Efficacy and Safety of a Tetravalent Dengue Vaccine (TAK-003) in Children With Prior Japanese Encephalitis or Yellow Fever Vaccination.

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.

Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2-17 years: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Takeda Vaccines.

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.

Rotavirus strain surveillance for three years following the introduction of rotavirus vaccine into Belém, Brazil.

The monovalent human rotavirus (RV) vaccine, RIX4414 (Rotarix™, GlaxoSmithKline Biologicals) was introduced into Brazil's Expanded Program on Immunization in March 2006. One year after vaccine introduction, the G2P[4] strain was found to be predominant, with an apparent extinction of many non-G2 strains. This study investigated the diversity of circulating strains in the three years following RIX4414 introduction. Between May 2008 and May 2011, stool samples were collected from children aged ≥12 weeks who were hospitalized for severe lab confirmed RV-gastroenteritis (≥3 liquid or semi-liquid motions over a 24-h period for <14 days, requiring ≥1 overnight hospital stay and intravenous rehydration therapy) in Belém, Brazil. RV-gastroenteritis was detected by ELISA and the G- and P-types were determined by RT-PCR assays. During the first year of surveillance nucleotide sequencing was used for typing those samples not previously typed by RT-PCR. A total of 1,726 of 10,030 severe gastroentertis hospitalizations (17.2%) were due to severe RVGE. G2P[4] was detected in 57.2% of circulating strains over the whole study period, however it predominated during the first 20 months from May 2008 to January 2009. G1P[8] increased in the last part of the study period from May 2010 to May 2011 and represented 36.6% (112/306) of the circulating strains. G2P[4] was the predominant RV strain circulating during the first 20 months of the study, followed by G1P[8]. These findings probably reflect a natural fluctuation in RV strains over time, rather than a vaccine-induced selective pressure.

Loss to follow-up in a cohort of HIV-infected patients in a regional referral outpatient clinic in Brazil.

One of the main aspects related to non-adherence to combined antiretroviral therapy (cART) for patients infected with the Human Immunodeficiency Virus (HIV) refers to the abandonment of outpatient care. This study was aimed to estimate the loss to follow-up in outpatient HIV care at a Regional Referral Clinic (SAE) for HIV/AIDS in the city of Juiz de Fora, Brazil, and to identify associated factors and predictors. This is a prospective cohort of patients older than 18 years, under cART and regular outpatient care. The study included patients who attended medical visits during July-August 2011. Those who did not return to the clinic for new medical appointments within 90 days after the sixth month of follow up were considered lost to follow-up in outpatient care. Variables with P value ≤0.25 in the univariate analysis were included in a logistic regression model, adopting a significance level of 0.05. Among the 250 patients included in the study, 44 (17.6 %) were lost to follow up in outpatient care. Among these, 38 (86.4 %) were located in the cART delivery database system (SICLOM). Younger patients (≤43 versus >43 years) (OR 2.30 CI 1.06-5.00, P = 0.04), and patients attended by physician "E", when compared with physicians "A", "B", "C" or "D" (OR 5.90 CI 2.64-13.18, P = 0.00) were more likely to be lost to follow-up. Patients admitted in the service for 7 years or more were also more likely to be to lost to follow-up (OR 2.27 CI 1.2-4.4, P = 0.01), although this association did not remain statistically significant in the multivariate analysis. Although the purpose of the study, to identify individual factors associated to loss to follow-up, positives associations with a specific physician and with patients admitted in the service for 7 years or more suggest organizational factors. Although the majority of patients lost to follow-up in outpatient care were detected by SICLOM, a detectable viral load in most of these patients suggest a quality of outpatient HIV care proved ineffective, despite the availability of cART. We conclude on the need for further studies to investigate structural factors associated to loss to follow-up when enhanced retention strategies should be implemented in order to maintain an effective outpatient HIV care.

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.

A machine learning model to assess potential misdiagnosed dengue hospitalization.

