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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. 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. 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. 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. Takeda Vaccines.

An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries. We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2–17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066. Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226–632) in two-dose, 421 (285–622) in one-dose, 719 (538–960) in one-dose plus 1-year booster, and 100 (50–201) in placebo recipients against DENV 1; 1052 (732–1511), 1319 (970–1794), 1200 (927–1553), and 208 (99–437) against DENV 2; 183 (113–298), 201 (135–298), 288 (211–392), and 71 (37–139) against DENV 3; and 152 (97–239), 164 (114–236), 219 (165–290), and 46 (26–82) against DENV 4; and tetravalent seropositivity rate was 89% (79–96), 86% (80–92), 97% (93–99), and 60% (47–72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19–0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported. TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study. Takeda Vaccines.

Although the peak incidence of human papillomavirus (HPV) infection occurs in most populations within 5–10 years of first sexual experience, all women remain at risk for acquisition of HPV infections. We tested the safety, immunogenicity, and efficacy of the quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like-particle vaccine in women aged 24–45 years. Women aged 24–45 years with no history of genital warts or cervical disease were enrolled from community health centres, academic health centres, and primary health-care providers into an ongoing multicentre, parallel, randomised, placebo-controlled, double-blind study. Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine (n=1911) or placebo (n=1908) at day 1, and months 2 and 6. All study site investigators and personnel, study participants, monitors, and central laboratory personnel were blinded to treatment allocation. Coprimary efficacy endpoints were 6 months' or more duration of infection and cervical and external genital disease due to HPV 6, 11, 16, 18; and due to HPV 16 and 18 alone. Primary efficacy analyses were done in a per-protocol population, but intention-to-treat analyses were also undertaken. This study is registered with ClinicalTrials.gov, number NCT00090220. 1910 women received at least one dose of vaccine and 1907 at least one dose of placebo. In the per-protocol population, efficacy against the first coprimary endpoint (disease or infection related to HPV 6, 11, 16, and 18) was 90·5% (95% CI 73·7–97·5, four of 1615 cases in the vaccine group vs 41/1607 in the placebo group) and 83·1% (50·6–95·8, four of 1601 cases vs 23/1579 cases) against the second coprimary endpoint (disease or infection related to HPV 16 and 18 alone). In the intention-to-treat population, efficacy against the first coprimary endpoint was 30·9% (95% CI 11·1–46·5, 108/1886 cases vs 154/1883 cases) and against the second coprimary endpoint was 22·6% (−2·9 to 41·9, 90/1886 cases vs 115/1883 cases), since infection and disease were present at baseline. We recorded no vaccine-related serious adverse events. The quadrivalent HPV vaccine is efficacious in women aged 24–45 years not infected with the relevant HPV types at enrolment. Merck (USA).

Background The impacts of multicomponent school water, sanitation, and hygiene (WaSH) interventions on children’s health are unclear. We conducted a cluster-randomized controlled trial to test the effects of a school WaSH intervention on children’s malnutrition, dehydration, health literacy (HL), and handwashing (HW) in Metro Manila, Philippines. Methods The trial lasted from June 2017 to March 2018 and included children, in grades 5, 6, 7, and 10, from 15 schools. At baseline 756 children were enrolled. Seventy-eight children in two clusters were purposively assigned to the control group (CG); 13 clusters were randomly assigned to one of three intervention groups: low-intensity health education (LIHE; two schools, n = 116 children), medium-intensity health education (MIHE; seven schools, n = 356 children), and high-intensity health education (HIHE; four schools, n = 206 children). The intervention consisted of health education (HE), WaSH policy workshops, provision of hygiene supplies, and WaSH facilities repairs. Outcomes were: height-for-age and body mass index-for-age Z scores (HAZ, BAZ); stunting, undernutrition, overnutrition, dehydration prevalence; HL and HW scores. We used anthropometry to measure children’s physical growth, urine test strips to measure dehydration, questionnaires to measure HL, and observation to measure HW practice. The same measurements were used during baseline and endline. We used multilevel mixed-effects logistic and linear regression models to assess intervention effects. Results None of the interventions reduced undernutrition prevalence or improved HAZ, BAZ, or overall HL scores. Low-intensity HE reduced stunting (adjusted odds ratio [aOR] 0.95; 95% CI 0.93 to 0.96), while low- (aOR 0.57; 95% CI 0.34 to 0.96) and high-intensity HE (aOR 0.63; 95% CI 0.42 to 0.93) reduced overnutrition. Medium- (adjusted incidence rate ratio [aIRR] 0.02; 95% CI 0.01 to 0.04) and high-intensity HE (aIRR 0.01; 95% CI 0.00 to 0.16) reduced severe dehydration. Medium- (aOR 3.18; 95% CI 1.34 to 7.55) and high-intensity HE (aOR 3.89; 95% CI 3.74 to 4.05) increased observed HW after using the toilet/urinal. Conclusion Increasing the intensity of HE reduced prevalence of stunting, overnutrition, and severe dehydration and increased prevalence of observed HW. Data may be relevant for school WaSH interventions in the Global South. Interventions may have been more effective if adherence was higher, exposure to interventions longer, parents/caregivers were more involved, or household WaSH was addressed. Trial registration number DRKS00021623.

