" ... and hygiene?" Our once and future mission.
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History, 18th Century↗
Biomedical subjects
S B Halstead
Publications and source records attributed to S B Halstead.
The XXth century dengue pandemic: need for surveillance and research.
By the last decade of the XXth century Aedes aegypti and the 4 dengue viruses had spread to nearly all countries of the tropical world. Some 2 billion persons live in dengue-endemic areas with tens of millions infected annually. Dengue pandemics were also documented in the XVIIIth and XIXth centuries; they were contained by organized anti-Aedes aegypti campaigns and urban improvements. The XXth century dengue pandemic has brought with it the simultaneous circulation of multiple serotypes and in its aftermath, endemic dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Nearly 3 million children have been hospitalized with this syndrome in the past 3 decades, mainly in South-East Asia. Recent outbreaks of DHF/DSS in the Pacific Islands, China, India, Sri Lanka, Cuba and Venezuela are indicators of the high intensity and rapid spread of dengue transmission. The magnitude of the XXth century dengue pandemic requires urgent improvements in early warning surveillance by WHO Member States and the development of the capacity to study underlying mechanisms of the disease. A key research question is why does DHF/DSS not occur with all second dengue infections? Two answers have been suggested: (1) a human resistance gene. Data from the 1981 DHF/DSS epidemic in Cuba have demonstrated the existence in blacks of a resistance gene. The effect of such a gene in reducing disease susceptibility of American and African blacks requires more study. (2) The existence of dengue "biotypes". Some, but not all biotypes may cause DHF/DSS during a second dengue infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Aedes↗
The International Clinical Epidemiology Network (INCLEN): a progress report.
The International Clinical Epidemiology Network (INCLEN) was established in 1982 to strengthen the research capacity of medical schools in the developing world through the development of Clinical Epidemiology Units (CEUs). The role of these units is to promote a rational approach to clinical and health care decision making, drawing on the methods of clinical epidemiology, biostatistics, health economics and health social science. This paper summarizes the evolution of the INCLEN model and the experience to date. Progress with Phase 1, the designation of sites for CEU development and the provision of advanced research training by developed country training centres has been substantial. The network now consists of 27 units: 26 in developing country medical schools in Asia, Latin America, India and Africa and 1 in France. More than 60% of the target of 270 fellows have completed training and returned to take up faculty positions in their unit. The remainder will be trained and on site by 1995. The non-return rate of fellows (2%) is very low. Research productivity is significant given only 60 fellows have been working in their CEUs for more than 3 years following the completion of training. An appropriate balance between hospital and community-based research is evident and changes in clinical and health care policy have been made based on the research conducted. The educational responsibilities of all units include courses and workshops in critical appraisal and clinical epidemiology for medical trainees and colleagues. Graduate training programs have emerged in 3 units so far. Major challenges lie ahead as we move into Phase 2 of the project--self sustainability and the transfer of training responsibility to the CEUs. The problems encountered during Phase 1 will need to be addressed. These include time protection for research, the limited availability of research funds, the low priority given to research careers and the poor linkage between health researchers and government policy makers. Our experience echos the recommendations of the recent report of the Commission on Health Research for Development, namely that donors and national governments should give increased priority to the role of health research in less developed countries. We conclude that with continuing support and special attention to the problems encountered, the INCLEN approach can contribute to ensuring that the medical establishment is part of the solution rather than the problem faced by health systems in less developed countries.
Developing Countries↗
Growth of dengue type 2 virus isolates in human peripheral blood leukocytes correlates with severe and mild dengue disease.
We tested three dengue type 2 (DEN-2) isolates from children with clinically apparent but mild secondary dengue infections, and 10 isolates from children with moderately severe dengue hemorrhagic fever, and noted significant growth differences in peripheral blood leukocytes, but not in C6/36 cells. We also observed cytopathic effects in C6/36 cells that correlated with disease severity. These preliminary observations suggest the possibility that viral factors, whether surface antigens, attachment sites for entry into leukocytes, or intrinsic replication properties in human mononuclear phagocytes, might contribute to enhanced DEN infection and to the severity of the disease.
Child↗
[The system of international control of infectious diseases].
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Communicable Disease Control↗
Measurement of antibody-dependent infection enhancement of four dengue virus serotypes by monoclonal and polyclonal antibodies.