Dengue, like other arboviruses with broad clinical spectra, can easily be misdiagnosed as other infectious diseases due to the overlap of signs and symptoms. During large outbreaks, severe dengue cases have the potential to overwhelm the health care system and understanding the burden of dengue hospitalizations is therefore important to better allocate medical care and public health resources. A machine learning model that used data from the Brazilian public healthcare system database and the National Institute of Meteorology (INMET) was developed to estimate potential misdiagnosed dengue hospitalizations in Brazil. The data was modeled into a hospitalization level linked dataset. Then, Random Forest, Logistic Regression and Support Vector Machine algorithms were assessed. The algorithms were trained by dividing the dataset in training/test set and performing a cross validation to select the best hyperparameters in each algorithm tested. The evaluation was done based on accuracy, precision, recall, F1 score, sensitivity, and specificity. The best model developed was Random Forest with an accuracy of 85% on the final reviewed test. This model shows that 3.4% (13,608) of all hospitalizations in the public healthcare system from 2014 to 2020 could have been dengue misdiagnosed as other diseases. The model was helpful in finding potentially misdiagnosed dengue and might be a useful tool to help public health decision makers in planning resource allocation.

Real world data study of prevalence and direct costs related to dengue management in Brazil's private healthcare from 2015 to 2020.

BACKGROUND: The burden of dengue in Brazil is poorly documented and is based on data from the public health care setting. This study estimated the prevalence and costs of dengue management in the private health care system in Brazil from 2015 to 2020 using a large claims database from Orizon. METHODS: We selected claims with dengue ICD codes (ICD-10 A90 or A91) from January 2015 to December 2020. Prevalence was estimated based on the population enrolled in health insurance plans in the given year. Costs were adjusted for the inflation up to December 2021 and evaluated by measures of central tendency and dispersion. RESULTS: A total of 63,882 unique beneficiaries were included, with a total of 64,186 dengue cases. The year with the highest prevalence was 2015 (1.6% of patients who used health plans), and there was also an increase in cases in 2016 and 2019. The median cost per hospitalization in 2015 was US$486.17, and in 2020, it reached US$696.72. The median cost of a case seen at an emergency room ranged from US$ 97.78 in 2015 to US$ 118.16 in 2017. CONCLUSIONS: The estimated prevalence of dengue in this population of private health-insured patients followed the epidemiological trends of the general population in Brazil, with the highest rates in 2015, 2016, and 2019. The cost of dengue management has increased in the private health care setting over the years.

Validation of a hierarchical deterministic record-linkage algorithm using data from 2 different cohorts of human immunodeficiency virus-infected persons and mortality databases in Brazil.

Loss to follow-up is a major source of bias in cohorts of patients with human immunodeficiency virus (HIV) and could lead to underestimation of mortality. The authors developed a hierarchical deterministic linkage algorithm to be used primarily with cohorts of HIV-infected persons to recover vital status information for patients lost to follow-up. Data from patients known to be deceased in 2 cohorts in Rio de Janeiro, Brazil, and data from the Rio de Janeiro State mortality database for 1999-2006 were used to validate the algorithm. A fully automated procedure yielded a sensitivity of 92.9% and specificity of 100% when no information was missing. When the automated procedure was combined with clerical review, in a scenario of 5% death prevalence and 20% missing mothers' names, sensitivity reached 96.5% and specificity 100%. In a practical application, the algorithm significantly increased death rates and decreased the rate of loss to follow-up in the cohorts. The finding that 23.9% of matched records did not give HIV or acquired immunodeficiency syndrome as the cause of death reinforces the need to search all-cause mortality databases and alerts for possible underestimation of death rates. These results indicate that the algorithm is accurate enough to recover vital status information on patients lost to follow-up in cohort studies.

Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration.

AIMS: To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. METHODS: The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. RESULTS: Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. CONCLUSIONS: Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.

Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2-17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study.

