A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian–Pacific and Latin American countries. This article in the New England Journal of Medicine reports the results of long-term follow-up interim analyses and integrated efficacy analyses. Abstract A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian–Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses. We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15. Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and 19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the 4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group. Pooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5) for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older, and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age. Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up, the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group.

28th July 2015 • comment

These findings suggest that the 2013 dengue epidemic in Angola was larger than indicated by passive surveillance data. Abstract During the 2013 dengue epidemic in Luanda, Angola, 811 dengue rapid diagnostic test-positive cases were reported to the Ministry of Health. To better understand the magnitude of the epidemic and identify risk factors for dengue virus (DENV) infection, we conducted cluster surveys around households of case-patients and randomly selected households 6 weeks after the peak of the epidemic. Of 173 case cluster participants, 16 (9%) exhibited evidence of recent DENV infection. Of 247 random cluster participants, 25 (10%) had evidence of recent DENV infection. Of 13 recently infected participants who had a recent febrile illness, 7 (54%) had sought medical care, and 1 (14%) was hospitalized with symptoms consistent with severe dengue; however, none received a diagnosis of dengue. Behavior associated with protection from DENV infection included recent use of mosquito repellent or a bed net. These findings suggest that the 2013 dengue epidemic was larger than indicated by passive surveillance data.

23rd July 2015 • comment

The increasing burden of dengue, and the relative failure of traditional vector control programs highlight the need to develop new control methods. SIT using self-limiting genetic technology is one such promising method. Abstract The increasing burden of dengue, and the relative failure of traditional vector control programs highlight the need to develop new control methods. SIT using self-limiting genetic technology is one such promising method. A self-limiting strain of Aedes aegypti, OX513A, has already reached the stage of field evaluation. Sustained releases of OX513A Ae. aegypti males led to 80% suppression of a target wild Ae. aegypti population in the Cayman Islands in 2010. Here we describe sustained series of field releases of OX513A Ae. aegypti males in a suburb of Juazeiro, Bahia, Brazil. This study spanned over a year and reduced the local Ae. aegypti population by 95% (95% CI: 92.2%-97.5%) based on adult trap data and 81% (95% CI: 74.9-85.2%) based on ovitrap indices compared to the adjacent no-release control area. The mating competitiveness of the released males (0.031; 95% CI: 0.025-0.036) was similar to that estimated in the Cayman trials (0.059; 95% CI: 0.011 - 0.210), indicating that environmental and target-strain differences had little impact on the mating success of the OX513A males. We conclude that sustained release of OX513A males may be an effective and widely useful method for suppression of the key dengue vector Ae. aegypti. The observed level of suppression would likely be sufficient to prevent dengue epidemics in the locality tested and other areas with similar or lower transmission.

14th July 2015 • comment

Academics in Germany, the US, Singapore and Sweden ask whether Dengue is still a 'neglected tropical disease'. Abstract Dengue is currently listed as a "neglected tropical disease" (NTD). But is dengue still an NTD or not? Classifying dengue as an NTD may carry advantages, but is it justified? This review considers the criteria for the definition of an NTD, the current diverse lists of NTDs by different stakeholders, and the commonalities and differences of dengue with other NTDs. We also review the current research gaps and research activities and the adequacy of funding for dengue research and development (R&D) (2003-2013). NTD definitions have been developed to a higher precision since the early 2000s, with the following main features: NTDs are characterised as a) poverty related, b) endemic to the tropics and subtropics, c) lacking public health attention, d) having poor research funding and shortcomings in R&D, e) usually associated with high morbidity but low mortality, and f) often having no specific treatment available. Dengue meets most of these criteria, but not all. Although dengue predominantly affects resource-limited countries, it does not necessarily only target the poor and marginalised in those countries. Dengue increasingly attracts public health attention, and in some affected countries it is now a high profile disease. Research funding for dengue has increased exponentially in the past two decades, in particular in the area of dengue vaccine development. However, despite advances in dengue research, dengue epidemics are increasing in frequency and magnitude, and dengue is expanding to new areas. Specific treatment and a highly effective vaccine remain elusive. Major research gaps exist in the area of integrated surveillance and vector control. Hence, although dengue differs from many of the NTDs, it still meets important criteria commonly used for NTDs. The current need for increased R&D spending, shared by dengue and other NTDs, is perhaps the key reason why dengue should continue to be considered an NTD.