A dose-sparing inactivated polio vaccine (IPV-Al), obtained by adsorption of inactivated virus to an aluminium hydroxide adjuvant, can help mitigate global supply and the cost constraints of IPV. The objective of this trial was to demonstrate the non-inferiority of IPV-Al to standard IPV. This phase 3, observer-blinded, randomised, controlled trial was conducted at 5 investigational sites in the Philippines. Infants not previously vaccinated with any polio vaccines were randomised to receive three IPV-Al (n = 502) or IPV vaccinations (n = 500) at 6, 10 and 14 weeks of age plus a booster vaccination at 9 months. The primary endpoint was type-specific seroconversion, defined as an antibody titre ≥4-fold higher than the estimated maternal antibody titre and a titre ≥8, one month after the primary vaccination series. Seroconversion rates following primary vaccination with IPV-Al (483 infants in the per-protocol analysis set) or IPV (478 infants) were: polio type 1, 97.1% versus 99.0%; type 2, 94.2% versus 99.0%; and type 3, 98.3% versus 99.6%. IPV-Al was non-inferior to IPV, as the lower 95% confidence limits of the treatment differences were above the predefined −10%-point limit: type 1, −1.85% (−3.85; −0.05); type 2, −4.75% (−7.28; −2.52); type 3, −1.24 (−2.84; 0.13). The booster effect (geometric mean titre (GMT) post-booster / GMT pre-booster) was: type 1, 63 versus 43; type 2, 54 versus 47; type 3, 112 versus 80. IPV-Al was well tolerated with a safety profile comparable to that of IPV. Serious adverse events were recorded for 29 infants (5.8%, 37 events) in the IPV-Al group compared to 28 (5.6%, 48 events) in the IPV group. Non-inferiority of IPV-Al to IPV with respect to seroconversion was confirmed and a robust booster response was demonstrated. Both vaccines had a similar safety profile. ClinicalTrials.gov identifier: NCT03032419.

Background Adequate nutrition is essential during pregnancy and lactation to provide sufficient energy and nutrients to meet the nutritional requirements of the mother, fetus and infant. The primary objective of this study was to assess the effect of a maternal nutritional supplement enriched with probiotics during pregnancy and early lactation on the incidence of infant diarrhea. Methods Healthy, pregnant (24–28 weeks gestation) women were randomized 1:1:1 to receive either no supplement or two servings per day of an oral supplement (140 kcal/serving) providing 7.9 g protein, multivitamin/minerals, and enriched or not with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis , from the third trimester of pregnancy until at least 2 months post-delivery. Incidence of infant diarrhea until 12 months post-delivery was analyzed by Poisson regression. The effect on maternal health, fetal growth, and infant growth and morbidity were also evaluated and analyzed by ANOVA. Results A total of 208 mother/infant pairs were included in the analysis. No significant difference in the incidence of infant diarrhea was observed between the three study groups. The mean maternal weight gains at delivery were similar among groups, despite an increase in caloric intake in the supplemented groups. No statistically significant differences between groups were observed in incidence of pregnancy-related or fetal adverse outcomes. Mean weight-, length-, BMI- and head circumference-for-age z-scores were below the WHO median value for all groups. Post-hoc analysis to compare the effect of the combined supplement groups versus the no supplement group on infant growth parameters showed, at 12 months, that the combined supplemented group had gained statistically significant more weight (8.97 vs. 8.61 kg, p  = 0.001) and height (74.2 vs. 73.4 cm, p  = 0.031), and had a higher weight-for-age z-score (− 0.62 vs. -0.88, p  = 0.045) than the no supplement group. Conclusions Maternal nutritional supplement with or without probiotics given during late pregnancy and early lactation was well tolerated and safe. Even though no difference in incidence of infant diarrhea was observed between the three groups, the analysis of the combined supplemented groups showed beneficial effects of maternal supplementation on infant weight and length gains at 12 months. Trial registration ClinicalTrial.gov: NCT01073033 . Registered 17.02.2010.