BACKGROUND: Development of vaccines that are effective against all four dengue virus serotypes (DENV-1-4) in all age groups is important. Here, we present 18-month interim data from an ongoing study undertaken to assess the immunogenicity and safety of Takeda's tetravalent dengue vaccine (TDV) candidate over 48 months in children living in dengue-endemic countries. METHODS: We undertook a phase 2, multicentre, randomised, double-blind, placebo-controlled study at three sites in the Dominican Republic, Panama, and the Philippines. We randomly assigned children aged 2-17 years to receive either two TDV doses 3 months apart (group 1), one TDV dose (group 2), one TDV dose and a booster dose 1 year later (group 3), or placebo (group 4). We did the randomisation (1:2:5:1) using an interactive web response system stratified by age. The primary endpoint of this 18-month interim analysis was DENV serotype-specific antibody geometric mean titres (GMTs) in the per-protocol immunogenicity subset on days 1, 28, 91, 180, 365, 393, and 540. Secondary safety endpoints were the proportions of participants with serious adverse events and with virologically confirmed dengue in the safety set, and solicited and unsolicited adverse events in the immunogenicity subset. This trial is registered with ClinicalTrials.gov, number NCT02302066. FINDINGS: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to group 1 (n=201), group 2 (n=398), group 3 (n=1002), and group 4 (n=199). 1794 participants received at least one dose of TDV or placebo (safety set), of whom 562 participated in the immunogenicity subset and 509 were included in the per-protocol set. Antibody titres remained elevated 18 months after vaccination in all TDV groups. At day 540, in groups 1, 2, 3, and 4, respectively, DENV-1 GMTs were 476 (95% CI 286-791), 461 (329-647), 1056 (804-1388), and 92 (49-173); DENV-2 GMTs were 1212 (842-1744), 1242 (947-1628), 1457 (1182-1796), and 177 (93-337); DENV-3 GMTs were 286 (171-478), 298 (205-433), 548 (411-730), and 78 (44-137); and DENV-4 GMTs were 98 (65-150), 102 (75-139), 172 (133-222), and 33 (21-52). Limited differences in GMTs were observed between groups 1 and 2 (in which participants received one and two doses of TDV, respectively). In baseline-seronegative participants, a 1-year booster clearly increased GMTs. Vaccine-related unsolicited adverse events occurred in 14 (2%) of 562 participants, but no vaccine-related serious adverse events arose. Symptomatic, virologically confirmed dengue was recorded in 21 (1·3%) of 1596 participants vaccinated with TDV compared with nine (4·5%) of 198 placebo recipients. INTERPRETATION: TDV was well tolerated and immunogenic against all four dengue serotypes, irrespective of baseline dengue serostatus. These data provide proof of concept for TDV and support the ongoing phase 3 efficacy assessment of two doses 3 months apart. FUNDING: Takeda Vaccines.

Clinical and epidemiological characteristics of yellow fever in Brazil: analysis of reported cases 1998-2002.

Yellow fever (YF), an arboviral infection of major public health importance in Brazil, is associated with high mortality and high epidemic potential. We analysed confirmed YF cases from the National Surveillance System from 1998-2002 and assessed risk factors for death among hospitalised patients. Variables assessed included age, gender, clinical signs and laboratory findings. A logistic regression model was used to identify independent predictors of death among hospitalised patients. From 1998-2002, among 2117 suspected YF cases reported to Brazil's Ministry of Health, 251 (11.9%) had confirmed YF, of whom 217 (86.5%) were hospitalised and the case fatality rate was 44.2%. Factors associated with higher mortality in univariate analysis included male gender (relative risk (RR) 1.96, 95% CI 1.17-2.28), age >40 years (RR 2.61, 95% CI 1.25-5.45), jaundice (RR 2.66, 95% CI 2.12-3.35), serum aspartate aminotransferase (AST) >1200 IU/l (RR 1.84, 95% CI 1.23-2.74), alanine aminotransferase >1500 IU/l (RR 2.09, 95% CI 1.38-3.17), total bilirubin >7.0mg/dl (RR 2.33, 95% CI 1.44-3.78), direct bilirubin >5.0mg/dl (RR 2.29, 95% CI 1.33-3.94) and blood urea nitrogen >100mg/dl (RR 5.77, 95% CI 1.43-23.22). In multivariate analysis, elevated AST and jaundice remained independently associated with higher mortality. These findings suggest that selected clinical and laboratory indicators may help clinicians recognise potentially fatal cases of YF.

Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study.

