As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see ‘Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101’). Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011. Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers. Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts. Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year. More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence. Mortality data were extremely sparse and generally represent hospital-based deaths only. Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year. Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis. These data should help to define control strategies and reinforce leishmaniasis advocacy.

Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.

BACKGROUND Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.” METHODS We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, −4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123.)

Zika virus (ZIKV) is causing an explosive outbreak of febrile disease in the Americas. There are no effective antiviral therapies or licensed vaccines for this virus, and mosquito control strategies have not been adequate to contain the virus. A promising candidate for arbovirus control and prevention relies on the introduction of the intracellular bacterium Wolbachia into Aedes aegypti mosquitoes. This primarily has been proposed as a tool to control dengue virus (DENV) transmission; however, evidence suggests Wolbachia infections confer protection for Ae. aegypti against other arboviruses. At present, it is unknown whether or not ZIKV can infect, disseminate, and be transmitted by Wolbachia-infected Ae. aegypti. Using Ae. aegypti infected with the wMel strain of Wolbachia that are being released in Medellin, Colombia, we report that these mosquitoes have reduced vector competence for ZIKV. These results support the use of Wolbachia biocontrol as a multivalent strategy against Ae. aegypti-transmitted viruses.

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BackgroundNew approaches to preventing chikungunya virus (CHIKV) are needed because current methods are limited to controlling mosquito populations, and they have not prevented the invasion of this virus into new locales, nor have they been sufficient to control the virus upon arrival. A promising candidate for arbovirus control and prevention relies on the introduction of the intracellular bacterium Wolbachia into Aedes aegypti mosquitoes. This primarily has been proposed as a tool to control dengue virus (DENV) transmission; however, evidence suggests Wolbachia infections confer protection for Ae. aegypti against CHIKV. Although this approach holds much promise for limiting virus transmission, at present our understanding of the ability of CHIKV to infect, disseminate, and be transmitted by wMel-infected Ae. aegypti currently being used at Wolbachia release sites is limited.Methodology/Principal FindingsUsing Ae. aegypti infected with the wMel strain of Wolbachia that are being released in Medellin, Colombia, we report that these mosquitoes have reduced vector competence for CHIKV, even with extremely high viral titers in the bloodmeal. In addition, we examined the dynamics of CHIKV infection over the course of four to seven days post feeding. Wolbachia-infected mosquitoes remained non-infective over the duration of seven days, i.e., no infectious virus was detected in the saliva when exposed to bloodmeals of moderate viremia, but CHIKV-exposed, wild type mosquitoes did have viral loads in the saliva consistent with what has been reported elsewhere. Finally, the presence of wMel infection had no impact on the lifespan of mosquitoes as compared to wild type mosquitoes following CHIKV infection.Conclusions/SignificanceThese results could have an impact on vector control strategies in areas where Ae. aegypti are transmitting both DENV and CHIKV; i.e., they argue for further exploration, both in the laboratory and the field, on the feasibility of expanding this technology beyond DENV.

BackgroundThe rise in dengue fever cases and the absence of dengue vaccines will likely cause governments to consider various types of effective means for controlling the disease. Given strong public interests in potential dengue vaccines, it is essential to understand the private economic benefits of dengue vaccines for accelerated introduction of vaccines into the public sector program and private markets of high-risk countries.Methodology/Principal FindingsA contingent valuation study for a hypothetical dengue vaccine was administered to 400 households in a multi-country setting: Vietnam, Thailand, and Colombia. All respondents received a description of the hypothetical dengue vaccine scenarios of 70% or 95% effectiveness for 10 or 30 years with a three dose series. Five price points were determined after pilot tests in order to reflect different local situations such as household income levels and general perceptions towards dengue fever. We adopted either Poisson or negative binomial regression models to calculate average willingness-to-pay (WTP), as well as median WTP. We found that there is a significant demand for dengue vaccines. The parametric median WTP is $26.4 ($8.8 per dose) in Vietnam, $70.3 ($23.4 per dose) in Thailand, and $23 ($7.7 per dose) in Colombia. Our study also suggests that respondents place more value on vaccinating young children than school age children and adults.Conclusions/SignificanceKnowing that dengue vaccines are not yet available, our study provides critical information to both public and private sectors. The study results can be used to ensure broad coverage with an affordable price and incorporated into cost benefit analyses, which can inform prioritization of alternative health interventions at the national level.

Summary Background 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. Methods 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. Findings 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 ...