Although its underlying mechanisms are poorly understood, data comparing each of the four dengue virus serotypes suggest that in vitro antibody-dependent infection enhancement is a reproducible and measurable phenomenon related to other serological measures of antibody-virus binding. Information characterizing infection enhancement may provide clues to disease pathogenesis for dengue and other viruses that exhibit antibody-enhanced infection. We propose criteria for the detection and quantification of in vitro antibody-dependent enhancement of flavivirus infection based on observations using all four dengue virus serotypes, macrophage-like cell lines and human peripheral blood monocytes, and various immune sera and monoclonal antibodies. It is proposed that antibody-dependent infection enhancement is defined by the following findings: (i) significantly increased virus production is measured in quantitative assays at different points on the growth curve; (ii) assays of the virus output of cells infected with mixtures of constant amounts of virus and serial dilutions of the pre-existing antibody source produce characteristic 'enhancement profiles' of rising and falling virus output over at least a 10(-3)-fold dilution range; (iii) for each enhancing antibody source the dilution producing maximal infection enhancement is related to other serological measures of binding to the envelope, or another virus component; (iv) infection enhancement is detected with different antibody sources and virus strains (when available) tested over a range of m.o.i.; (v) other causes of enhanced virus production are ruled out.
Animals↗
Global epidemiology of dengue hemorrhagic fever.
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Dengue↗
Pathogenesis of dengue: challenges to molecular biology.
Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.
Adolescent↗
Heterologous flavivirus infection-enhancing antibodies in sera of Nigerians.
Human sera collected from Nigerians were examined for plaque reduction neutralizing and infection-enhancing antibodies against dengue 2, yellow fever, and West Nile viruses. Neutralization tests showed that 17 of 19 sera contained flavivirus neutralizing antibody; 11 were positive to all 3 viruses, 5 to dengue and yellow fever, and 1 to dengue virus only. Two sera had no detectable neutralizing antibody to any of the flaviviruses. Enhancement assays showed that 17 flavivirus neutralizing antibody-positive sera contained infection-enhancing antibodies to dengue 2, and 16 had antibody to yellow fever. Although 11 sera were positive for West Nile neutralizing antibody, 17 enhanced this virus. Heterologous infection-enhancing antibody titers were lower than the homologous ones. Broadly reacting sera and those with high neutralizing antibody titers produced the highest infection-enhancing antibody titers.
Antibodies, Viral↗
Study of the distribution of antibody-dependent enhancement determinants on dengue 2 isolates using dengue 2-derived monoclonal antibodies.
Dengue 2 (DEN-2) strains isolated from children during the 1980 metropolitan Bangkok epidemic were shown to possess antigenic homogeneity when studied for determinants mediating antibody-dependent infection enhancement using DEN-2 monoclonal antibodies. All isolates possessed multiple enhancing determinants, but those associated with mild and severe dengue syndromes could not be distinguished. Either the basis of disease severity in dengue is more complex than the mere presence or absence of virus epitopes involved in enhanced infection or enhancing epitopes have differences not detected in this system with monoclonal antibodies raised to the same serotype.
Animals↗
Disease severity-related antigenic differences in dengue 2 strains detected by dengue 4 monoclonal antibodies.
Low-passage epidemic Thai isolates of dengue 2 (DEN-2) were distinguished on the basis of associated disease severity by detection of virus determinants involved in enhanced macrophage infection when incubated with a panel of monoclonal antibodies derived from a DEN-4 strain associated with grade II dengue hemorrhagic fever (DHF). DEN-2 strains associated with DHF typically had multiple determinants that were involved in antibody-dependent enhancement of infection, whereas those associated with uncomplicated disease had few. These data provide further evidence that in epidemic areas where DHF is associated with prior circulation of low-level monotypic antibody, severe dengue disease could represent antibody-enhanced infection of human monocytes/macrophages.
Animals↗
Profiles of antibody-dependent enhancement of dengue virus type 2 infection.
Antibody-dependent infection enhancement (ADE) was studied with P-388D1 mouse macrophage-like cells, 21 dengue virus type 2 (DEN-2) strains, and 8 monoclonal antibodies reactive with flavivirus group-specific or dengue serotype-specific determinants. Testing a constant number of virions against serial dilutions of antibody for their ability to infect P-388D1 cells, a reproducible 'enhancement profile' was observed. The profile was characterized by (1) appearance, peak, decline, and disappearance of infection enhancement when antibody-containing ascitic fluids were diluted beyond the neutralizing endpoint, and (2) evolution over an approximate 10,000-fold dilutional range. The profiles were similar regardless of whether viruses were complexed with antibody at flavivirus group or serotype determinants, but the antibody dilution at which infection enhancement was maximal varied with the neutralization titer of the antibody. Neutralization and antibody-dependent enhancement of dengue infection appear to be biological outcomes of interactions between antibodies and single viral epitopes at different antibody: virus ratios.
Animals↗
Dengue 4 virus monoclonal antibodies identify epitopes that mediate immune infection enhancement of dengue 2 viruses.
