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At least 973 records · Page 54Linked to original sources
PubMed2005

An evaluation of dengue type-2 inactivated, recombinant subunit, and live-attenuated vaccine candidates in the rhesus macaque model.

The safety, immunogenicity, and protective efficacy of two non-replicating antigen-based vaccines and one live-attenuated virus (LAV) vaccine for dengue type-2 (dengue-2) virus were evaluated in the rhesus macaque model. The non-replicating vaccines consisted of whole, purified inactivated virus (PIV) and a recombinant subunit protein containing the amino-(N)-terminal 80% of envelope protein (r80E), each formulated with one of five different adjuvants. Each formulation was administered to three animals on a 0, 3-month schedule. Following the primary immunizations, 37 of 39 animals demonstrated dengue-2 virus neutralizing antibodies. After the booster immunizations all animals had dengue neutralizing antibodies with peak titers ranging from 1:100 to 1:9700. The highest neutralizing antibody titers were observed in the groups that received r80E antigen formulated with AS04, AS05, or AS08 adjuvant, and PIV formulated with AS05 or AS08 adjuvant. These newer adjuvants are based on alum, fraction QS-21 of saponin, and monophosphoryl lipid A (MPL). Protection was evaluated by dengue-2 virus challenge 2 months after the booster by the measurement of circulating virus (viremia) and post-challenge immune responses. Several groups exhibited nearly complete protection against viremia by bioassay, although there was evidence for challenge virus replication by Taqmantrade mark and immunological assays. None of the vaccines conferred sterile immunity.

Animals↗
PubMed2006

Amino acid changes in the recombinant Dengue 3 Envelope domain III determine its antigenicity and immunogenicity in mice.

The immunogenicity of the Envelope fragment from amino acid 284 to 426 of Dengue viruses, obtained as fusion proteins with P64k in Escherichia coli, has been previously tested by our group. Here, we studied two fusion proteins with P64k carrying the Envelope fragment from two strains of Dengue 3: H87 prototype strain (PD9) and an isolate from the Nicaragua 1994 outbreak (PD18). Sequence comparison of the Dengue Envelope fragments showed four amino acid differences. Only PD18 reacted with human antisera and induced a higher functional immune response in mice than PD9. Moreover, mice immunized with PD18 were less susceptible to Dengue 3 administered intracerebrally than those immunized with PD9. The results reveal that not all sequences of the Dengue Envelope fragment, at least in the context of P64k, are antigenic and generate a functional immune response against the native virus. This finding has direct implications for the design of vaccines based on fragments of the Envelope protein.

Amino Acid Sequence↗
PubMed2001

Comparison of techniques for extracting viral RNA from isolation-negative serum for dengue diagnosis by the polymerase chain reaction.

Aiming at the improvement of the molecular diagnosis of dengue, three well-established methods of RNA extraction from serum of patients with clinical symptoms of dengue were compared. The methods were based on the QIAamp Viral RNA kit, the Chomczynski-Sacchi technique and TRIzol. One hundred samples were examined using the same protocol for reverse transcription-polymerase chain reaction (RT-PCR). Out of the 100 samples tested, none was positive by either the Chomczynski-Sacchi technique or TRIzol, and six were positive using the QIAamp viral RNA kit. Of the six positive samples, only one was collected before 5 days of the beginning of the disease, and it was also positive for viral isolation. These results were confirmed later by serology (MAC-ELISA) that showed that 19 samples were positive for IgM antibodies against dengue. These data indicate that PCR is a useful method for detection of dengue virus infections in IgM-positive samples, and the best method of RNA extraction from clinical samples, to be used for dengue diagnosis by PCR is the QIAamp Viral RNA kit.

Antibodies, Viral↗
PubMed2002

Optimizing dengue diagnosis by RT-PCR in IgM-positive samples: comparison of whole blood, buffy-coat and serum as clinical samples.

Dengue, a major public health problem in tropical and sub-tropical regions, is the most important arboviral disease of humans. Early diagnosis is very important on follow-up of infected patients, especially those at risk of the severe manifestations of this disease. Aiming at the improvement of the molecular diagnosis of these infections and due to the lack of studies that indicated the best sample for dengue virus detection by RT-PCR, viral detection by RT-PCR in blood, serum and buffy-coat of 75 IgM-positive serum samples for dengue was evaluated. Out of the 75 samples, 17 were positive for dengue using RT-PCR and from these samples, three were positive in the blood, 14 positive in the serum and eight positive in the buffy-coat. These results indicate that serum is the best clinical sample for RT-PCR amplification of dengue genomes.

Animals↗
PubMed1997

Use of Epstein-Barr virus-transformed, autologous B-lymphoblastoid cells as antigen-presenting cells for establishment and maintenance of dengue virus-specific, human cytotoxic T lymphocyte clones.