A recombinant live attenuated tetravalent dengue vaccine (TDV) is safe and immunogenic in adults and children in dengue-naïve populations. Data are needed in dengue endemic populations. In a phase I, randomized, controlled, blind-observer study in the Philippines, groups of participants aged 2–5, 6–11, 12–17, and 18–45 years received either three TDV vaccinations at months 0, 3.5, and 12 (TDV–TDV–TDV group) or licensed typhoid vaccination at month 0 and TDV at months 3.5 and 12 (TyVi–TDV–TDV group) and were followed for safety (including biological safety and vaccine virus viremia) and immunogenicity. No serious adverse vaccine related events and no significant trends in biological safety parameters were reported. Injection site pain, headache, malaise, myalgia, fever, and asthenia were reported most frequently, as mild to moderate in most cases and transient. Reactogenicity did not increase with successive vaccinations and was no higher in children than in adults and adolescents. Low levels of vaccinal viremia were detected in both groups after each TDV vaccination. After three TDV vaccinations, the seropositivity rates against serotypes 1–4 were: 91%, 100%, 96%, 100%, respectively, in 2–5 year-olds; 88%, 96% 96%, 92% in 6–11 year-olds; 88%, 83%, 92%, 96% in adolescents; and 100% for all serotypes in adults. A similar response was observed after two doses for the TyVi–TDV–TDV group. The safety profile of TDV in a flavivirus endemic population was consistent with previous reports from flavivirus naïve populations. A vaccine regimen of either three TDV vaccinations administered over a year or two TDV vaccinations given more than 8 months apart resulted in a balanced antibody response to all four dengue serotypes in this flavivirus-exposed population, including children.

[Display omitted] •Rabies post-exposure prophylaxis (PEP) regimen completion time may affect compliance.•A 1-week 4-site PEP with Verorab ± pERIG was non-inferior to the standard 2-site regimen + pERIG.•Immunogenicity and antibody persistence was higher with the 4- versus the 2-site regimen.•Tenderness/pain adverse reactions were similar between the 4- and 2-site regimens.•These results suggest a valuable role for the 1-week 4-site regimen in rabies PEP. Rabies post-exposure prophylaxis (PEP) via intradermal (ID) administration is standard practice in Asia. Accumulating evidence suggests that PEP shortened to 3 visits in one week does not adversely affect seroconversion rates or immune memory. To determine whether the seroconversion rate at Day14 with a 1-week, 4-site (4-4-4-0-0) ID vaccination regimen with or without rabies immunoglobulin (RIG) was non-inferior to the updated Thai Red Cross (TRC) 28-day, 2-site (2-2-2-0-2) ID regimen with RIG during rabies PEP. We also assessed one-year antibody persistence. This phase III, mono-center, open-label, randomized-controlled trial assigned participants aged ≤50 years (n = 600) exposed to suspected rabid animals and sustaining WHO Category II injuries (automatic allocation to G1) or Category III injuries (randomized to G2 or G3) to the following groups (1:1:1 ratio): G1 (n = 200), 1-week 4-site ID regimen with the purified Vero cell rabies vaccine (PVRV; Verorab®) without RIG; G2 (n = 201), 1-week 4-site ID regimen with PVRV, and purified equine rabies immunoglobulin (pERIG); G3 (n = 199), TRC 28-day, 2-site ID regimen with PVRV, and pERIG. Non-inferiority tests compared G1 vs. G3 and G2 vs. G3. Seroconversion rate was the proportion (%) of vaccinees with rabies virus neutralizing antibodies (RVNA) titers ≥0.5 IU/mL measured by rapid fluorescent focus inhibition test. On Day14, after the third vaccine administration, seroconversion rates were non-inferior in both comparisons and were, respectively, 100%, 99.4%, 98.8% in G1, G2, G3 with a decrease to 97.6%, 89%, 79.8% at Year 1. At Day14, RVNA geometric mean titers were 11.3 IU/mL; 9.89 IU/mL; 6.15 IU/mL, respectively, decreasing to 2.96 IU/mL, 1.37 IU/mL, 0.97 IU/mL at Year1. Safety and tolerability were similar between the three groups. The seroconversion rate at Day 14 with the 1-week 4-site ID regimen, both with and without pERIG, was non-inferior to the reference TRC 28-day 2-site ID regimen with pERIG during rabies PEP with PVRV. ClinicalTrials.gov ID: NCT01622062.

