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

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

Perceived stress during the prenatal period: assessing measurement invariance of the Perceived Stress Scale (PSS-10) across cultures and birth parity.

Maternal prenatal stress places a substantial burden on mother's mental health. Expectant mothers in low- and middle-income countries (LMICs) have thus far received less attention than mothers in high-income settings. This is particularly problematic, as a range of triggers, such as exposure to traumatic events (e.g. natural disasters, previous pregnancy losses) and adverse life circumstances (e.g. poverty, community violence), put mothers at increased risk of experiencing prenatal stress. The ten-item Perceived Stress Scale (PSS-10) is a widely recognised index of subjective experience of stress that is increasingly used in LMICs. However, evidence for its measurement equivalence across settings is lacking. This study aims to assess measurement invariance of the PSS-10 across eight LMICs and across birth parity. This research was carried out as part of the Evidence for Better Lives Study (EBLS, vrc.crim.cam.ac.uk/vrcresearch/EBLS). The PSS-10 was administered to N = 1,208 expectant mothers from Ghana, Jamaica, Pakistan, the Philippines, Romania, South Africa, Sri Lanka and Vietnam during the third trimester of pregnancy. Confirmatory factor analysis suggested a good model fit of a two-factor model across all sites, with items on experiences of stress loading onto a negative factor and items on perceived coping onto a positive factor. Configural and metric, but not full or partial scalar invariance, were established across all sites. Configural, metric and full scalar invariance could be established across birth parity. On average, first-time mothers reported less stress than mothers who already had children. Our findings indicate that the PSS-10 holds utility in assessing stress across a broad range of culturally diverse settings; however, caution should be taken when comparing mean stress levels across sites.

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

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

Efficacy of a 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.

The impact of maternal adverse childhood experiences and prenatal depressive symptoms on foetal attachment: Preliminary evidence from expectant mothers across eight middle-income countries.

BACKGROUND: Mothers from middle-income countries (MIC) are estimated to have higher rates of adverse childhood experiences (ACEs) and depression during pregnancy compared to mothers from high income countries. Prenatal depression can adversely impact on a mother's feelings towards her foetus and thus may be partially responsible for intergenerational transmission of risk associated with maternal ACEs. However, the extent to which prenatal depressive symptoms mediate the association between maternal ACEs and foetal attachment is unknown. METHODS: Data on foetal attachment, ACEs, and prenatal depression came from mothers in their third trimester of pregnancy (n = 1,185) located across eight MICs, participating in the prospective birth cohort Evidence for Better Lives Study - Foundational Research (EBLS-FR). Data were from the baseline measurement. RESULTS: Full-sample path mediation analyses, adjusting for relevant covariates, suggested a full mediating effect of prenatal depression. However, at the individual-country level, both positive and negative effects of ACEs on foetal attachment were observed after the inclusion of depressive symptoms as a mediator, suggesting cultural and geographical factors may influence a mother's empathic development after ACE exposure. LIMITATIONS: As no follow-up measurements of depressive symptoms or postnatal attachment were included in the analyses, the findings cannot be extrapolated to the postnatal period and beyond. Further, causality cannot be inferred as the study was observational. CONCLUSIONS: The findings reinforce the importance of screening for prenatal depression during antenatal care in MICs. Addressing prenatal depression within maternal health care may support foetal attachment and contribute to reducing the intergenerational transmission of disadvantage.

Prenatal attachment: using measurement invariance to test the validity of comparisons across eight culturally diverse countries.

Studies in high-income countries (HICs) have shown that variability in maternal-fetal attachment (MFA) predict important maternal health and child outcomes. However, the validity of MFA ratings in low- and middle-income countries (LMICs) remains unknown. Addressing this gap, we assessed measurement invariance to test the conceptual equivalence of the Prenatal Attachment Inventory (PAI: Muller, 1993) across eight LMICs. Our aim was to determine whether the PAI yields similar information from pregnant women across different cultural contexts. We administered the 18-item PAI to 1181 mothers in the third trimester (Mean age = 28.27 years old, SD = 5.81 years, range = 18-48 years) expecting their first infant (n = 359) or a later-born infant (n = 820) as part of a prospective birth cohort study involving eight middle-income countries: Ghana, Jamaica, Pakistan, Philippines, Romania, South Africa, Sri Lanka and Vietnam. We used Multiple Group Confirmatory Factor Analyses to assess across-site measurement invariance. A single latent factor with partial measurement invariance was found across all sites except Pakistan. Group comparisons showed that mean levels of MFA were lowest for expectant mothers in Vietnam and highest for expectant mothers in Sri Lanka. MFA was higher in first-time mothers than in mothers expecting a later-born child. The PAI yields similar information about MFA across culturally distinct middle-income countries. These findings strengthen confidence in the use of the tool across different settings; future studies should explore the use of the PAI as a screen for maternal behaviour that place children at risk.

