Phase 1 Trial of the Dengue Virus Type 4 Vaccine Candidate rDEN4Δ30-4995 in Healthy Adult Volunteers

Wright, Peter F.; Durbin, Anna P.; Whitehead, Stephen S.; Ikizler, Mine R.; Henderson, Susan; Blaney, Joseph E.; Thumar, Bhavin; Ankrah, Sharon; Rock, Michael T.; McKinney, Brett A.; Murphy, Brian R.; Schmidt, Alexander

doi:10.4269/ajtmh.2009.09-0131

Cited by 37 publications

(30 citation statements)

References 43 publications

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“…The assay was identical to that used in the Laboratory of Infectious Disease (National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health, Bethesda, MD). 14 Exchange of 20 serum samples from a DENV vaccine trial 15 determined that our results for serotype 4 were comparable to those obtained at the National Institutes of Health. This is an important consideration because variability has been shown in the DENV neutralization assay.…”

Section: Methodssupporting

confidence: 67%

Serologic Imprint of Dengue Virus in Urban Haiti: Characterization of Humoral Immunity to Dengue in Infants and Young Children

Rioth¹,

Beauharnais²,

Noël³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Dengue is endemic to Haiti but not recognized as an important illness in the autochthonous population. To evaluate the prevalence of antibodies to dengue virus (DENV), serum samples from infants and young children 7–36 months of age (n = 166) were assayed by plaque reduction neutralization assays to each DENV serotype. Dengue virus serotype 1 had infected 40% of this study population, followed by serotype 2 (12%), serotype 3 (11%), and serotype 4 (2%). Fifty-three percent of infants and young children less than 12 months of age had already experienced DENV infection, and the seroprevalence of antibody to DENV increased to 65% by 36 months. Heterotypic antibody responses were an important component of the total dengue immunity profile.

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Section: Methodssupporting

confidence: 67%

Serologic Imprint of Dengue Virus in Urban Haiti: Characterization of Humoral Immunity to Dengue in Infants and Young Children

Rioth¹,

Beauharnais²,

Noël³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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“…Significant progress in the development of dengue vaccine candidates has been achieved lately 135,136 . An Acambis/Sanofi Pasteur yellow fever-dengue chimeric vaccine is in advanced Phase II testing in children in Thailand and others are in Phase 1 or advanced preclinical evaluation.…”

Section: Vaccine Developmentmentioning

confidence: 99%

Dengue: a continuing global threat

et al. 2010

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Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ~50 million dengue infections and ~500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.Dengue is the most important arthropod-borne viral infection of humans. Worldwide, an estimated 2.5 billion people are at risk of infection, approximately 975 million of whom live in urban areas in tropical and sub-tropical countries in Southeast Asia, the Pacific and the Americas 1 . Transmission also occurs in Africa and the Eastern Mediterranean, and rural Europe PMC Funders GroupAuthor Manuscript Nat Rev Microbiol. Author manuscript; available in PMC 2015 February 19. Published in final edited form as:Nat Rev Microbiol. 2010 December ; 8(12 0): S7-16. doi:10.1038/nrmicro2460. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts communities are increasingly being affected. It is estimated that more than 50 million infections occur each year, including 500,000 hospitalizations for dengue haemorrhagic fever, mainly among children, with the case fatality rate exceeding 5% in some areas [1][2][3][4] . The geographical areas in which dengue transmission occurs have expanded in recent years (FIG. 1), and all four dengue virus serotypes (DENV-1-4) are now circulating in Asia, Africa and the Americas, a dramatically different scenario from that which prevailed 20 or 30 years ago (FIG. 2). The molecular epidemiology of these serotypes has been studied in an attempt to understand their evolutionary relationships 11 .This Review will provide an update on our understanding of the pathogenesis of this successful pathogen, how we diagnose and control infection and the progress that has been made in vaccine development. Dengue virus pathogenesisDengue viruses belong to the genus flavivirus within the Flaviviridae family. DENV-1-4 evolved in non-human primates from a common ancestor and each entered the urban cycle independently an estimated 500-1,000 years ago 12 . The virion comprises a spherical particle, 40-50 nm in diameter, with a lipopolysaccharide envelope. The positive singlestrand RNA genome (FIG. 3), which is approximately 11 kb in length, has a single open reading frame that encodes three structural proteins -the capsid (C), membrane (M) and envelope (E) glycoproteins -and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 [18][19][20] . ADE occurs when mononuclear phagocytes are infected through their Fc receptors by immune complexes that form between DE...

