first introduced into Rio Grande do Norte in early June 2014, while the 2019 outbreak clade diverged around April 2018, during a period of increased Chikungunya incidence in the Southeast region, which might have acted as a source of virus dispersion towards the Northeast region. Together, these results confirm that the ECSA lineage continues to spread across the country through interregional importation events, likely mediated by human mobility.


Subject(s)
Chikungunya Fever/virology , Chikungunya virus/genetics , Brazil/epidemiology , Chikungunya Fever/epidemiology , Disease Outbreaks , Genotype , Humans , Phylogeny , Whole Genome Sequencing
17.
Am J Trop Med Hyg ; 104(1): 136-144, 2021 01.
Article in English | MEDLINE | ID: mdl-33169661

ABSTRACT

A phase III dengue vaccine trial including 9- to 16-year-olds in Latin America (NCT01374516) was ongoing at the time of a Zika outbreak. We explored interactions between dengue and Zika, in the context of dengue vaccination. Symptomatic virologically confirmed Zika (VCZ) was evaluated using acute-phase sera from febrile participants (January 2013-March 2018). Neutralizing antibody geometric mean titers (GMTs) were evaluated pre- and post-Zika outbreak (months 25 and 72) in 2,000 randomly selected participants. Baseline dengue serostatus was determined using the plaque reduction neutralization test or inferred post hoc using nonstructural protein 1 IgG ELISA at M13 (case-cohort analysis). Vaccine efficacy against VCZ and serologically suspected Zika (SSZ) was estimated. Overall, 239/10,157 (2.4%) acute-phase samples were VCZ positive during the study. Dengue vaccine efficacy against VCZ was 27.8% (95% CI: 0.3; 47.7) among baseline dengue-seropositive participants. No vaccine effect was evident against SSZ. Zika antibody GMTs increased from pre- to post-Zika epidemic, with smaller increases observed for participants who were dengue seropositive at baseline than for those who were dengue seronegative: post-/pre-Zika GMT ratios for baseline dengue-seropositive participants were 21.5 (vaccine group) and 30.8 (placebo); and for dengue seronegatives, 88.1 and 89.5, respectively. Dengue antibody GMTs post-Zika were higher in dengue vaccine and placebo recipients with SSZ than those without SSZ in both dengue seropositives and seronegatives. Dengue vaccine did not enhance symptomatic Zika illness in dengue-seropositive individuals, rather it reduced the risk of VCZ. Zika infection boosted preexisting vaccine-induced or naturally occurring dengue-neutralizing antibodies.


Subject(s)
Dengue Vaccines/immunology , Dengue/complications , Dengue/prevention & control , Zika Virus Infection/complications , Adolescent , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Child , Coinfection , Epidemics , Female , Humans , Latin America/epidemiology , Male
19.
Rev Soc Bras Med Trop ; 53: e20190517, 2020.
Article in English | MEDLINE | ID: mdl-32756797

ABSTRACT

Since the emergence of the chikungunya virus in Brazil in 2014, more than 700,000 cases have been reported throughout the country, corresponding to one-third of all cases reported in the Americas. In addition to its high attack rates, resulting in hundreds of thousands of cases, the disease has high chronicity rates with persistent joint manifestations for more than 3 months, which can spread to more than half of the patients affected in the acute phase. Pain associated with musculoskeletal manifestations, often disabling, has an effect on patients' quality of life at different stages of the disease. Currently, the challenge faced by specialists is identifying the best therapy to be instituted for symptom relief despite the limited number of published intervention studies. In 2016, a multidisciplinary group published pharmacological treatment protocols for pain in patients with chikungunya, which was incorporated into the guidelines for clinical management of the Brazilian Ministry of Health in 2017; in that same year, a consensus was published by the Brazilian Society of Rheumatology about diagnosis and treatment. After 5 years of experience with chikungunya epidemics, in 2019, specialists involved in the protocols of the Brazilian Society of Rheumatology and Brazilian Ministry of Health prepared an update with the main objective of developing flowcharts for the therapeutic approach of musculoskeletal manifestations in adult patients to enable specialists at different levels of healthcare to spread and apply this guideline in a systematic and simplified manner.


Subject(s)
Chikungunya Fever , Rheumatology , Adult , Brazil , Chikungunya Fever/complications , Chikungunya Fever/diagnosis , Chikungunya Fever/therapy , Consensus , Humans , Quality of Life
20.
Am J Trop Med Hyg ; 102(2): 268-273, 2020 02.
Article in English | MEDLINE | ID: mdl-31872796

ABSTRACT

In immunocompromised patients, visceral leishmaniasis (VL) can present with atypical clinical symptoms that include poor response to treatment. No optimal therapeutic regimen is available for such cases. In a splenectomized male patient, we observed a disseminated form of the disease in the liver, bone marrow, lymph nodes, and gastrointestinal tract. There was an apparent clinical improvement when he was initially treated with liposomal amphotericin B (L-AmB), but this was followed by a relapse involving severe clinical symptoms. He was finally treated successfully with a combination of L-AmB, meglumine antimoniate, and pentamidine isethionate. It is important to include asplenia as an immunosuppressive condition that induces exotic VL pathologies. In such cases, combination anti-Leishmania drug therapy should be considered.


Subject(s)
Amphotericin B/therapeutic use , Leishmaniasis, Visceral/drug therapy , Meglumine Antimoniate/therapeutic use , Pentamidine/therapeutic use , Splenectomy , Amphotericin B/administration & dosage , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/therapeutic use , Bone Marrow/parasitology , Drug Therapy, Combination , Humans , Immunocompromised Host , Intestinal Mucosa/parasitology , Leishmaniasis, Visceral/immunology , Lymph Nodes/parasitology , Male , Meglumine Antimoniate/administration & dosage , Middle Aged , Pentamidine/administration & dosage
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