BACKGROUND: Dengue is the most common mosquito-borne viral disease in human beings, and vector control has not halted its spread worldwide. A dengue vaccine for individuals aged 9 years and older has been licensed, but there remains urgent medical need for a vaccine that is safe and effective against all four dengue virus serotypes (DENV-1-4) in recipients of all ages. Here, we present the preplanned interim analyses at 6 months of a tetravalent dengue vaccine candidate (TDV), which is comprised of an attenuated DENV-2 virus strain (TDV-2) and three chimeric viruses containing the premembrane and envelope protein genes of DENV-1, DENV-3, and DENV-4 genetically engineered into the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4). METHODS: An ongoing phase 2, randomised, double-blind, placebo-controlled trial of a TDV is being done at three sites in dengue-endemic countries (Dominican Republic, Panama, and the Philippines) to determine its safety and immunogenicity over 48 months in healthy participants aged 2-17 years who were randomly assigned (1:2:5:1) using an interactive web response system (stratified by age) to subcutaneous TDV injection (one 0·5 mL dose containing 2·5 × 104 plaque-forming units [PFU] of TDV-1; 6·3 × 103 PFU of TDV-2; 3·2 × 104 PFU of TDV-3; and 4·0 × 105 PFU of TDV-4) in different dose schedules (two-dose regimen at 0 and 3 months, one dose at 0 months, or one dose at 0 months and a booster at 12 months) or placebo. The primary endpoint of this 6 month interim analysis was geometric mean titres (GMTs) of neutralising antibodies against DENV-1-4 in the per-protocol immunogenicity subset at 1 month, 3 months, and 6 months after the first injection. Safety was assessed as a secondary outcome as percentage of participants with serious adverse events in all participants who were injected (safety set), and solicited and unsolicited adverse events (immunogenicity subset). This trial is registered with ClinicalTrials.gov, number NCT02302066. FINDINGS: 1800 participants were enrolled between Dec 5, 2014, and Feb 13, 2015. 1794 participants were given study injection as follows: 200 participants were given two-dose regimen at 0 and 3 months (group 1), 398 were given one dose at 0 months (group 2), 998 were given one dose at 0 months and will be given (trial ongoing) a booster at 12 months (group 3), and 198 were given placebo (group 4). These 1794 participants were included in the safety set; 562 participants were randomly assigned to the immunogenicity subset, of which 503 were included in the per-protocol set. TDV elicited neutralising antibodies against all DENV serotypes, which peaked at 1 month and remained elevated above baseline at 6 months. At 6 months, GMTs of neutralising antibodies against DENV-1 were 489 (95% CI 321-746) for group 1, 434 (306-615) for group 2, 532 (384-738) for group 3, and 62 (32-120) for group 4; GMTs of neutralising antibodies against DENV-2 were 1565 (1145-2140) for group 1, 1639 (1286-2088) for group 2, 1288 (1031-1610) for group 3, and 86 (44-169) for group 4; GMTs of neutralising antibodies against DENV-3 were 160 (104-248) for group 1, 151 (106-214) for group 2, 173 (124-240) for group 3, and 40 (23-71) for group 4; and GMTs of neutralising antibodies against DENV-4 were 117 (79-175) for group 1, 110 (80-149) for group 2, 93 (69-125) for group 3, and 24 (15-38) for group 4. No vaccine-related serious adverse events occurred; 15 (3%) of 562 participants in the immunogenicity subset reported vaccine-related unsolicited adverse events. The reactogenicity profile of TDV was acceptable, and similar to previous findings with TDV. INTERPRETATION: TDV is safe and immunogenic in individuals aged 2-17 years, irrespective of previous dengue exposure. A second TDV dose induced enhanced immunogenicity against DENV-3 and DENV-4 in children who were seronegative before vaccination. These data supported the initiation of phase 3 evaluation of the efficacy and safety of TDV given in a two-dose schedule 3 months apart, with analyses that take into account baseline age and dengue serostatus. FUNDING: Takeda Vaccines.

Operational research principles for a routine service process for monitoring the human immunodeficiency virus/acquired immunodeficiency syndrome treatment cascade: data from a cohort in Brazil.

INTRODUCTION:: Bottlenecks still exist during human immunodeficiency virus care that may delay the achievement of better outcomes. METHODS:: We established a monitoring system to trace patients throughout the human immunodeficiency virus/acquired immunodeficiency syndrome care process in Juiz de Fora, Brazil, to identify potential bottlenecks. RESULTS:: Among 250 patients, 17.6% abandoned follow-up. Our monitoring system tracked 86.4% of patients through the medication logistics control system and 2.3% through the mortality information system. Two percent of patients were not located by our monitoring system. CONCLUSIONS:: A pathway care process contributes to a better understanding of the barriers to the treatment cascade.