What Research Questions Should the Next Generation of Birth Cohort Studies Address? An International Delphi Study of Experts.

OBJECTIVE: Birth cohort studies (BCS) have generated a wealth of invaluable basic scientific and policy-relevant information on a wide range of issues in child health and development. This study sought to explore what research questions are currently a priority for the next generation of BCS using a 3-round Delphi survey of interdisciplinary experts. METHODS: Twenty-four (Round I, N = 17; Round II, N = 21; Round III, N = 18) experts across a wide range of fields (eg, psychology, public health, and maternal/child health) agreed to participate. In Round I, the expert panel was invited to freely respond to the question, "what are the key scientific questions future birth cohort studies should address?" Content analysis of answers was used to identify 47 questions for rating on perceived importance by the panel in Round II and consensus-achieving questions were identified. Questions that did not reach consensus in Round II were posed again for expert re-rating in Round III. RESULTS: Twenty six of 47 questions reached consensus in Round II, with an additional 6 reaching consensus in Round III. Consensus-achieving questions rated highly on importance spanned a number of topics, including environmental effects on child development, intergenerational transmission of disadvantage, and designing BCS to inform intervention strategies. CONCLUSION: Investigating the effects of family/environmental factors and social disadvantage on a child's development should be prioritized in designing future BCS. The panel also recommended that future BCS are designed to inform intervention strategies.

Evidence for Better Lives Study: a comparative birth-cohort study on child exposure to violence and other adversities in eight low- and middle-income countries - foundational research (study protocol).

INTRODUCTION: Violence against children is a health, human rights and social problem affecting approximately half of the world's children. Its effects begin at prenatal stages with long-lasting impacts on later health and well-being. The Evidence for Better Lives Study (EBLS) aims to produce high-quality longitudinal data from cities in eight low- and middle-income countries-Ghana, Jamaica, Pakistan, the Philippines, Romania, South Africa, Sri Lanka and Vietnam-to support effective intervention to reduce violence against children. EBLS-Foundational Research (EBLS-FR) tests critical aspects of the planned EBLS, including participant recruitment and retention, data collection and analysis. Alongside epidemiological estimates of levels and predictors of exposure to violence and adversity during pregnancy, we plan to explore mechanisms that may link exposure to violence to mothers' biological stress markers and subjective well-being. METHODS AND ANALYSES: EBLS-FR is a short longitudinal study with a sample of 1200 pregnant women. Data are collected during the last trimester of pregnancy and 2 to 6 months after birth. The questionnaire for participating women has been translated into nine languages. Measures obtained from mothers will include, among others, mental and physical health, attitudes to corporal punishment, adverse childhood experiences, prenatal intimate partner violence, substance use and social/community support. Hair and dry blood spot samples are collected from the pregnant women to measure stress markers. To explore research participation among fathers, EBLS-FR is recruiting 300 fathers in the Philippines and Sri Lanka. ETHICS AND DISSEMINATION: The study received ethical approvals at all recruiting sites and universities in the project. Results will be disseminated through journal publications, conferences and seminar presentations involving local communities, health services and other stakeholders. Findings from this work will help to adjust the subsequent stages of the EBLS project.

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.

The Intergenerational Effects of Intimate Partner Violence in Pregnancy: Mediating Pathways and Implications for Prevention.

Prenatal intimate partner violence (P-IPV) can have significant adverse impacts on both mother and fetus. Existing P-IPV interventions focus on the safety of the mother and on reducing revictimization; yet expanding these to address the adverse impact on the fetus has considerable potential for preventing long-term negative developmental outcomes. In this review, we draw together evidence on major pathways linking exposure to P-IPV and child outcomes, arguing that these pathways represent potential targets to improve P-IPV intervention efforts. Using a narrative review of 112 articles, we discuss candidate pathways linking P-IPV to child outcomes, as well as their implications for intervention. Articles were identified via key word searches of social science and medical databases and by inspection of reference lists of the most relevant articles, including recent reviews and meta-analyses. Articles were included if they addressed issues relevant to understanding the effects of P-IPV on child outcomes via six core pathways: maternal stress and mental illness, maternal-fetal attachment, maternal substance use, maternal nutritional intake, maternal antenatal health-care utilization, and infection. We also included articles relevant for linking these pathways to P-IPV interventions. We conclude that developing comprehensive P-IPV interventions that target immediate risk to the mother as well as long-term child outcomes via the candidate mediating pathways identified have significant potential to help reduce the global burden of P-IPV.

