The WHO R&D Blueprint: 2018 review of emerging infectious diseases requiring urgent research and development efforts.

The Research and Development (R&D) Blueprint is a World Health Organization initiative to reduce the time between the declaration of a public health emergency and the availability of effective diagnostic tests, vaccines, and treatments that can save lives and avert a public health crisis. The scope of the Blueprint extends to severe emerging diseases for which there are insufficient or no presently existing medical countermeasures or pipelines to produce them. In February 2018, WHO held an informal expert consultation to review and update the list of priority diseases, employing a prioritization methodology which uses the Delphi technique, questionnaires, multi-criteria decision analysis, and expert review to identify relevant diseases. The committee determined that, given their potential to cause a public health emergency and the absence of efficacious drugs and/or vaccines, there is an urgent need for accelerated R&D for (in no order of priority) Crimean-Congo haemorrhagic fever, Ebola virus and Marburg virus disease, Lassa fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), Nipah and henipaviral diseases, Rift Valley fever and Zika virus disease. The experts also included "Disease X," representing the awareness that a previously unknown pathogen could cause a major public health emergency. This report describes the methods and results of the 2018 prioritization review.

World Health Organization Methodology to Prioritize Emerging Infectious Diseases in Need of Research and Development.

The World Health Organization R&D Blueprint aims to accelerate the availability of medical technologies during epidemics by focusing on a list of prioritized emerging diseases for which medical countermeasures are insufficient or nonexistent. The prioritization process has 3 components: a Delphi process to narrow down a list of potential priority diseases, a multicriteria decision analysis to rank the short list of diseases, and a final Delphi round to arrive at a final list of 10 diseases. A group of international experts applied this process in January 2017, resulting in a list of 10 priority diseases. The robustness of the list was tested by performing a sensitivity analysis. The new process corrected major shortcomings in the pre-R&D Blueprint approach to disease prioritization and increased confidence in the results.

Aetiology of acute meningoencephalitis in Cambodian children, 2010-2013.

Acute meningoencephalitis (AME) is associated with considerable morbidity and mortality in children in developing countries. Clinical specimens were collected from children presenting with AME at two Cambodian paediatric hospitals to determine the major aetiologies associated with AME in the country. Cerebrospinal fluid (CSF) and blood samples were screened by molecular and cell culture methods for a range of pathogens previously associated with AME in the region. CSF and serum (acute and convalescent) were screened for antibodies to arboviruses such as Japanese encephalitis virus (JEV), dengue virus (DENV), and chikungunya virus (CHIKV). From July 2010 through December 2013, 1160 children (one month to 15 years of age) presenting with AME to two major paediatric hospitals were enroled into the study. Pathogens associated with AME were identified using molecular diagnostics, cell culture and serology. According to a diagnostic algorithm, a confirmed or highly probable aetiologic agent was detected in 35.0% (n=406) of AME cases, with a further 9.2% (total: 44.2%, n=513) aetiologies defined as suspected. JEV (24.4%, n=283) was the most commonly identified pathogen followed by Orientia tsutsugamushi (4.7%, n=55), DENV (4.6%, n=53), enteroviruses (3.5%, n=41), CHIKV (2.0%, n=23) and Streptococcus pneumoniae (1.6%, n=19). The majority of aetiologies identified for paediatric AME in Cambodia were vaccine preventable and/or treatable with appropriate antimicrobials.

Severe dengue: questioning the paradigm.

Severe dengue has been recognised for more than 200 years, but attempts to define, categorize and explain the condition have hotly contested for more than four decades. Resolution of this controversy may provide new insights for the management of patients.

Dengue-3 virus genomic differences that correlate with in vitro phenotype on a human cell line but not with disease severity.

We compared the full genome sequence of nine clinical isolates of dengue virus obtained during an epidemic of dengue-3 in French Polynesia in 1989, from patients with various presentations of disease. The isolates, all belonging to Genotype I, had 25 amino acid substitutions. There was no association with disease severity. When cultured in the K562 human erythroleukemia cell line, the isolates induced a range of cell growth inhibitions that was not associated with the degree of disease severity. By contrast, some substitutions--charge changes in NS1 and NS5, side-chain differences in NS1, loss of the E-153 potential glycosylation site, and 11 nucleotide insertions in the 3'UTR--that have been suggested to result in an increase or attenuation of dengue infection, appeared to be associated with the level of inhibition. These data represent the first documented study of an association between differences in the full dengue-3 genome of clinical isolates and the in vitro phenotype of these isolates on a human cell line.

West Nile: worldwide current situation in animals and humans.