We have been maintaining dengue virus specific CD8+ cytoxic T lymphocyte (CTL) clones by repeated stimulation using autologous peripheral blood mononuclear cells (PBMC) as antigen presenting cells (APCs). In the present study, Epstein-Barr virus (EBV)-transformed autologous lymphoblastoid cell lines (LCL) were compared with autologous PBMC as APCs for long term culture of a dengue virus-specific, HLA class I-restricted CD8+ CTL clone CB2.8. We substituted autologous LCL for autologous PBMC and maintained CB2.8 for several months. CB2.8 cultured using LCL as APCs maintained antigen specific cytolytic activity. No demonstrable difference in the specificity or in the level of cytolytic activity against a panel of target cells was noted between the CB2.8 maintained with LCL and those maintained with PBMC. Lysis of the target cells was blocked by the anti-HLA-class I antibody indicating that HLA class I-restriction was also maintained. We then compared autologous LCL with autologous PBMC in the establishment of CD4 + CTL clones from the PBMC of a dengue-1 immune donor. Dengue 1-specific clones were derived from limiting dilution cultures using either type of APCs. Similar numbers of dengue virus-specific CD4+ CTL clones were established using LCL or PBMC as APCs. These results indicate that autologous LCL act as APCs for long term culture of virus-specific CTL clones and represent a cost effective alternative to repeated collection of PBMC.

Adult↗
PubMed2002

Heparin inhibits dengue-2 virus infection of five human liver cell lines.

Liver is suggested to be the major target of dengue virus infection and plays an important role in the immunopathogenesis of dengue hemorrhagic fever. Previously, we reported that five human liver cell lines (HuH-7, HA22T, Hep3B, PLC, and Chang liver) with various degrees of differentiation and tumorigenicity showed different susceptibility for dengue virus infection. Here, we demonstrate that heparin, an analogue of heparan sulfate (HS), can compete with HS on cell membrane for virus binding and subsequently inhibits the replication of dengue-2 and Japanese encephalitis viruses in hepatoma and BHK-21 cells, respectively. It indicates that the binding of these viruses with HS is an important process for their invasion. Moreover, the inhibitory effect of heparin correlates with the infectivity of the virus in the cells. All together, our results suggest that HS is an important host component for dengue and Japanese encephalitis virus replication, which can be effectively blocked by heparin.

Animals↗
PubMed2000

Live attenuated tetravalent dengue vaccine.

The development of a live attenuated tetravalent dengue vaccine is currently the best strategy to obtain a vaccine against dengue viruses. The Mahidol University group developed candidate live attenuated vaccines by attenuation through serial passages in certified primary cell cultures. Dengue serotype 1, 2 and 4 viruses were developed in primary dog kidney cells, whereas dengue serotype 3 was serially passaged in primary African green monkey kidney cells. Tissue culture passaged strain viruses were subjected to biological marker studies. Candidate vaccines have been tested as monovalent (single virus), bivalent (two viruses), trivalent (three viruses) and tetravalent (all four serotype viruses) vaccines in Thai volunteers. They were found to be safe and immunogenic in both adults and children. The Mahidol live attenuated dengue 2 virus was also tested in American volunteers and resulted in good immune response indistinguishable from those induced in Thai volunteers. The master seeds from the four live attenuated virus strains developed were provided to Pasteur Merieux Connaught of France for production on an industrial scale following good manufacturing practice guidelines.

Adolescent↗
PubMedDate not supplied

Dengue encephalitis in French Guiana.

Thousands of cases of dengue fever (DF) and several cases of dengue haemorrhagic fever were recorded in French Guiana during the recent outbreak of dengue-2 virus (1991-1992) and in subsequent years. One case with clinical signs typical of classical DF with neurological complications is reported in this study. The neurological features (encephalitis) appeared during the acute phase, 2 days after the onset of fever. Dengue-2 virus was detected in both the cerebrospinal fluid and blood sample. This case was fatal. This first reported case of classical DF with encephalitis in French Guiana is a new demonstration of the potential neurovirulence of dengue viruses.

Aedes↗
PubMed1982

Immunological enhancement and the pathogenesis of dengue haemorrhagic fever.

Laboratory studies have provided evidence that the replication of dengue viruses in preparations of primary peripheral blood mononuclear cells of human or simian origin, or in macrophage-like cell lines of human or murine origin, may be enhanced by sub-neutralizing concentrations of homotypic dengue antibody, by heterotypic dengue antibody, or by antibody against heterologous flaviviruses. The mechanism underlying this phenomenon is discussed in the context of dengue haemorrhagic fever and the dengue shock syndrome.

Animals↗
PubMed2004

Ocular manifestations in Dengue fever.

