Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item 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(Elsevier, 2024) Tricou, V.; Yu, D.; Reynales, H.; Biswal, S.; Saez-Llorens, X.; Sirivichayakul, C.; Lopez, P.; Borja-Tabora, C.; Bravo, L.; Kosalaraksa, P.; Vargas, L.M.; Alera, M.T.; Rivera, L.; Watanaveeradej, V.; Dietze, R.; Fernando, L.; Wickramasinghe, V.P.; Moreira, E.D.; Fernando, A.D.; Gunasekera, D.; Luz, K.; Oliveira, A.L.; Tuboi, S.; Escudero, I.; Hutagalung, Y.; Lloyd, E.; Rauscher, M.; Zent, O.; Folschweiller, N.; LeFevre, I.; Espinoza, F.; Wallace, D.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.Item Perceived stress during the prenatal period: assessing measurement invariance of the Perceived Stress Scale (PSS-10) across cultures and birth parity(Springer, 2022) Katus, L.; Foley, S.; Murray, A.L.; Thanh, B.Y.L.; Taut, D.; Baban, A.; Madrid, B.; Fernando, A.D.; Sikander, S.; Ward, C.L.; Osafo, J.; Marlow, M.; Toit, S.D.; Walker, S.; Van Vo, T.; Fearon, P.; Valdebenito, S.; Eisner, M.P.; Hughes, C.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.Item Correction to: Prenatal attachment: Using measurement invariance to test the validity of comparisons across eight culturally diverse countries(Springer, 2021) Foley, S.; Hughes, C.; Murray, A.L.; Baban, A.; Fernando, A.D.; Madrid, B.; Osafo, J.; Sikander, S.; Abbasi, F.; Walker, S.; Van, T.V.; Luong-Thanh, B.Y.; Tomlinson, M.; Fearon, P.; Ward, C.L.; Valdebenito, S.; Eisner, M.[This corrects the article Archives of Women's Mental Health.2021; 24(4): 619-625] Erratum for Prenatal attachment: using measurement invariance to test the validity of comparisons across eight culturally diverse countriesItem Prenatal attachment: using measurement invariance to test the validity of comparisons across eight culturally diverse countries(Springer, 2021) Foley, S.; Hughes, C.; Murray, A.L.; Baban, A.; Fernando, A.D.; Madrid, B.; Osafo, J.; Sikander, S.; Abbasi, F.; Walker, S.; Luong-Thanh, B.Y.; Bảo, Y.L.T.; Tomlinson, M.; Fearon, P.; Ward, C.L.; Valdebenito, S.; Eisner, M.ABSTRACT: 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. KEYWORDS: Cross-cultural; Lower-middle income; Maternal-fetal attachment; Measurement invariance; Parity; Pregnancy.Item Efficacy of a dengue vaccine candidate (TAK-003) in healthy children and adolescents two years after vaccination(University of Chicago Press, 2022) López-Medina, E.; Biswal, S.; Saez-Llorens, X.; Borja-Tabora, C.; Bravo, L.; Sirivichayakul, C.; Vargas, L.M.; Alera, M.T.; Velásquez, H.; Reynales, H.; Rivera, L.; Watanaveeradej, V.; Rodriguez-Arenales, E.J.; Yu, D.; Espinoza, F.; Dietze, R.; Fernando, L.; Wickramasinghe, P.; Moreira Jr, E.D.; Fernando, A.D.; Gunasekera, D.; Luz, K.; da Cunha, R.V.; Tricou, V.; Rauscher, M.; Liu, M.; LeFevre, I.; Wallace, D.; Kosalaraksa, P.; Borkowski, A.; TIDES study group.BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing Phase 3 efficacy study; we present an update after 2 years. METHODS: 20,099 children (4-16 years old) were randomized to receive two doses of TAK-003 or placebo three months apart and are under long-term febrile surveillance to detect dengue by serotype-specific RT-PCR. (NCT02747927). RESULTS: Cumulative efficacy against dengue over ~27 months since first dose was 72.7% (95% CI: 67.1 - 77.3), which included efficacy of 67.0% (95% CI: 53.6 - 76.5) in dengue-naïve and 89.2% (82.4 - 93.3) against hospitalized dengue. In the second year after vaccination, a decline in efficacy was observed [56.2% (42.3 - 66.8)] with the largest decline in 4 - 5 year-old children [24.5% (-34.2 - 57.5)]; efficacy was 60.6% (43.8 - 72.4) in 6 - 11 year and 71.2% (41.0 - 85.9) in 12 - 16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to the efficacy differences in year by year analysis. No related serious adverse events occurred during the second year. CONCLUSION: 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. KEYWORDS: Dengue; TAK-003; efficacy; immunogenicity; persistence; safety; vaccine.Item 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)(BMJ Publishing Group Ltd, 2020) Valdebenito, S.; Murray, A.; Hughes, C.; Băban, A.; Fernando, A.D.; Madrid, B.J.; Ward, C.; Osafo, J.; Dunne, M.; Sikander, S.; Walker, S.P.; Thang, V.V.; Tomlinson, M.; Fearon, P.; Shenderovich, Y.; Marlow, M.; Chathurika, D.; Taut, D.; Eisner, M.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. Keywords: Child protection; Community child health; EPIDEMIOLOGY; MENTAL HEALTH; Prenatal diagnosis.Item Developing pathways for a safer childhood(Sri Lanka College of Paediatricians, 2012) Fernando, A.D.No Abstract Available