World Health Organization Priority Research Articles

Targeting the Non-structural Protein 1 from Dengue Virus to a Dendritic Cell Population Confers Protective Immunity to Lethal Virus Challenge

Dengue is the most prevalent arboviral infection, affecting millions of people every year. Attempts to control such infection are being made, and the development of a vaccine is a World Health Organization priority. Among the proteins being tested as vaccine candidates in preclinical settings is the non-structural protein 1 (NS1). In the present study, we tested the immune responses generated by targeting the NS1 protein to two different dendritic cell populations. Dendritic cells (DCs) are important antigen presenting cells, and targeting proteins to maturing DCs has proved to be an efficient means of immunization. Antigen targeting is accomplished by the use of a monoclonal antibody (mAb) directed against a DC cell surface receptor fused to the protein of interest. We used two mAbs (αDEC205 and αDCIR2) to target two distinct DC populations, expressing either DEC205 or DCIR2 endocytic receptors, respectively, in mice. The fusion mAbs were successfully produced, bound to their respective receptors, and were used to immunize BALB/c mice in the presence of polyriboinosinic: polyribocytidylic acid (poly (I:C)), as a DC maturation stimulus. We observed induction of strong anti-NS1 antibody responses and similar antigen binding affinity irrespectively of the DC population targeted. Nevertheless, the IgG1/IgG2a ratios were different between mouse groups immunized with αDEC-NS1 and αDCIR2-NS1 mAbs. When we tested the induction of cellular immune responses, the number of IFN-γ producing cells was higher in αDEC-NS1 immunized animals. In addition, mice immunized with the αDEC-NS1 mAb were significantly protected from a lethal intracranial challenge with the DENV2 NGC strain when compared to mice immunized with αDCIR2-NS1 mAb. Protection was partially mediated by CD4+ and CD8+ T cells as depletion of these populations reduced both survival and morbidity signs. We conclude that targeting the NS1 protein to the DEC205+ DC population with poly (I:C) opens perspectives for dengue vaccine development.

P5.105 Identification and Functional Annotation of Secreted Proteins of Chlamydia Trachomatis Using Bioinformatics Tools

BackgroundThe large number of sexually transmitted diseases cases caused globally each year by Chlamydia trachomatis has made this organism a World Health Organization priority for vaccine development. Even after a...

Classification of diseases and the neurodevelopmental disorders: the challenge for DSM‐5 and ICD‐11