PURPOSE: To report a case of Dengue fever resulting in permanent visual loss in both eyes due to retinal capillary occlusion. METHODS: Case report. RESULTS: Severe permanent visual loss occurred in a patient with Dengue fever. Dilated fundus exam showed vascular sheathing with associated retinal hemorrhages at the equator and cotton wool spots in the maculae of both eyes. Fluorescein angiography revealed areas of capillary nonperfusion at the equator and in the macula. The diagnosis of Dengue fever was confirmed by serology detecting IgM antibodies to the Dengue virus. CONCLUSION: Ocular abnormalities may be seen in patients with Dengue fever, therefore ophthalmoscopy should be performed in patients presenting with severe forms of the disease.

Adult↗
PubMed2000

Epidemiologic studies on Dengue in Santiago de Cuba, 1997.

A small, isolated outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) due to dengue virus type 2 (DEN-2) was documented in Santiago de Cuba on the island of Cuba beginning in January 1997. There were 205 DHF/DSS cases, all in persons older than age 15 years. All but three had evidence of a prior dengue infection, with the only known opportunity being the islandwide dengue virus type 1 (DEN-1) epidemic of 1977-1979. Virtually complete clinical and laboratory surveillance of overt disease was achieved. From December 1997 to January 1998, a random, age-stratified serum sample was obtained from 1,151 persons in 40 residential clusters in Santiago. Sera were tested for DEN-1 and DEN-2 neutralizing antibodies. The prevalence of DEN-2 antibodies in children age 15 years and under, born after the 1981 DEN-2 epidemic, was taken as the 1997 DEN-2 infection rate. This was adjusted slightly to accommodate observed cases, resulting in an estimated infection rate of 4.3%. Dengue fever and DHF/DSS attack rates were calculated from estimated total primary and secondary DEN-2 infections. Only 3% of 13,116 primary infections were overt. The DHF/DSS attack rate for adults of all ages was 420 per 10,000 secondary DEN-2 infections.

Adolescent↗
PubMedDate not supplied

Disease exacerbation caused by sequential dengue infections: myth or reality?

Dengue can be caused by any one of four viruses that are antigenically related but not cross-protective. It has been proposed that the disease may be more severe if an infection with one dengue serotype follows infection with another serotype. Both experimental and epidemiologic data have been cited to substantiate this concept, but the present reviewer does not find the data convincing. The issue is of practical importance because of its relevance to the use of dengue vaccines now under development. It is impossible to prove that clinical manifestations of dengue are not exacerbated by sequential infections. Negative findings can always be countered by arguments that exacerbation occurs only with certain serotypes, only with certain strains of those serotypes, or only when infections occur at critical intervals. Interested persons can examine the relevant data and decide whether the concept of disease exacerbation following sequential dengue infections is myth or reality.

Dengue↗
PubMedDate not supplied

Selective primary health care: strategies for control of disease in the developing world. XI. Dengue.

Since World War II, dengue viruses have progressively extended their geographic domain and have increased as causes of human morbidity and mortality. This complex of four flaviviruses is principally transmitted to humans by the bite of Aedes aegypti, the yellow fever vector. Factors that promote the indoor storage of water are congenial to the breeding of A. aegypti. These include the dislocations of wars, overpopulation , and urbanization. By the mid-20th century, A. aegypti eradication campaigns had nearly succeeded in much of the Western Hemisphere. Since then, there has been a steady degradation in ability to cope with this species despite the fact that a newly emerged, severe immunopathologic disorder, dengue hemorrhagic fever/dengue shock syndrome, endows dengue epidemics with grave consequences. Development of a vaccine against dengue is complicated by the need to develop four different live attenuated vaccines and by a justifiable caution imposed by dengue immunopathology. A wide range of proven methods have been and are available to reduce populations of A. aegypti. This paper argues that the eradication strategy adopted earlier in this century is still viable and cost effective. Critical to a successful control program is a prioritied approach, a thorough, disciplined planning effort, a commitment to assessment, adequate compensation of staff, and, above all, the will to succeed.

Aedes↗
PubMed1979

In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody.

Five pairs of juvenile, dengue virus-susceptible rhesus monkeys were given normal or dengue-immune human cord-blood serum injected intravenously to a final dilution of 1:300. The pool of immune human cord-blood serum had a titer of antibody to dengue type 2 virus (D2V) of 1:140 in the plaque-reduction neutralization test and a titer of human monocyte infection enhancement of greater than 1:2,000,000. Fifteen minutes after inoculation of serum, animals were infected with D2V (strain no. 16681). Daily titers of viremia were always higher in the animals that had received antiserum to D2V than in animals that had received normal cord-blood serum. Ratios of infection enhancement ranged from 2.7 to 51.4. The demonstration of antibody dependence of dengue virus infection in subhuman primates--a complex, outbred experimental host--supports the hypothesis that the severity of dengue in humans is regulated by antibody.

