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An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children. We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2–14 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281. We randomly assigned 10 275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56·5% (95% CI 43·8–66·4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries. Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2–14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit. Sanofi Pasteur.

The public health burden of dengue is unknown; here cartographic approaches are used to provide insight into the global, regional and national burden of dengue, with the finding that the global number of infections per year is around 390 million, more than three times the estimate of the World Health Organization. Mapping the spread of dengue The mosquito-borne viral infection dengue is found in tropical and subtropical regions worldwide, predominantly in urban and semi-urban areas. The incidence of dengue is on the increase, but the current global distribution is poorly known. Simon Hay and colleagues have applied novel mapping techniques to an extensive evidence base of nearly 10,000 case records. The outcome is an estimate of around 390 million new infections per year, more than double the most recent estimate from the World Health Organization. Importantly, this work extends the mapping to provide global estimates of the symptomatic and asymptomatic dengue case burden, at 96 and 294 million, respectively. Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes 1 . For some patients, dengue is a life-threatening illness 2 . There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread 3 . The contemporary worldwide distribution of the risk of dengue virus infection 4 and its public health burden are poorly known 2 , 5 . Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284–528) dengue infections per year, of which 96 million (67–136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization 2 . Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

Roughly half the world's population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4–11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI −13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. Sanofi Pasteur.

After 55 years of absence, dengue has re-emerged in the WHO European region both as locally transmitted sporadic cases and as an outbreak in Madeira, driven by the introduction of people infected with the virus and the invasion of the vector mosquito species Aedes aegypti and Aedes albopictus. Models predict a further spread of A albopictus, particularly under climate change conditions. Dengue transmission models suggest a low risk in Europe, but these models too rarely include transmission by A albopictus (the main established vector). Further information gaps exist with regard to the Caucasus and central Asian countries of the WHO European region. Many European countries have implemented surveillance and control measures for invasive mosquitoes, but only a few include surveillance for dengue. As long as no dengue-specific prophylaxis or therapeutics are available, integrated vector management is the most sustainable control option. The rapid elimination of newly introduced A aegypti populations should be targeted in the European region, particularly in southern Europe and the Caucasus, where the species was present for decades until the 1950s.

Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18–45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov, number NCT01224639. We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. Takeda Vaccines.

Dengue, a viral infection transmitted by Aedes mosquitoes, is an emerging global health threat exacerbated by climate change. Rising temperatures and altered precipitation patterns create favourable conditions for vector proliferation and extended transmission periods, increasing the risk of dengue in endemic regions and facilitating its spread to non-endemic areas. Understanding the interplay between critical genetic factors and dengue susceptibility is crucial for developing effective public health strategies. The Human Leukocyte Antigen (HLA) genes encode proteins essential for an effective immune response against pathogens, and their genetic variations influence susceptibility to severe dengue. In this study, we conducted a comprehensive meta-analysis of HLA alleles associated with dengue infection and dengue severity. We analysed 19 case-control studies on dengue infections in populations worldwide to infer HLA associations with various pathological forms of dengue and to examine differences across different populations. Our findings indicate that HLA-A*02 increases susceptibility to dengue fever (DF), while HLA-A*03 increases the risk of Dengue Haemorrhagic Fever (DHF), with these increased susceptibilities primarily observed in Southeast Asian populations. Additionally, HLA-A*24 is associated with DHF and all symptomatic dengue infections (DEN), contributing to dengue risk in both Southeast Asia and the Caribbean. Conversely, HLA-A*33 and HLA-B*44 show a protective effect against DHF but show significant regional heterogeneity, highlighting divergent, population-specific susceptibility profiles. This study underscores the importance of population-specific genetic risk assessments for dengue infection and emphasizes the need for targeted medical interventions and improved predictive models to mitigate dengue’s impact, especially as climate change accelerates disease spread.