Nineteen monoclonal antibodies produced to dengue type 4 virus (DEN-4) strain 4328-S were tested for their ability to mediate antibody-dependent infection enhancement (ADE) with seven DEN-2 strains in P-388D1 mouse macrophage-like cells. In this first study of the distribution of enhancing epitopes on multiple DEN-2 strains reacted with monoclonal antibodies to a different serotype (DEN-4), DEN-4 monospecific antibodies produced ADE with DEN-2 viruses, indicating the presence of DEN-4-like determinants on DEN-2 viruses. Analysis differentiated at least one and possibly more DEN-2 strain subgroups, one of which (isolates AHF-110 and AHF-191) was previously identified by DEN-2 monoclonal antibody analysis. The study demonstrates the heterogeneous distribution of dengue complex and DEN-4 epitopes on DEN-2 strains. Monoclonal antibodies are valuable tools for study of the biology of ADE and its relation to dengue shock syndrome.
Animals↗
Potiskum virus: enhancement of replication in a macrophage-like cell line.
Replication of Potiskum virus was studied in P388D1 macrophage-like cell line in the presence and absence of subneutralizing concentrations of specific antiviral antibody. The cultures were infected at multiplicities of infection (MOI) ranging from 0.4 to 0.0004. The virus replicated to high titres at all MOI tested, but there was an enhancement of virus replication in cultures supplemented with the antibody. Enhancement of replication was MOI dependent, the highest ratios being obtained in cultures infected at lowest MOI. In enhancement assays using various dilutions of immune mouse ascitic fluid (IMAF), the highest enhancement ratio was observed at dilution 1 : 500; the enhancing antibody titre was 5,000.
Animals↗
Cross-infection enhancement among African flaviviruses by immune mouse ascitic fluids.
Cross-infection enhancement of seven African flaviviruses by subneutralising concentrations of antibody in immune ascitic fluids was investigated in P388D1 cell culture. Infection by all the seven flaviviruses tested was enhanced by homologous and at least one of six heterologous immune mouse ascitic fluids (IMAF) tested. Enhancement ratios and enhancing antibody titres were higher in homologous than in heterologous enhancement. Zika, Wesselsbron, Uganda S and West Nile viruses were enhanced in culture by all the IMAF tested. Enhancement of Dakar bat and Yellow fever viruses was produced by five heterologous IMAF, but Potiskum virus was enhanced by one heterologous flavivirus antibody. The antibody to Potiskum virus was the most potent mediator of heterologous infection enhancement; all six heterologous flaviviruses were markedly enhanced by this antibody.
Animals↗
Comparison of dengue virus plaque reduction neutralization by macro and "semi-micro' methods in LLC-MK2 cells.
A simplified "semi-micro' plaque reduction neutralization test (PRNT) for dengue antibody in LLC-MK2 cells in disposable tissue culture plates is described. The assay compares favorably with the standard PRNT in glass prescription bottles, with relative sensitivity and specificity both 100% at a 1:40 screening dilution by 70% plaque reduction criteria. The assay is easy to perform, economical of time, expense, and storage space, and is suitable for study of sera available in small volumes, such as those obtained on filter paper or by the capillary method. The LLC-MK2 semi-micro PRNT is an acceptable alternative to the standard PRNT, particularly in laboratories that use these cells routinely for other tissue culture work and for flavivirus vaccine development.
Antibodies, Viral↗
Simplified plaque reduction neutralization assay for dengue viruses by semimicro methods in BHK-21 cells: comparison of the BHK suspension test with standard plaque reduction neutralization.
A newly modified semimicro plaque reduction neutralization test (PRNT) in BHK cells was compared with a standard PRNT in bottles with LLC-MK2 monolayers and with an LLC-MK2 PRNT adapted to semimicro methods. The BHK semimicro PRNT compared favorably in terms of sensitivity in detecting dengue antibody (96%), specificity at a screening dilution (95%), and ability to detect seroconversion to dengue viruses of three serotypes (93%). Disagreements between the BHK test and the LLC-MK2 tests were attributed to greater sensitivity of the BHK test in detecting dengue type 2 (DEN-2) antibody in acute-phase sera and to apparent low-level DEN-1/DEN-3 cross-reactions in some sera in all three tests. The BHK PRNT was easier, faster, and more economical than either of the LLC-MK2 tests. Many of the benefits of the BHK PRNT derive from the fact that cells are infected while still in suspension, at the time of cell splitting, hence the term "BHK suspension test."
Animals↗
Serological response to rubella revaccination.
To document the serological response, 21 seronegative rubella vaccinees (hemagglutination inhibition [HI] titer less than 10) were revaccinated with RA 27/3 rubella vaccine. All demonstrated an anamnestic response. Although RA 27/3 vaccine was an effective booster, antibody boost was not maintained in some persons. Of 15 persons tested, 24 to 27 months after revaccination, six had a significant HI antibody drop (fourfold or greater); only one had lost all detectable HI antibody. Although all 21 study participants were initially HI seronegative by rubella HI testing, 16 (76.2%) possessed neutralization and/or enzyme-linked immunosorbent assay antibodies before revaccination. As more persons with vaccine-induced immunity join the adult population pool, more sensitive test methods may be needed to assess serological status accurately.
Antibodies, Viral↗