Real world data study of prevalence and direct costs related to dengue management in Brazil's private healthcare from 2015 to 2020

ABSTRACT Background: The burden of dengue in Brazil is poorly documented and is based on data from the public health care setting. This study estimated the prevalence and costs of dengue management in the private health care system in Brazil from 2015 to 2020 using a large claims database from Orizon. Methods: We selected claims with dengue ICD codes (ICD-10 A90 or A91) from January 2015 to December 2020. Prevalence was estimated based on the population enrolled in health insurance plans in the given year. Costs were adjusted for the inflation up to December 2021 and evaluated by measures of central tendency and dispersion. Results: A total of 63,882 unique beneficiaries were included, with a total of 64,186 dengue cases. The year with the highest prevalence was 2015 (1.6% of patients who used health plans), and there was also an increase in cases in 2016 and 2019. The median cost per hospitalization in 2015 was US$486.17, and in 2020, it reached US$696.72. The median cost of a case seen at an emergency room ranged from US$ 97.78 in 2015 to US$ 118.16 in 2017. Conclusions: The estimated prevalence of dengue in this population of private health-insured patients followed the epidemiological trends of the general population in Brazil, with the highest rates in 2015, 2016, and 2019. The cost of dengue management has increased in the private health care setting over the years.

A cross-sectional study assessing the pharyngeal carriage of Neisseria meningitidis in subjects aged 1-24 years in the city of Embu das Artes, São Paulo, Brazil.

Meningococcal carriage is a prerequisite for invasive infection. This cross-sectional study assessed the pharyngeal carriage prevalence in healthy subjects aged 1-24 years in Embu das Artes city, São Paulo, Brazil. Pharyngeal swabs were examined for the presence of Neisseria meningitidis. The isolates were tested for different serogroups using agglutination and polymerase chain reaction. A logistic regression model assessed any independent association between Neisseria meningitidis carriage and various risk factors. A total of 87/967 subjects (9%, 95% Confidence Interval (CI): 7.3-11.0) tested positive for N. meningitidis: 6.2% (95% CI: 3.8-9.4) in 1-4 years, 8.5% (95% CI: 5.1-13.0) in 5-9 years, 12.5% (95% CI: 7.8-18.6) in 10-14 years, 12.6% (95% CI: 7.4-19.7) in 15-19 years and 9% (95% CI: 4.9-14.9) in 20-24 years age groups. Highest carriage prevalence was observed in adolescents 10-19 years old. Serogroup C was predominant (18.4%) followed by serogroup B (12.6%). The 15-19 years age group showed a significant association between number of household members and carriers of N. meningitidis. This cross-sectional study is the first in Brazil to evaluate meningococcal carriage prevalence and associated factors in a wide age range.

Sustained Decrease in Gastroenteritis-related Deaths and Hospitalizations in Children Less Than 5 Years of Age After the Introduction of Rotavirus Vaccination: A Time-Trend Analysis in Brazil (2001-2010).

BACKGROUND: Rotavirus (RV) vaccine, Rotarix, was introduced into the Brazil national immunization program in 2006. To estimate population-level vaccine effect, we conducted a time-trend analysis on all-cause gastroenteritis (GE)-related death certificate-reported deaths (DCRDs), hospital deaths (HDs) and hospitalizations trends in <5-year-olds before and after RV vaccine introduction. METHODS: National level all-cause GE-related death certificate [Mortality Information System] and admission (Hospital Information System) data were aggregated and analyzed. Negative-binomial regression models (adjusting for age, year and region) compared DCRDs, HDs and hospitalization trends in <5-year-olds between baseline (2001-2005) and postvaccine introduction periods (Mortality Information System: 2007-2009 and Hospital Information System: 2007-2010). Negative-binomial regression models were fitted to data for each outcome before 2006, and the predicted annual frequencies of each outcome were plotted against corresponding observed annual frequencies. RESULTS: During the postvaccine introduction period, there was an overall age-independent GE-related DCRDs reduction (20.9%, P = 0.04) observed in children <5 years of age; a reduction was also seen in infants <1 year of age (20.8%, P = 0.003). Age-independent GE-related HDs and hospitalizations reductions (57.1%, P < 0.0001 and 26.6%, P < 0.0001, respectively) were observed in <5-year-olds; HDs reductions were also observed for each age group (<1-year-olds: 55.0%, P < 0.0001 and 1- to <5-year-olds: 59.5%, P < 0.0001). Observed annual frequencies of GE-related DCRDs, HDs and hospitalizations were lower than the predicted value in each age group in all years after 2006. CONCLUSIONS: GE-related DCRDs, HDs and hospitalizations were significantly reduced in <1 and in 1- to <5-year-old Brazilian children after Rotarix introduction, which provides additional evidence of the direct and indirect population-level effect of RV vaccination on GE-related mortality and morbidity in children.