Fundamental to communication about and research into diseases is a diagnostic classification system based on phenomenology and pathophysiology. There are two major diagnostic classification systems for mental and behavior disorders in current use: the DSM-IV published by the American Psychiatric Association and the ICD-10 published by the World Health Organization.1, 2 Each includes the neurodevelopmental disorders affecting coordination, speech, language, and specific academic learning; and in addition autism, attention-deficit–hyperactivity disorder, tics and Tourette disorder, stereotyped movements, and intellectual disability. Both the DSM-IV and ICD-10 are currently being revised and I have been privileged to be a member of the neurodevelopmental work groups for both systems. The challenges to revision are many – including whether change is needed at all! Some have proposed a radical merger for the ICD-10 of mental and behavioural disorders with neurological disorders, arguing that organic/inorganic distinctions are no longer tenable,3 but that may be for future editions. Hyman has written about the dangers of ‘reification’; that simply by creating classification systems, research is inhibited into whether the diagnoses are ‘real’ or not.4 A number of the current diagnoses are seldom used. A further challenge is the recognition that many disorders that were once considered categorical are now considered dimensional.5, 6 Working in the field of neurodisability what had struck me most forcibly about the current classification systems was how frequently the children and young people I met did not quite meet criteria for certain disorders, necessitating a ‘not otherwise specified’ diagnosis; how they seemed to change from one diagnosis to another as they grew older; how variably different clinicians used certain diagnoses (notably Asperger disorder, autism, and pervasive developmental disorder not otherwise specified [including atypical autism]); and also how often the children and young people seemed to have a complicated mix of disorders which was not allowed for by the diagnostic systems. One agreeable feature of sharing experiences in the workgroups with others from across the globe is that they had found the same. The American Psychiatric Association and World Health Organization have each approached the task from a different basis but with an intention to harmonize. For both systems reliability, validity, and utility are important. The DSM is a classification system setting criteria for diagnosis and research, which is also a clinical tool and the basis of remuneration in the USA. The World Health Organization's priority is a broader utility and the ICD-11 is intended to have clinical, teaching, training, and health statistics use world-wide not only for mental health professionals but importantly for primary care staff and others across many different cultural settings. More contentiously, in the western world, both diagnostic systems have moved beyond medical classification and been used to set eligibility for both services and benefits. A major change has been that during the current revision of the DSM-IV the importance of the classification system to users, i.e. those with mental, behavioural, and neurodevelopmental problems themselves, has been recognized and public involvement has been sought. The DSM-5 proposals have attracted a large number of comments both positive and negative including the view that ‘normality’ is being medicalized. What we do know about the pathophysiology of neurodevelopmental and mental and behavioural disorders indicates a complex mix of genetic and non-genetic risk factors. In the absence of biomarkers, diagnostic criteria for mental and behavioral disorders will continue to depend upon surface features of behavior (i.e. phenomenology), but the work groups have proposed that diagnoses without a clear scientific basis will be removed. As an example, in the DSM-5, autism spectrum disorder replaces autism, Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified thus ‘lumping’ rather than ‘splitting’ and leaving the field open for future research into more valid subgroups. The uniqueness of the individual will be recognized by specifying pattern of onset, course, and associated descriptive features (e.g. intellectual ability). Dimensions will be recognized by promoting a quantitative approach to symptom severity and while symptoms have to be impairing of everyday function for the diagnosis of a disorder in DSM-5, the framework of the ICF7 is promoted as the basis of measurement of impairment for the individual. Whether this is regarded as progress by other users remains to be seen but I think description of the individual, their strengths and weaknesses, other problems, and hence their needs will be an improvement.

Population Genomics of Chlamydia trachomatis: Insights on Drift, Selection, Recombination, and Population Structure

The large number of sexually transmitted diseases and ocular trachoma cases that are caused globally each year by Chlamydia trachomatis has made this organism a World Health Organization priority for vaccine development. However, there is no gene transfer system for Chlamydia to help identify potential vaccine targets. To accelerate discoveries toward this goal, here we analyzed the broadest diversity of C. trachomatis genomes to date, including 25 geographically dispersed clinical and seven reference strains representing 14 of the 19 known serotypes. Strikingly, all 32 genomes were found to have evidence of DNA acquisition by homologous recombination in their history. Four distinct clades were identified, which correspond to all C. trachomatis disease phenotypes: lymphogranuloma venereum (LGV; Clade 1); noninvasive urogenital infections (Clade 2); ocular trachoma (Clade 3); and protocolitis (Clade 4; also includes some noninvasive urogenital infections). Although the ancestral relationship between clades varied, most strains acted as donor and recipient of recombination with no evidence for barriers to genetic exchange. The niche-specific LGV and trachoma clades have undergone less recombination, although the opportunity for mixing with strains from other clades that infect the rectal and ocular mucosa, respectively, is evident. Furthermore, there are numerous occasions for gene conversion events through sequential infections at the same anatomic sites. The size of recombinant segments is relatively small (~357 bp) compared with in vitro experiments of various C. trachomatis strains but is consistent with in vitro estimates for other bacterial species including Escherichia coli and Helicobacter pylori. Selection has also played a crucial role during the diversification of the organism. Clade 2 had the lowest nonsynonymous to synonymous ratio (dN/dS) but the highest effect of recombination, which is consistent with the widespread occurrence of synonymous substitutions in recombined genomic segments. The trachoma Clade 3 had the highest dN/dS estimates, which may be caused by an increased effect of genetic drift from niche specialization and a reduced effective population size. The degree of drift, selection, and recombination in C. trachomatis suggests that the challenge will remain to identify genomic regions that are stable and cross protective for the development of an efficacious vaccine.

Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization

Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

OX40 Ligand Fusion Protein Delivered Simultaneously With the BCG Vaccine Provides Superior Protection Against Murine Mycobacterium tuberculosis Infection

Mycobacterium tuberculosis infection claims approximately 2 million lives per year, and improved efficacy of the BCG vaccine remains a World Health Organization priority. Successful vaccination against M. tuberculosis requires the induction and maintenance of T cells. Targeting molecules that promote T-cell survival may therefore provide an alternative strategy to classic adjuvants. We show that the interaction between T-cell-expressed OX40 and OX40L on antigen-presenting cells is critical for effective immunity to BCG. However, because OX40L is lost rapidly from antigen-presenting cells following BCG vaccination, maintenance of OX40-expressing vaccine-activated T cells may not be optimal. Delivering an OX40L:Ig fusion protein simultaneously with BCG provided superior immunity to intravenous and aerosol M. tuberculosis challenge even 6 months after vaccination, an effect that depends on natural killer 1.1(+) cells. Attenuated vaccines may therefore lack sufficient innate stimulation to maintain vaccine-specific T cells, which can be replaced by reagents binding inducible T-cell costimulators.

Substance Abuse Treatment, HIV/AIDS, and the Continuum of Response for People Who Inject Drugs

The continuum of response (CoR) to HIV/AIDS is a framework for implementation of HIV prevention, care, and treatment programs based on a national strategic plan for HIV/AIDS services. The CoR for people who inject drugs (PWID) is an important extension of the developed CoR to HIV/AIDS. The CoR-PWID employs stakeholders who together plan, develop, pilot, and provide a full range of services that address the various prevention, care/support, and treatment needs of people, families, and communities infected or affected by HIV/AIDS and injection drug use. The CoR-PWID comprises a broad range of services that include but are not limited to the World Health Organization priority interventions for HIV/AIDS prevention, treatment, and care in the health sector and the package of essential interventions for the prevention, treatment, and care of HIV for people who inject drugs. Implementation of these well-defined, essential prevention, care/support, and treatment services, in addition to locally defined needed services, in a coordinated fashion is important to clients, their families, and communities. The CoR-PWID is, therefore, a necessary framework essential for service development for countries that address HIV/AIDS in populations of PWID.

A conceptual framework for the revision of the ICD‐10 classification of mental and behavioural disorders

A conceptual framework for the revision of the ICD‐10 classification of mental and behavioural disorders

Prevalence study of yaws in the Democratic Republic of Congo using the lot quality assurance sampling method.

BackgroundUntil the 1970s the prevalence of non-venereal trepanomatosis, including yaws, was greatly reduced after worldwide mass treatment. In 2005, cases were again reported in the Democratic Republic of the Congo. We carried out a survey to estimate the village-level prevalence of yaws in the region of Equator in the north of the country in order to define appropriate strategies to effectively treat the affected population.Methodology/Principal FindingsWe designed a community-based survey using the Lot Quality Assurance Sampling method to classify the prevalence of active yaws in 14 groups of villages (lots). The classification into high, moderate, or low yaws prevalence corresponded to World Health Organization prevalence thresholds for identifying appropriate operational treatment strategies. Active yaws cases were defined by suggestive clinical signs and positive rapid plasma reagin and Treponema pallidum hemagglutination serological tests. The overall prevalence in the study area was 4.7% (95% confidence interval: 3.4–6.0). Two of 14 lots had high prevalence (>10%), three moderate prevalence (5–10%) and nine low prevalence (<5%.).Conclusions/SignificanceAlthough yaws is no longer a World Health Organization priority disease, the presence of yaws in a region where it was supposed to be eradicated demonstrates the importance of continued surveillance and control efforts. Yaws should remain a public health priority in countries where previously it was known to be endemic. The integration of sensitive surveillance systems together with free access to effective treatment is recommended. As a consequence of our study results, more than 16,000 people received free treatment against yaws.