West Nile (WN) virus is a mosquito-borne flavivirus that is native to Africa, Europe, and Western Asia. It mainly circulates among birds, but can infect many species of mammals, as well as amphibians and reptiles. Epidemics can occur in rural as well as urban areas. Transmission of WN virus, sometimes involving significant mortality in humans and horses, has been documented at erratic intervals in many countries, but never in the New World until it appeared in New York City in 1999. During the next four summers it spread with incredible speed to large portions of 46 US states, and to Canada, Mexico, Central America and the Caribbean. In many respects, WN virus is an outstanding example of a zoonotic pathogen that has leaped geographical barriers and can cause severe disease in human and equine. In Europe, in the past two decades there have been a number of significant outbreaks in several countries. However, very little is known of the ecology and natural history of WN virus transmission in Europe and most WN outbreaks in humans and animals remain unpredictable and difficult to control.

Elevation of soluble VCAM-1 plasma levels in children with acute dengue virus infection of varying severity.

Approximately 1,000 million infections with dengue viruses are estimated to occur annually. The majority of the cases develop mild disease, whereas only small proportion of the infected individuals develop severe hemorrhagic manifestations at the end of the acute phase of illness. In this study, the value of plasma levels of vascular cell adhesion molecule 1 (VCAM-1) in the pathogenesis and prognosis of dengue illness was investigated in children with dengue infections of varying severity. The plasma levels of soluble VCAM-1 (sVCAM-1) were measured in serial plasma samples obtained from 168 children aged between 7 months and 14 years with confirmed dengue infection. Of those children, 71 were suffering from dengue fever, 30 were suffering from dengue hemorrhagic fever, and 67 were suffering from dengue shock syndrome. Plasma samples obtained from 21 patients with febrile illness other than dengue served as controls. A commercially available kit (R&D Systems, Oxon, UK) was used to measure the levels of sVCAM-1 in plasma samples. sVCAM-1 was elevated during acute dengue infection, and significantly elevated among dengue shock syndrome patients as compared to dengue fever or dengue hemorrhagic fever patients (P < 0.05). Statistical analysis revealed that sVCAM-1 was associated with dengue disease severity and the time post infection (acute vs. convalescent phase) and not with age, sex, or previous exposure of the patients to dengue infection. A significant difference was found in the plasma levels of sVCAM-1 between dengue shock syndrome and dengue fever patients, however, the prognostic value of this marker in the acute stage of dengue illness proved to be limited. These data also favor to study the further elucidation of the role of sVCAM-1 in the pathogenesis of dengue infections.

Elevated levels of total and dengue virus-specific immunoglobulin E in patients with varying disease severity.

The kinetics of total and dengue virus-specific immunoglobulin E (IgE) were studied in serial serum samples obtained from 168 patients, 41 of whom suffered from primary dengue virus infection and 127 suffered from secondary dengue virus infection. Seventy-one patients were classified as dengue fever, 30 as dengue hemorrhagic fever, and 67 as dengue shock syndrome. A control group included single serum samples from patients with a herpes virus infection (n = 14), non-dengue febrile patients (n = 10), and healthy blood donors (n = 10). Patients with dengue virus infection had higher levels of total and dengue virus-specific IgE than non-dengue patients (P < 0.05). Patients with secondary dengue virus infections had not significantly increased levels of both total and dengue virus-specific IgE in the acute phase of disease compared to patients with primary dengue virus infections. Dengue virus-specific IgE was significantly higher in dengue hemorrhagic fever and/or dengue shock syndrome patients compared to dengue fever and non-dengue patients (P < 0.05). In conclusion, this study showed elevated total and dengue virus-specific IgE serum antibody levels in the acute stage of disease. Therefore, measurement of both total and dengue virus-specific IgE serum antibodies can be used as an additional prognostic marker in the development of severe complications in dengue virus infections. In addition, the presence and increase of dengue virus-specific IgE serum antibodies in patients with dengue virus infections is suggestive of the pathogenetic role that IgE may play in the hemostatic disorders observed in dengue hemorrhagic fever and dengue shock syndrome.

West Nile virus outbreak in horses, southern France, 2000: results of a serosurvey.

During late summer and autumn 2000, a West Nile fever outbreak in southern France resulted in 76 equine clinical cases; 21 horses died. We report the results of a large serosurvey of all equines within a 10-km radius of laboratory-confirmed cases. Blood samples were obtained from 5,107 equines, distributed in groups of 1 to 91 animals. West Nile virus immunoglobulin (Ig) G antibodies were found in 8.5% of animals (n=432). Forty-two percent of the IgG-positive animals were also IgM positive. Horses living in small groups were more affected than those in large groups. The results suggest that West Nile virus is not endemic in the affected area, the Camargue; rather, sporadic outbreaks are separated by long silent periods.