Continuous increase of cardiovascular diseases, diabetes, and non-HIV related cancers as causes of death in HIV-infected individuals in Brazil: an analysis of nationwide data.

INTRODUCTION: After antiretroviral therapy (ART) became available, there was a decline in the number of deaths in persons infected with HIV. Thereafter, there was a decrease in the proportion of deaths attributed to opportunistic infections and an increase in the proportion of deaths attributed to chronic comorbidities. Herein we extend previous observations from a nationwide survey on temporal trends in causes of death in HIV-infected patients in Brazil. METHODS: We describe temporal trends in causes of death among adults who had HIV/AIDS listed in the death certificate to those who did not. All death certificates issued in Brazil from 1999 to 2011 and listed in the national mortality database were included. Generalized linear mixed-effects logistic models were used to study temporal trends in proportions. RESULTS: In the HIV-infected population, there was an annual adjusted average increase of 6.0%, 12.0%, 4.0% and 4.1% for cancer, external causes, cardiovascular diseases (CVD) and diabetes mellitus (DM), respectively, compared to 3.0%, 4.0%, 1.0% and 3.9%, in the non-HIV group. For tuberculosis (TB), there was an adjusted average increase of 0.3%/year and a decrease of 3.0%/year in the HIV and the non-HIV groups, respectively. Compared to 1999, the odds ratio (OR) for cancer, external causes, CVD, DM, or TB in the HIV group were, respectively, 2.31, 4.17, 1.76, 2.27 and 1.02, while for the non-HIV group, the corresponding OR were 1.31, 1.63, 1.14, 1.62 and 0.67. Interactions between year as a continuous or categorical variable and HIV were significant (p<0.001) for all conditions, except for DM when year was considered as a continuous variable (p = 0.76). CONCLUSIONS: Non HIV-related co-morbidities continue to increase more rapidly as causes of death among HIV-infected individuals than in those without HIV infection, highlighting the need for targeting prevention measures and surveillance for chronic diseases among those patients.

Operational research principles for a routine service process for monitoring the human immunodeficiency virus/acquired immunodeficiency syndrome treatment cascade: data from a cohort in Brazil

Abstract INTRODUCTION: Bottlenecks still exist during human immunodeficiency virus care that may delay the achievement of better outcomes. METHODS: We established a monitoring system to trace patients throughout the human immunodeficiency virus/acquired immunodeficiency syndrome care process in Juiz de Fora, Brazil, to identify potential bottlenecks. RESULTS: Among 250 patients, 17.6% abandoned follow-up. Our monitoring system tracked 86.4% of patients through the medication logistics control system and 2.3% through the mortality information system. Two percent of patients were not located by our monitoring system. CONCLUSIONS: A pathway care process contributes to a better understanding of the barriers to the treatment cascade.

A cross-sectional study assessing the pharyngeal carriage of Neisseria meningitidis in subjects aged 1-24 years in the city of Embu das Artes, São Paulo, Brazil

ABSTRACT Meningococcal carriage is a prerequisite for invasive infection. This cross-sectional study assessed the pharyngeal carriage prevalence in healthy subjects aged 1-24 years in Embu das Artes city, São Paulo, Brazil. Pharyngeal swabs were examined for the presence of Neisseria meningitidis. The isolates were tested for different serogroups using agglutination and polymerase chain reaction. A logistic regression model assessed any independent association between Neisseria meningitidis carriage and various risk factors. A total of 87/967 subjects (9%, 95% Confidence Interval (CI): 7.3-11.0) tested positive for N. meningitidis: 6.2% (95% CI: 3.8-9.4) in 1-4 years, 8.5% (95% CI: 5.1-13.0) in 5-9 years, 12.5% (95% CI: 7.8-18.6) in 10-14 years, 12.6% (95% CI: 7.4-19.7) in 15-19 years and 9% (95% CI: 4.9-14.9) in 20-24 years age groups. Highest carriage prevalence was observed in adolescents 10-19 years old. Serogroup C was predominant (18.4%) followed by serogroup B (12.6%). The 15-19 years age group showed a significant association between number of household members and carriers of N. meningitidis. This cross-sectional study is the first in Brazil to evaluate meningococcal carriage prevalence and associated factors in a wide age range.