Synthesis, characterization, and immunogenicity in mice of Shigella sonnei O-specific oligosaccharide-core-protein conjugates

Shigellosis, an enteric disease, is on the World Health Organization's priority prevention list. In one study, the Shigella sonnei O-specific polysaccharide (O-SP)-protein conjugate showed 72% protection against disease in Israeli army recruits exposed to high rates (8-14%) of infection. The protection was related to vaccine-induced IgG anti-O-SP levels. Synthetic oligosaccharides of Shigella dysenteriae type 1, bound by their reducing ends to a carrier protein ("sun"-type configuration), induced significantly higher antibody levels than the native O-SP bound to protein by multiple-point attachments ("lattice"-type configuration). Attempts to synthesize the S. sonnei O-SP based oligosaccharides were not successful. Here, we describe the isolation, characterization, and conjugation of low-molecular-mass O-SP-core (O-SPC) fragments. The O-SPC fragments were bound by their reducing ends similar to the preparation of the synthetic S. dysenteriae type 1 conjugates. The O-SPC conjugates used oxime linkages between the terminal Kdo residues at the reducing ends of the S. sonnei saccharides and aminooxy linkers bound to BSA or a recombinant diphtheria toxin. The coupling reaction was carried out at a neutral pH and room temperature. IgG antibody levels induced in young outbred mice by the S. sonnei O-SPC conjugates were significantly higher then those elicited by the O-SP conjugates. Accordingly, we propose to evaluate clinically these conjugates.

Infection control as a major World Health Organization priority for developing countries

Healthcare-associated infection affects hundreds of millions of people worldwide and is a major global issue for patient safety. It complicates between 5 and 10% of admissions in acute care hospitals in industrialised countries. In developing countries, the risk is two to twenty times higher and the proportion of infected patients frequently exceeds 25%. A growing awareness of this problem prompted the World Health Organization to promote the creation of the World Alliance for Patient Safety. Prevention of healthcare-associated infection is the target of the Alliance First Global Patient Safety Challenge, 'Clean Care is Safer Care', launched in October 2005. After 2 years, a formal statement has been signed by 72 ministries of health as a pledge of their support to implement actions to reduce healthcare-associated infection; of these, 30 are developing countries. Additional countries, mostly from the developing world, have planned to sign by the end of 2008 and will represent in total more than three-quarters of the world's population. Given the emphasis of the proposed strategy on simple and affordable solutions, the impact of the Challenge is expected to be high in developing countries. The combined efforts expected under the Challenge have the potential to save millions of lives, prevent morbidities and long-term disability for hundreds of millions of patients, and lead to major cost savings through the improvement of basic infection control measures in any healthcare setting, regardless of resources available or level of development.

VACCINE-DERIVED POLIOVIRUSES AND THE ENDGAME STRATEGY FOR GLOBAL POLIO ERADICATION

As the global eradication of wild poliovirus nears, the World Health Organization (WHO) is addressing challenges unprecedented in public health. The live, attenuated oral poliovirus vaccine (OPV), used for more than four decades to interrupt poliovirus transmission, and the vaccine of choice for developing countries, is genetically unstable. Reversion of the small number of substitutions conferring the attenuated phenotype frequently occurs during OPV replication in humans and is the underlying cause of the rare cases of vaccine-associated paralytic poliomyelitis (VAPP) in OPV recipients and their close contacts. Whereas VAPP has long been recognized, two other adverse events have been identified more recently: (a) long-term excretion of highly evolved vaccine-derived polioviruses (VDPVs) in persons with primary immunodeficiencies, and (b) polio outbreaks associated with circulating VDPVs in areas with low rates of OPV coverage. Developing a posteradication strategy to minimize the risks of VDPV emergence and spread has become an urgent WHO priority.