Cultural adaptation, translation and validation of the ISPCAN Child Abuse Screening Tool - Retrospective Version (ICAST-R) for young adults in Sri Lanka.

The aim of the present study was to adapt and validate the ISPCAN child abuse screening tool-retrospective version (ICAST-R) in Sri Lanka with a view to investigating the experiences of physical, sexual and emotional abuse during childhood. The adaptation was performed using qualitative research methods with young adults, parents, teachers, and a multidisciplinary group of experts. The translation to Sinhala (the local Sri Lankan dialect) was carried out by a nominal group technique. A multidisciplinary team of experts assessed the Sinhala ICAST-R (SICAST-R) for its content validity. Moreover, acceptability, reliability and construct validity were determined by conducting a validation study among 200 schooling young adults. The principal component analysis (PCA) technique was used to assess the construct validity. Response rates for each item were taken as evidence of acceptability. The internal consistency was assessed by Cronbach's alpha, and test-retest reliability after two weeks was assessed using Cohen's kappa coefficient. The adaptation of ICAST-R included the introduction of an objective manner by which to measure severity of abuse and the inclusion of a set of questions regarding help-seeking behavior following physical and emotional abusive experiences. The SICAST-R showed adequate content validity and high acceptability, with response rates ranging from 90.3% to 99.5%. The minimum Cohen's kappa coefficient was 0.76, indicating good test-retest reliability. The internal consistency (Cronbach's alpha) for the total tool was 0.708, with the three constructs being 0.398, 0.844 and 0.637 for physical, sexual and emotional abuse, respectively. The PCA demonstrated good reproducibility for sexual and emotional abuse with the hypothesized structure. Overall, the SICAST-R showed adequate validity for the assessment of experiences of physical, sexual and emotional abuse during childhood among Sri Lankan young adults.

Physical, sexual and emotional abuse during childhood: Experiences of a sample of Sri Lankan Young adults.

Abuse during childhood is a human tragedy leading to lifelong adverse health, social, and economic consequences for survivors. This descriptive, cross-sectional study aimed to determine the prevalence of childhood physical, sexual and emotional abusive experiences among students (aged 18-19 years) in a Sri Lankan district. Multistage cluster sampling was used to select a sample of 1500 students. Experiences of physical, sexual and emotional abuse and age at abuse, perpetrators, consequences and severity were assessed using a version of ISPCAN Child Abuse Screening Tool-Retrospective Version (ICAST-R) which was culturally adapted and validated by the authors for use amongst Sinhalese students. The prevalence of the various forms of abuse during childhood was as follows: physical: 45.4% (95% CI: 42.9-7.9); sexual: 9.1% (95% CI: 7.6-10.5); emotional: 27.9% (95% CI: 25.7-30.2). The corresponding percentages of individuals categorized as having experienced severe or very severe abuse were as follows, physical: 0.3% (2/672); sexual: 4.05% (3/135); emotional: 8.8% (36/412). Experience of physical abuse was more prevalent amongst male students (54.8% vs. 38.3%) as was emotional abuse (33.9% vs. 23.2%), whereas experience of sexual abuse was more prevalent amongst female students (11.5% vs. 6.4%). Parents and teachers were the commonest perpetrators of physical and emotional abuse. Most of the sexually abusive acts were committed by neighbors or strangers. Some physically abusive acts were more frequent at earlier ages than emotional and sexual abusive acts, which were more common in late adolescence. The results indicate the necessity of targeted interventions to address this public health issue.

Posterior reversible encephalopathy syndrome in a survivor of valproate-induced acute liver failure: a case report.

INTRODUCTION: Posterior reversible encephalopathy syndrome is an extremely rare radiological diagnosis that has not been reported previously in association with acute liver failure. CASE PRESENTATION: A 6-year-old Sri Lankan girl developed acute liver failure with severe hepatic encephalopathy due to sodium valproate. She was successfully treated medically with N-acetylcysteine and L-carnitine. During recovery she again developed features of encephalopathy and had repeated convulsions associated with moderate hypertension. The diagnosis of posterior reversible encephalopathy syndrome was made on clinical and radiological grounds and she showed a gradual improvement with control of blood pressure. CONCLUSIONS: This report adds to the evidence behind treatment of valproate-induced acute liver failure with N-acetylcysteine and L-carnitine and illustrates a rare but interesting association between acute liver failure and posterior reversible encephalopathy syndrome.