4th May 2015 • comment

Abstract The increasing population of Aedes aegypti mosquitoes on Madeira Island (Portugal) resulted in the first autochthonous dengue outbreak, which occurred in October 2012. Our study establishes the first genetic evaluation based on the mitochondrial DNA (mtDNA) genes [cytochrome oxidase subunit I (COI) and NADH dehydrogenase subunit 4 (ND4)] and knockdown resistance ( kdr ) mutations exploring the colonisation history and the genetic diversity of this insular vector population. We included mosquito populations from Brazil and Venezuela in the analysis as putative geographic sources. The Ae. aegypti population from Madeira showed extremely low mtDNA genetic variability, with a single haplotype for COI and ND4. We also detected the presence of two important kdr mutations and the quasi-fixation of one of these mutations (F1534C). These results are consistent with a unique recent founder event that occurred on the island of Ae. aegypti mosquitoes that carry kdr mutations associated with insecticide resistance. Finally, we also report the presence of the F1534C kdr mutation in the Brazil and Venezuela populations. To our knowledge, this is the first time this mutation has been found in South American Ae. aegypti mosquitoes. Given the present risk of Ae. aegypti re-invading continental Europe from Madeira and the recent dengue outbreaks on the island, this information is important to plan surveillance and control measures.

17th March 2015 • comment
3rd February 2015 • comment

The Mekong Delta is vulnerable to climate change and dengue incidence. Research points to a positive association between dengue incidence and temperature and humidity. Poisson model affords the best prediction of dengue incidence for a-year period; the SARIMA model affords good prediction of dengue incidence for a 3-month period; the simple multiple model affords an inaccurate prediction of dengue incidence. Abstract The Mekong Delta is highly vulnerable to climate change and a dengue endemic area in Vietnam. This study aims to examine the association between climate factors and dengue incidence and to identify the best climate prediction model for dengue incidence in Can Tho city, the Mekong Delta area in Vietnam. We used three different regression models comprising: standard multiple regression model (SMR), seasonal autoregressive integrated moving average model (SARIMA), and Poisson distributed lag model (PDLM) to examine the association between climate factors and dengue incidence over the period 2003–2010. We validated the models by forecasting dengue cases for the period of January–December, 2011 using the mean absolute percentage error (MAPE). Receiver operating characteristics curves were used to analyze the sensitivity of the forecast of a dengue outbreak. The results indicate that temperature and relative humidity are significantly associated with changes in dengue incidence consistently across the model methods used, but not cumulative rainfall. The Poisson distributed lag model (PDLM) performs the best prediction of dengue incidence for a 6, 9, and 12-month period and diagnosis of an outbreak however the SARIMA model performs a better prediction of dengue incidence for a 3-month period. The simple or standard multiple regression performed highly imprecise prediction of dengue incidence. We recommend a follow-up study to validate the model on a larger scale in the Mekong Delta region and to analyze the possibility of incorporating a climate-based dengue early warning method into the national dengue surveillance system.

29th January 2015 • comment

A new class of antibody found in the blood of patients with dengue fever has boosted hopes for a vaccine against the virus, which debilitates millions and kills tens of thousands each year. Cases of dengue fever have soared in the past 50 years to nearly 100 million a year as improved transport and urbanisation have brought more people into contact with the mosquito-borne virus.

13th January 2015 • comment

Dengue is the most common arthropod-borne infection worldwide, affecting at least 50 million people every year and endemic in more than 100 countries. The dengue virus is a single-stranded RNA virus with four major serotypes. Infection with one serotype confers homotypic immunity but not heterologous immunity, and secondary infection with another serotype may lead to more severe disease.

7th November 2014 • comment

A phase 3, randomised, observer-masked, placebo-controlled trial of a new tetravalent vaccine against dengue fever. Abstract Background: 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. Methods: 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. Findings: 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. Interpretation: 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.

7th November 2014 • comment

Japan reported more patients with dengue fever after last week finding the country’s first domestic cases of the mosquito-borne disease since the 1940s. Nineteen people in Japan have been confirmed to have dengue fever in addition to the three cases confirmed last month, public broadcaster NHK reported today, citing the nation’s health ministry.