International rural health needs and services research: a nursing and midwifery response.

As the importance of evidence-based practice in global health care increases, the need for constant, accurate feedback from those in practice is critical, yet the requirement to rapidly obtain and disseminate data on a global basis is a challenge for all health professionals. The Internet allows for global participation in data collection that dramatically streamlines the traditional survey process. This new paradigm applies to surveys that are short, issue focused, and time sensitive. The Global Network of World Health Organization (WHO) Collaborating Centres for Nursing and Midwifery Development used a sample of international nurses in 70 countries to identify the worldwide rural health issues of WHO priority health needs, treatment modalities, health care interventions, and providers, as well as the current state of rural health research on a global level. This article presents the results of the survey regarding rural health needs and nursing and midwifery's response to them internationally, demonstrates Internet data collection, and shows how this research paradigm can help establish an evidence base for nursing practice.

ILAE/IBE/WHO Global Campaign "out of the shadows": global and regional developments.

ILAE/IBE/WHO Global Campaign "out of the shadows": global and regional developments.

Trends in cigarette smoking in 36 populations from the early 1980s to the mid-1990s: findings from the WHO MONICA Project.

This report analyzes cigarette smoking over 10 years in populations in the World Health Organization (WHO) MONICA Project (to monitor trends and determinants of cardiovascular disease). Over 300,000 randomly selected subjects aged 25 to 64 years participated in surveys conducted in geographically defined populations. For men, smoking prevalence decreased by more than 5% in 16 of the 36 study populations, remained static in most others, but increased in Beijing. Where prevalence decreased, this was largely due to higher proportions of never smokers in the younger age groups rather than to smokers quitting. Among women, smoking prevalence increased by more than 5% in 6 populations and decreased by more than 5% in 9 populations. For women, smoking tended to increase in populations with low prevalence and decrease in populations with higher prevalence; for men, the reverse pattern was observed. These data illustrate the evolution of the smoking epidemic in populations and provide the basis for targeted public health interventions to support the WHO priority for tobacco control.

Safe uses of pesticides within the WHO programme.

Introduction Chemicals continue to play a significant role in a variety of pest control activities around the world, both in agriculture and in public health, and this trend will be sustained for many years to come. Although by definition, and in reality, pesticides are poisons, the majority of people recognize the advantage of their use in view of the benefits derived, such as the control of disease vectors and an increase in food and fibre production. Unfortunately, pesticides are frequently misused and this gives rise to considerable, and growing, public concern. In general pesticides, like drugs, are among the most carefully studied chemicals, and this makes the toxicological evaluation of active material possible and meaningful. In many countries registration procedures are elaborated upon in great detail, offering possibilities for preparing precise precautionary measures for their production, transport, storage and use. Unfortunately, in many areas, the implementation of carefully prescribed safety measures is lacking and pesticides are greatly misused. Among various activities of the World Health Organization (WHO) in the area of safe use of pesticides, special attention is paid to identifying sources related to increases in health hazards. Pest resistance to certain types of pesticides (e.g. DDT or anticoagulants) or a significant increase of pesticide costs, require a search for alternative compounds which may be more effective or cheaper, but only occasionally safer. One of WHO's priorities is to encourage the development of new, safer and more effective compounds, specifically suited to the needs of integrated pest management. By publishing data sheets on pesticides, preparing specifications, classifying pesticides by hazard or evaluating new compounds through the pesticide evaluation scheme, WHO is assisting all those concerned to reduce pesticide users' risk to an acceptable level. At the initial stage of use, pesticides were regarded as a highly advantageous means of abolishing famine and eradicating vector-borne diseases. However, with gradual development of resistance to virtually all classes of compounds, with undesirable effects on non-target species and proven or alleged adverse effects on humans, particularly following misuse, greater and greater public concern has resulted. Being poisonous by their nature, pesticides may cause harm to humans and to the environment. However, a terminological distinction should be made between