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

Background. Antibodies induced by infection with any 1 of 4 dengue virus (DENV) serotypes (DENV-1-4) may influence the clinical outcome of subsequent heterologous infections. To quantify potential cross-protective effects, we estimated disease risk as a function of DENV infection, using data from longitudinal studies performed from September 2006 through February 2011 in Iquitos, Peru, during periods of DENV-3 and DENV-4 transmission. Methods. DENV infections before and during the study period were determined by analysis of serial serum samples with virus neutralization tests. Third and fourth infections were classified as postsecondary infections. Dengue fever cases were detected by door-to-door surveillance for acute febrile illness. Results. Among susceptible participants, 39% (420/1077) and 53% (1595/2997) seroconverted to DENV-3 and DENV-4, respectively. Disease was detected in 7% of DENV-3 infections and 10% of DENV-4 infections. Disease during postsecondary infections was reduced by 93% for DENV-3 and 64% for DENV-4, compared with primary and secondary infections. Despite lower disease rates, postsecondary infections constituted a significant proportion of apparent infections (14% [for DENV-3 infections], 45% [for DENV-4 infections]). Conclusions. Preexisting heterotypic antibodies markedly reduced but did not eliminate the risk of disease in this study population. These results improve understanding of how preinfection history can be associated with dengue outcomes and DENV transmission dynamics.

Background Increases in human population size, dengue vector-density and human mobility cause rapid spread of dengue virus in Indonesia. We investigated the changes in dengue haemorrhagic fever (DHF) incidence in Indonesia over a 45-year period and determined age-specific trends in annual DHF incidence. Methods Using an on-going nationwide dengue surveillance program starting in 1968, we evaluated all DHF cases and related deaths longitudinally up to 2013. Population demographics were used to calculate annual incidence and case fatality ratios (CFRs). Age-specific data on DHF available from 1993 onwards were used to assess trends in DHF age-distribution. Time-dependency of DHF incidence and CFRs was assessed using the Cochrane-Armitage trend test. Results The annual DHF incidence increased from 0.05/100,000 in 1968 to ~ 35-40/100,000 in 2013, with superimposed epidemics demonstrating a similar increasing trend with the highest epidemic occurring in 2010 (85.70/100,000; p < 0.01). The CFR declined from 41% in 1968 to 0.73% in 2013 (p < 0.01). Mean age of DHF cases increased during the observation period. Highest incidence of DHF was observed among children aged 5 to 14 years up to 1998, but declined thereafter (p < 0.01). In those aged 15 years or over, DHF incidence increased (p < 0.01) and surpassed that of 5 to 14 year olds from 1999 onwards. Conclusions Incidence of DHF over the past 45 years in Indonesia increased rapidly with peak incidence shifting from young children to older age groups. The shifting age pattern should have consequences for targeted surveillance and prevention.

Dengue is a mosquito-borne disease of growing global health importance. Prevention efforts focus on mosquito control, with limited success. New insights into the spatiotemporal drivers of dengue dynamics are needed to design improved disease-prevention strategies. Given the restricted range of movement of the primary mosquito vector, Aedes aegypti , local human movements may be an important driver of dengue virus (DENV) amplification and spread. Using contact-site cluster investigations in a case-control design, we demonstrate that, at an individual level, risk for human infection is defined by visits to places where contact with infected mosquitoes is likely, independent of distance from the home. Our data indicate that house-to-house human movements underlie spatial patterns of DENV incidence, causing marked heterogeneity in transmission rates. At a collective level, transmission appears to be shaped by social connections because routine movements among the same places, such as the homes of family and friends, are often similar for the infected individual and their contacts. Thus, routine, house-to-house human movements do play a key role in spread of this vector-borne pathogen at fine spatial scales. This finding has important implications for dengue prevention, challenging the appropriateness of current approaches to vector control. We argue that reexamination of existing paradigms regarding the spatiotemporal dynamics of DENV and other vector-borne pathogens, especially the importance of human movement, will lead to improvements in disease prevention.