1st September 2014 • comment

    • Risk of dengue fever in Europe is likely to increase, researchers claim Dengue is a viral infection carried and spread by mosquitoes thrive in warm, humid conditions, which could include areas in Europe. This is dependent on climate change continuing on its current trajectory Italy's Po Valley and areas in southern Spain are at risk. University of East Anglia's research is based on data collected in Mexico

25th August 2014 • comment
22nd August 2014 • comment
19th August 2014 • comment

Abstract Objective: To describe the mortality of dengue in Mexico during 1980 to 2009. Method: Dengue mortality data for Mexico were obtained from Instituto Nacional de Estadistica, Geografía e Informática. We used standardized and non-standardized dengue mortality rates per 1,000,000 people and determined the mortality trend. The groups were based on International Classification of Diseases coding criteria (ICD-9 E061 and ICD-10 A91X). The results were stratified by age groups and the frequencies of dengue deaths were compared using relative risk (RR) with its 95% confidence interval. Results: During 1980 to 2009 in Mexico, 549 deaths due to dengue were reported. We found an important variation in the mortality rates during the years studied. We were able to identify three periods: 1980 to 1992, 1994 to 2000, and 2001 to 2009. The mortality rates found are from 0.88/1,000,000 through 0.00/1,000,000. The average mortality rates by decade: 1980 to 1989: 0.53/1,000,000; 1990 to 1999: 0.06/1,000,000; 2000 to 2009: 0.12/1,000,000. In the analysis of mortality by community size during 2000 to 2009, we observed in the small communities with less than 2499 people, the risk is 1.25 times higher than in those with more than 20,000 people. Conclusions: We found, in general, a sustained decline in the number of deaths by dengue over the last 30 years in Mexico. However, a slow increase was observed since 1994, which may be related to the circulation of DENV2 and DENV3, among other factors. We need to strengthen prevention programs in smaller communities (<2499) where we found a higher risk of mortality due to dengue.

8th July 2014 • comment

Article looks at the risk of dengue fever outbreaks in southern Europe as temperatures increase. Abstract Background Dengue fever is the most prevalent mosquito-borne viral disease worldwide. Dengue transmission is critically dependent on climatic factors and there is much concern as to whether climate change would spread the disease to areas currently unaffected. The occurrence of autochthonous infections in Croatia and France in 2010 has raised concerns about a potential re-emergence of dengue in Europe. The objective of this study is to estimate dengue risk in Europe under climate change scenarios. Methods We used a Generalized Additive Model (GAM) to estimate dengue fever risk as a function of climatic variables (maximum temperature, minimum temperature, precipitation, humidity) and socioeconomic factors (population density, urbanisation, GDP per capita and population size), under contemporary conditions (1985–2007) in Mexico. We then used our model estimates to project dengue incidence under baseline conditions (1961–1990) and three climate change scenarios: short-term 2011–2040, medium-term 2041–2070 and long-term 2071–2100 across Europe. The model was used to calculate average number of yearly dengue cases at a spatial resolution of 10 × 10 km grid covering all land surface of the currently 27 EU member states. To our knowledge, this is the first attempt to model dengue fever risk in Europe in terms of disease occurrence rather than mosquito presence. Results The results were presented using Geographical Information System (GIS) and allowed identification of areas at high risk. Dengue fever hot spots were clustered around the coastal areas of the Mediterranean and Adriatic seas and the Po Valley in northern Italy. Conclusions This risk assessment study is likely to be a valuable tool assisting effective and targeted adaptation responses to reduce the likely increased burden of dengue fever in a warmer world.

9th March 2014 • comment

Using Wolbachia for dengue control may have an unintended consequences in that this study appeas to show that higher West Nile Virus infection rates in Wolbachia-infected mosquitoes.  The authors suggest that caution should be applied before releasing Wolbachia-infected insects as part of a vector-borne disease control programme. Abstract Novel strategies are required to control mosquitoes and the pathogens they transmit. One attractive approach involves maternally inherited endosymbiotic Wolbachia bacteria. After artificial infection with Wolbachia, many mosquitoes become refractory to infection and transmission of diverse pathogens. We evaluated the effects of Wolbachia (wAlbB strain) on infection, dissemination and transmission of West Nile virus (WNV) in the naturally uninfected mosquito Culex tarsalis, which is an important WNV vector in North America. After inoculation into adult female mosquitoes, Wolbachia reached high titers and disseminated widely to numerous tissues including the head, thoracic flight muscles, fat body and ovarian follicles. Contrary to other systems, Wolbachia did not inhibit WNV in this mosquito. Rather, WNV infection rate was significantly higher in Wolbachia-infected mosquitoes compared to controls. Quantitative PCR of selected innate immune genes indicated that REL1 (the activator of the antiviral Toll immune pathway) was down regulated in Wolbachia-infected relative to control mosquitoes. This is the first observation of Wolbachia-induced enhancement of a human pathogen in mosquitoes, suggesting that caution should be applied before releasing Wolbachia-infected insects as part of a vector-borne disease control program.

9th March 2014 • comment