Phase 1 Studies of Walter Reed Army Institute of Research Candidate Attenuated Dengue Vaccines: Selection of Safe and Immunogenic Monovalent Vaccines

Kanesa-thasan, Niranjan; Edelman, Robert; Tacket, Carol O.; Wasserman, Steven S.; Vaughn, David W.; Coster, Trinka S.; Kim-Ahn, Gina; Dubois, Doria R.; Putnak, J. Robert; King, Alan D.; Summers, Peter L.; Innis, Bruce L.; Eckels, Kenneth H.; Hoke, Charles H.

doi:10.4269/ajtmh.2003.69.17

Cited by 54 publications

(40 citation statements)

References 18 publications

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“…In the monovalent DEN vaccine trials, guinea pig complement tended to enhance cross-reactive neutralizing antibodies induced by monovalent vaccines against heterospecific DEN strains. 4,5 Thus, to enhance the specificity of the serologic response against each of the four serotypes in the tetravalent vaccine formulations (and to obtain a more accurate estimate of the immunogenicity of each dengue strain), we did not use complement in the PRNT assays of serum obtained from tetravalent-vaccinated volunteers.…”

Section: Discussionmentioning

confidence: 99%

“…For the past 20 years, many monovalent, live DEN vaccine candidates representing the four serotypes have been evaluated in pre-clinical and clinical studies by United States Army and University of Maryland investigators [3][4][5]7,8,[14][15][16][17][18] Most candidates were either under-attenuated and made volunteers too ill or over-attenuated and failed to infect and immunize people. Thai DEN vaccine candidates appear to be immunogenic and relatively free of side effects.…”

Section: Discussionmentioning

confidence: 99%

“…2 Several Walter Reed Army Institute of Research (WRAIR) vaccine candidates, tested under investigational new drugs (INDs) filed between 1989 and 1998, have performed well in Phase 1 trials conducted at the University of Maryland 3 and at WRAIR. 4,5 The best four monovalent components for a tetravalent vaccine have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Trial of 16 Formulations of a Tetravalent Live-Attenuated Dengue Vaccine

Edelman

Wasserman

Bodison

et al. 2003

The American Journal of Tropical Medicine and Hygiene

161

112

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Abstract. Laboratory-attenuated strains of each of the four dengue serotypes previously tested as monovalent vaccines in volunteers were combined and tested for immunogenicity, safety, and reactogenicity in 16 dosage combinations. Tetravalent vaccines made using combinations of high (10 5−6 plaque-forming units [PFU]/dose) or low (10 3.5−4.5 PFU/dose) dosage formulations of each of the four viruses were inoculated in 64 flavivirus non-immune adult volunteers to determine which, if any, formulation raised neutralizing antibodies in at least 75% of volunteers to at least three of four dengue serotypes following one or two inoculations. Such formulations, if safe and sufficiently non-reactogenic, would be considered for an expanded Phase II trial in the future. Formulations 1−15 were each inoculated into three or four volunteers (total ‫ס‬ 54) on days 0 and 28. Formulation 16 was tested in 10 volunteers, five volunteers inoculated on days 0 and 30, one volunteer on days 0 and 120, and four volunteers on days 0, 30, and 120. Blood was drawn for serologic assays immediately before and one month after each vaccination, and for viremia assay on day 10 after each vaccination. The 16 formulations were safe, but variably reactogenic after the first vaccination, and nearly non-reactogenic after the second and third vaccinations. Reactogenicity was positively correlated with immunogenicity. Similar proportions of volunteers seroconverted to dengue-1 (69%), dengue-2 (78%), and dengue-3 (69%), but significantly fewer volunteers seroconverted to dengue-4 (38%). The geometric mean 50% plaque reduction neutralization test titers in persons who seroconverted were significantly higher to dengue-1 (1:94) than to dengue-2 (1:15), dengue-3 (1:10), and dengue-4 (1:2). Seven formulations met the serologic criteria required for an expanded trial, and three of these were sufficiently attenuated clinically to justify further testing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phase I Trial of 16 Formulations of a Tetravalent Live-Attenuated Dengue Vaccine

Edelman

Wasserman

Bodison

et al. 2003

The American Journal of Tropical Medicine and Hygiene

161

112

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“…However, the development of a live-attenuated DEN virus vaccine has been complicated by several factors. First, it has been difficult to develop monovalent vaccines against each of the four serotypes that exhibit a satisfactory balance between attenuation and immunogenicity (25,26). Second, an effective live-attenuated DEN virus vaccine must consist of a tetravalent formulation of components representing each serotype because multiple serotypes typically cocirculate in a region, each DEN serotype is capable of causing disease, and the introduction of additional serotypes is common (18,37,42).…”

mentioning

confidence: 99%

Recombinant, Live-Attenuated Tetravalent Dengue Virus Vaccine Formulations Induce a Balanced, Broad, and Protective Neutralizing Antibody Response against Each of the Four Serotypes in Rhesus Monkeys

