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\"This book presents the first historical study of dengue fever epidemics from the 18th century to today and examines how the virus has become a pervasive global threat. Through a series of city-focused chapters, Packard reveals how social, economic, and ecological factors have shaped dengue's spread and responses to its outbreaks\"-- Provided by publisher.

It is estimated that there are 390 million cases of dengue virus infection each year. In this double-blind, placebo-controlled trial, a tetravalent dengue vaccine was evaluated in 20,071 children. The vaccine was found to be 80% effective in preventing dengue infection.

Dengue is a mosquito-borne viral illness that causes hundreds of millions of infections each year. No specific therapy exists. In this randomized, controlled trial involving Latin American children, a tetravalent dengue vaccine showed significant protective efficacy. Dengue is a mosquito-borne disease that is present in many parts of the world. From 2003 through 2013, the number of dengue cases that were reported to the Pan American Health Organization (PAHO) increased by a factor of five. 1 – 3 The disease is caused by one of four closely related virus serotypes from the genus flavivirus. Mosquitoes that transmit the virus are present in tropical and subtropical regions worldwide and in some temperate areas of the United States, Europe, Africa, and the Middle East. 4 Dengue is an increasing public health problem despite efforts to manage epidemics through vector control. 5 Several . . .

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.

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2–14 y (CYD14) and 9–16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenicmatch between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.

Development of a vaccine to prevent dengue infection is an unmet global need. In this report, further data on the safety and efficacy from two phase 3 trials of a tetravalent dengue vaccine are presented. A recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has been assessed in two phase 3 randomized efficacy trials involving more than 31,000 children between the ages of 2 and 14 years in the Asian–Pacific region (CYD14 trial) and between the ages of 9 and 16 years in Latin America (CYD15 trial). 1 , 2 The vaccine was administered in three doses: at baseline, at 6 months, and at 12 months. Vaccine efficacy against virologically confirmed dengue and safety were assessed during a 25-month efficacy surveillance phase (i.e., until 13 months after the third dose was administered). Reactogenicity and immunogenicity were also assessed . . .

The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development. Multivalent vaccines that confer protection to multiple serotypes of Dengue virus have been established. Here the authors examine the presence of vaccine induced multivalent antibodies and how these link to protection in a human challenge model of Dengue virus.

In this cluster-randomized trial conducted in Indonesia, deployment of mosquitoes infected with the w Mel strain of Wolbachia pipientis resulted in fewer symptomatic, virologically confirmed dengue infections and hospitalizations among residents.

Dengue viruses (DENV1–4) cause dengue fever and dengue hemorrhagic fever. Developing a live attenuated tetravalent dengue vaccine (LATDV) faces challenges in overcoming viral interference to induce a balanced immune response. KD-382 is an LATDV candidate being developed by KM Biologics Co., Ltd. for dengue prevention. This first-in-human Phase I study of KD-382 is a randomized, placebo-controlled, double-blind, ascending-dose study in 60 flavivirus antibody-naïve healthy subjects aged 18–65 years. The study was conducted in two parts evaluating low dose (Part 1) and standard dose (Part 2). In each part, subjects were randomized in a 3:2:1 ratio to receive either KD-382 as a single dose, two doses, or placebo. Subjects received subcutaneous injections on Days 1 and 29 and were followed up for 1 year. Eight (Part 1: 3; Part 2: 5) of 60 vaccinated subjects were withdrawn from the study. Both low and standard doses of KD-382, regardless of the dosing regimen, showed a 100 % seroconversion rate for all four serotypes (DENV1–4) at Day 57 and retained 100 % seropositivity for DENV1, 2, and 4 through the 12-month follow-up. For DENV3, a single dose in the low dose group of KD-382 retained a 100 % seroconversion rate at Months 3 and 12, while in the standard dose group, it was 91.7 % at Month 12. The most frequently reported solicited local treatment-emergent adverse events (TEAEs) were erythema, followed by pain and injection site pruritus; solicited systemic TEAEs were fatigue, followed by headache and myalgia. No serious or severe solicited TEAEs, or TEAEs leading to study vaccine withdrawal or death were reported. KD-382 was safe and well-tolerated in flavivirus antibody-naïve healthy subjects. It elicited a long-lasting neutralizing antibody response for all four DENV serotypes during the 1-year follow-up, even with single-dose administration. Australia New Zealand Clinical Trial Registry: ACTRN12618001027202.

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.