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“…The rDEN4D30-200,201 and rDEN4D30-4995 candidates were more attenuated than the rDEN4D30 parent in monkeys and SCID mice reconstituted with human liver cells (HuH 7) [20,119] but still elicited neutralizing antibodies. Clinical trials were performed with both vaccines (Table 13) [112,113]. These studies showed that the vaccines were more attenuated than parental rDEN4D30, produced no viremia, little or no hepatotoxicity (0% of subjects for rDEN4D30-200,201; 10% for rDEN4D30-4995), and lower neutralizing antibody levels, and a lower incidence of neutropenia and generalized rash.…”

Section: Chimeric Dengue/dengue and Deletion Mutant Vaccine Candidatementioning

confidence: 99%

“…The -4995 candidate was associated with a localized rash around the injection site in a high proportion of subjects. Sera from vaccinees in different trials who received rDEN4D30-4995, rDEN4D30-200,201 and rDEN4D30 in different trials were compared in a single neutralization test [112]. The rDEN4D30-200,201 candidate had a GMT only twofold lower than rDEN4D30.…”

Section: Chimeric Dengue/dengue and Deletion Mutant Vaccine Candidatementioning

confidence: 99%

Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses

Monath¹

2010

Replicating Vaccines

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Many arthropod-borne flaviviruses are important human pathogens responsible for diverse illnesses, including yellow fever (YF), Japanese encephalitis (JE), and TBE and dengue. Live, attenuated vaccines have afforded the most effective and economical means of prevention and control, as illustrated by YF 17D and JE SA14-14-2 vaccines. Recent advances in recombinant DNA technology have made it possible to explore a novel approach for developing live attenuated flavivirus vaccines against other flaviviruses. Full-length cDNA clones allow construction of infectious virus bearing attenuating mutations or deletions incorporated in the viral genome. It is also possible to create chimeric flaviviruses in which the structural protein genes for the target antigens of a flavivirus are replaced by the corresponding genes of another flavivirus. By combining these molecular techniques, the DNA sequences of DEN4 containing a deletion in the 3 0 NCR, a DEN2 PDK-53 candidate vaccine and YF 17D vaccine have been used as the genetic backbone to construct chimeric flaviviruses with the required attenuation phenotype and expression of the target antigens. Encouraging results from preclinical and clinical studies have shown that several chimeric flavivirus vaccines have the safety profile and satisfactory immunogenicity and protective efficacy to warrant development as products for human use. The chimeric flavivirus strategy has led to the rapid development of novel live, attenuated vaccines against DEN, TBE, JE and WN. This chapter reviews an extensive body of work on the development of these vaccine candidates, one of which is licensed and others are in advanced clinical development.A similar approach is being used to create vaccines against alphaviruses. Here the experience is less, but some promising data have been developed, particularly using SIN virus as a vector for structural genes of heterologous alphaviruses. The principal issues for this technology will be to achieve convincing nonclinical data on safety, the proper balance of attenuation and immunogenicity, and proof of concept in large animal models and ultimately humans.

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Phase 1 Trial of the Dengue Virus Type 4 Vaccine Candidate rDEN4Δ30-4995 in Healthy Adult Volunteers

Cited by 37 publications

References 43 publications

Serologic Imprint of Dengue Virus in Urban Haiti: Characterization of Humoral Immunity to Dengue in Infants and Young Children

Serologic Imprint of Dengue Virus in Urban Haiti: Characterization of Humoral Immunity to Dengue in Infants and Young Children

Dengue: a continuing global threat

Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses

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