Animals↗
PubMed1982

Induction and characterization of delayed-type hypersensitivity to dengue virus in mice.

Delayed-type hypersensitivity (DTH) to dengue virus type 4 in mice is described. The DTH reaction (measured by footpad swelling) was maximal at 24 hr after challenge and was enhanced significantly when mice were pretreated with cyclophosphamide. The response was maximal six days after infection with an immunizing dose of approximately 10(7.3) 50% lethal doses per mouse. Histologic examination of the test footpad showed a predominantly mononuclear cell infiltrate at 24 hr after challenge. fibrin deposition was also noted. DTH reactivity was transferable to normal mice by injection of immune spleen cells but not of immune serum. The DTH reaction was apparently specific for dengue virus type 4 because significantly lower responses were detected when dengue virus types 1-3 and Japanese encephalitis virus were used as challenge antigens in mice infected with dengue virus type 4. The probable importance and significance of these findings in relation to the host immune response and the pathogenesis of dengue virus infection are discussed.

Animals↗
PubMed2004

Cytokine production in brain of mice experimentally infected with dengue virus.

Dengue virus encephalopathy was experimentally induced in newborn mice by i.p. inoculation of dengue 2 virus. At 6 and 9 days post-infection, motor incoordination and posterior limb paralysis were observed with focal necrosis, apoptotic cells, perivascular inflammatory cuffing and astrocytosis, mainly in the cortex and hippocampus. Expression of dengue virus genome and mRNA encoding for TNF-alpha, IL-1alpha, IL-2, IL-6, IL-1beta, IL-12 p40, IFNalpha, and IFNbeta; in addition host survival and inflammatory response genes MAC-1, EB22, GFAP, ICAM-1 and A20, were increased, suggesting that experimental dengue encephalitis could be associated with virus replication, inflammatory cytokine production or both. Similar findings have been observed in human dengue virus infection. Therefore, our results can be useful to elucidate and support the physiopathology of the disease.

Animals↗
PubMed1983

Effect of experimental dengue virus infection on immune response of the host. I. Nature of changes in T suppressor cell activity regulating the B and T cell responses to heterologous antigens.

Dengue virus-infected mice showed a depressed antibody response to polyvinylpyrrolidone (PVP) when compared to controls. In both control and dengue virus-infected animals which were treated with anti-thymocyte serum (ATS) and primed with PVP, there was a heightened antibody response to PVP, suggesting that the anti-PVP response was controlled by T suppressor cells. The increase in the anti-PVP response in dengue virus-infected, ATS-treated animals was found to be similar to that seen in ATS-treated controls. T cells from infected animals could transfer suppression of anti-PVP response to normal mice, whereas the T cells from control animals could not induce significant suppression. The T cells from dengue virus-infected animals which had received 2,4-dinitrofluorobenzene (DNFB) tolerogen could induce in normal mice a significantly higher percentage of tolerance to contact sensitivity to DNFB when compared to the control T cells. The adherent and B cells from both infected and control animals failed to induce significant tolerance. These findings suggested that during dengue virus infection, there is enhanced T suppressor cell activity regulating the B cell response to PVP and T cell response to DNFB.

Animals↗
PubMed2001

Mapping of a dengue virus neutralizing epitope critical for the infectivity of all serotypes: insight into the neutralization mechanism.

Dengue virus infections are a growing public health concern and strategies to control the spread of the virus are urgently needed. The murine monoclonal antibody 4E11 might be of interest, since it neutralizes dengue viruses of all serotypes by binding to the 296-400 segment of the major dengue virus envelope glycoprotein (DE). When phage-displayed peptide libraries were screened by affinity for 4E11, phage clone C1 was selected with a 50% frequency. C1 shared three of nine residues with DE(306-314) and showed significant reactivity to 4E11 in ELISA. C1-induced antibodies cross-reacted with DE(296-400) in mice, suggesting that it was a structural equivalent of the native epitope of 4E11 on DE. Accordingly, 4E11 bound to the DE(306-314) synthetic peptide and this reaction was inhibited by DE(296-400). Moreover, DE(306-314) could block dengue virus infection of target cells in an in vitro assay. A three-dimensional model of DE revealed that the three amino acids shared by DE(296-400) and C1 were exposed to the solvent and suggested that most of the amino acids comprising the 4E11 epitope were located in the DE(306-314) region. Since 4E11 blocked the binding of DE(296-400) to heparin, which is a highly sulfated heparan sulfate (HSHS) molecule, 4E11 may act by neutralizing the interaction of DE(306-314) with target cell-displayed HSHS. Our data suggest that the DE(306-314) segment is critical for the infectivity of all dengue virus serotypes and that molecules that block the binding of DE(306-314) to HSHS may be antiviral reagents of therapeutic interest.

Amino Acid Sequence↗