Background Child health in many low- and middle-income countries lags behind international goals and affects children’s education, well-being, and general development. Large-scale school health programmes can be effective in reducing preventable diseases through cost-effective interventions. This paper outlines the baseline and 1-year results of a longitudinal health study assessing the impact of the Fit for School Programme in the Philippines. Methods A longitudinal 4-year cohort study was conducted in the province of Camiguin, Mindanao (experimental group); an external concurrent control group was studied in Gingoog, Mindanao. The study has three experimental groups: group 1—daily handwashing with soap, daily brushing with fluoride toothpaste, biannual deworming with 400 mg albendazole (Essential Health Care Program [EHCP]); group 2—EHCP plus twice-a-year access to school-based Oral Urgent Treatment; group 3—EHCP plus weekly toothbrushing with high-fluoride concentration gel. A non-concurrent internal control group was also included. Baseline data on anthropometric indicators to calculate body mass index (BMI), soil-transmitted helminths (STH) infection in stool samples, and dental caries were collected in August 2009 and August 2010. Data were analysed to assess validity of the control group design, baseline, and 1-year results. Results In the cohort study, 412 children were examined at baseline and 341 1 year after intervention. The baseline results were in line with national averages for STH infection, BMI, and dental caries in group 1 and the control groups. Children lost to follow-up had similar baseline characteristics in the experimental and control groups. After 1 year, group 1 showed a significantly higher increase in mean BMI and lower prevalence of moderate to heavy STH infection than the external concurrent control group. The increases in caries and dental infections were reduced but not statistically significant. The results for groups 2 and 3 will be reported separately. Conclusions Despite the short 1-year observation period, the study found a reduction in the prevalence of moderate to heavy STH infections, a rise in mean BMI, and a (statistically non-significant) reduction in dental caries and infections. The study design proved functional in actual field conditions. Critical aspects affecting the validity of cohort studies are analysed and discussed. Trial registration DRKS00003431 WHO Universal Trial Number U1111-1126-0718

Background Mosquito-borne viruses are imposing an ever increasing health burden worldwide. In addition to the recent Zika and chikungunya virus epidemics, dengue viruses have become the fastest growing problem with a 40-fold increase in the number of reported cases over the past five decades. Current mosquito control techniques involving larval source reduction, larviciding, and space spray of adulticides are costly, laborious, and of debatable efficacy. There remains an urgent need for the development of intervention methods that can be reasonably implemented in the context of modern day urbanisation. Auto-dissemination (AD) of insecticide by adult mosquitoes offers a potentially practical and useful tool in an integrated vector control programme. Recently, an immediately employable AD device, the In2Care® mosquito trap, has been commercialised and shows promise as an effective tool. However, there remains a lack of demonstration of epidemiological efficacy. Methods/design This trial aims to assess the extent to which implementation of In2Care® mosquito traps can reduce vector Aedes ( Stegomyia ) spp. adult mosquito densities and dengue virus transmission as measured by sequential sero-conversion rates in children 6–16 years of age in a dengue endemic location: Lipa City, Philippines. To achieve this, we will carry out a parallel, two-armed cluster randomised trial evaluating AD efficacy for reducing the incidence of dengue over a 2-year period with 4 consecutive months of vector control during peak dengue transmission each year. Discussion For decades, it has been commonly accepted that an integrated approach to mosquito control is required. The World Health Organization (WHO) Global Strategic Framework for Integrated Vector Management recommends a range of interventions, in combination, to increase control impact to reduce transmission. This efficacy trial of the first commercial product using the AD approach will be informative in assessing the general utility of AD in reducing not only adult vector densities but, more importantly, reducing the incidence of dengue. The AD technique may complement source reduction and larviciding campaigns by more efficiently targeting the most productive containers and those beyond human reach. If successful, this mosquito control strategy could prove an invaluable tool in the fight against urban mosquito vectors and a reduction in the burden of associated disease. Trial registration ISRCTN44272773 . Registered on 31 January 2019.