Blaney

Matro

Murphy

et al. 2005

J Virol

150

119

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Three tetravalent vaccine (TV) formulations of previously described monovalent dengue (DEN) virus vaccine candidates were compared to a tetravalent formulation of wild-type DEN viruses (T-wt) for replication in SCID mice transplanted with human liver cells (SCID-HuH-7) or for replication and immunogenicity in rhesus monkeys. TV-1 consists of recombinant DEN1, -2, -3, and -4, each with a 30-nucleotide deletion in the 3 untranslated region (⌬30). TV-2 consists of rDEN1⌬30, rDEN4⌬30, and two antigenic chimeric viruses, rDEN2/ 4⌬30 and rDEN3/4⌬30, both also bearing the ⌬30 mutation. TV-3 consists of rDEN1⌬30, rDEN2⌬30, rDEN4⌬30, and a 10-fold higher dose of rDEN3/4⌬30. TV-1 and TV-2 were attenuated in SCID-HuH-7 mice with minimal interference in replication among the virus components. TV-1, -2, and -3 were attenuated in rhesus monkeys as measured by duration and peak of viremia. Each monkey immunized with TV-1 and TV-3 seroconverted to the four DEN components by day 28 with neutralization titers ranging from 1:52 to 1:273 and 1:59 to 1:144 for TV-1 and TV-3, respectively. TV-2 induced low antibody titers to DEN2 and DEN3, but a booster immunization after 4 months increased the neutralizing antibody titers to greater than 1:100 against each serotype and elicited broad neutralizing activity against 19 of 20 DEN subtypes. A single dose of TV-2 induced protection against wild-type DEN1, DEN3, and DEN4 challenge, but not DEN2. However, two doses of TV-2 or TV-3 induced protection against DEN2 challenge. Two tetravalent formulations, TV-2 and TV-3, possess properties of a successful DEN vaccine and can be considered for evaluation in clinical trials.The mosquito-borne dengue (DEN) viruses, members of the Flaviviridae family, contain a single-stranded positive-sense RNA genome (36). A single polypeptide is cotranslationally processed by viral and cellular proteases generating three structural proteins (C, M, and E) and at least 7 nonstructural proteins. The genome organization of the DEN viruses is 5Ј UTR-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-UTR-3Ј (UTR-untranslated region, C-capsid, prM-membrane precursor, E-envelope, NS-nonstructural). There are four DEN virus serotypes (DEN1, DEN2, DEN3, and DEN4) which circulate in tropical and subtropical regions of the world inhabited by more than 2.5 billion people (12). Annually, there are an estimated 50 to 100 million DEN virus infections and hundreds of thousands of cases of the more severe and potentially lethal DEN hemorrhagic fever/shock syndrome, with children bearing much of the disease burden (13). DEN viruses are endemic in at least 100 countries and cause more human disease than any other mosquito-borne virus. In at least eight Asian countries, the DEN viruses are a leading cause of hospitalization and death in children (45). Unfortunately, many countries affected by DEN viruses have very limited financial resources for healthcare, and the economic burden of DEN disease is considerable (1, 45). An economical vaccine that prevents disease caused by the DEN viruses is a...

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“…In the PDK-53 vaccine strain, the virus lost its capability to induce viremia in non-human primates, while stimulating robust neutralizing immune responses after 53 passages in primary dog kidney cells (11). A number of other clinical studies testing monovalent and tetravalent vaccines including the PDK-53 component as listed in Osorio et al (12), have shown to cause few adverse effects, but provide reliable immunogenicity (11,13,14). However, it is currently unknown to what extent the PDK-53 strain induces MMP production.…”

Section: Introductionmentioning

confidence: 99%

Relationship between MMP Expression and Virulence of Dengue Virus Type-2 in Infected Mosquito and Mammalian Cells

et al. 2016

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SUMMARY:Dengue virus infections are mostly asymptomatic but can produce a mild, self-limiting acute febrile illness, dengue fever, or a life threatening severe illness, dengue hemorrhagic fever. Dengue hemorrhagic fever is associated with increased vascular permeability partly as a result of elevated levels of matrix metalloproteinases (MMPs). We characterized MMP-2 and MMP-9 production in mosquito and mammalian cells after infection with three strains of dengue virus type-2 (D2-) ranging in virulence: 16681, the prototype New Guinea C (NGC), and PDK-53 vaccine strain. These strains were used to test variations in viral properties in vaccine candidates and confirm the production of MMP as a possible marker for virulence. A zymogram gelatinolytic activity assay was used to assess MMP-2 and MMP-9 production. We found that dengue-infected mosquito and mammalian cell lines had unique MMP-2 and MMP-9 production patterns depending on the virulence of the infecting dengue strain and the duration infection. MMP levels were highest after infection with the most virulent strain D2-16681, followed by the prototype NGC strain, in both cell lines. The MMP levels appeared to correspond with the relative amounts of infectious virions produced later in infection. Our findings improve our understanding of dengue pathogenesis and may facilitate the selection of markers to further the development of dengue vaccines.

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Phase 1 Studies of Walter Reed Army Institute of Research Candidate Attenuated Dengue Vaccines: Selection of Safe and Immunogenic Monovalent Vaccines

Cited by 54 publications

References 18 publications

Phase I Trial of 16 Formulations of a Tetravalent Live-Attenuated Dengue Vaccine

Phase I Trial of 16 Formulations of a Tetravalent Live-Attenuated Dengue Vaccine

Recombinant, Live-Attenuated Tetravalent Dengue Virus Vaccine Formulations Induce a Balanced, Broad, and Protective Neutralizing Antibody Response against Each of the Four Serotypes in Rhesus Monkeys

Relationship between MMP Expression and Virulence of Dengue Virus Type-2 in Infected Mosquito and Mammalian Cells

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