Preparation of an Attenuated Dengue 4 (341750 Carib) Virus Vaccine

Hoke, Charles H.; Malinoski, Frank; Eckels, Kenneth H.; Scott, Robert McNair; Dubois, Doria R.; Summers, Peter L.; Simms, Thomas; Burrous, Jeanne; Hasty, Sherman E.; Bancroft, William H.

doi:10.4269/ajtmh.1990.43.219

Cited by 50 publications

(30 citation statements)

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“…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%

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

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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%

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

Self Cite

161

112

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“…[8][9][10][11][12] Other published work includes phase I studies in human volunteers for two DEN 4 strains, the terminally-diluted H-241 and uncloned 341750 Carib. 5,13 The Walter Reed Army Institute of Research has selected PDK-passaged dengue viruses of each serotype for Phase II human trials. The results of pre-clinical and clinical studies on candidate vaccines prepared from viruses attenuated in Hawaii that include DEN 2 (S16803) at PDK 50, fetal rhesus lung (FRhL) 3 and DEN-4 (431750 Carib) at PDK passage 20, and FRhL-4 plus one each PDKpassaged DEN-1 and DEN-3 strains are reported in this supplement.…”

Section: Introductionmentioning

confidence: 99%

Biologic Properties of Dengue Viruses Following Serial Passage in Primary Dog Kidney Cells: Studies at the University of Hawaii

Halstead

Marchette

2003

The American Journal of Tropical Medicine and Hygiene

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Abstract. Serial passage at low dilution of seven different wild-type dengue (DEN) viruses into primary dog kidney (PDK) cell cultures placed selective pressure that resulted in the following changes from parental phenotype: smaller plaques in LLC-MK2 cells, absent plaque formation in green monkey kidney cells, lack of a cytopathic effect in LLC-MK2 cells, shut-off of virus replication at high temperatures (temperature sensitivity), reduced virulence for rhesus monkeys manifested by reduced or absent viremia and/or absence of a secondary-type antibody response following homotypic challenge, and progressive increase in the mean day of death following intracerebral inoculation of sucking mice. Two DEN-1 strains showed most of these changes by the 15th PDK passage. Only one of two DEN-2 strains studied was carried to the 50th PDK passage at the University of Hawaii. For the latter strain, both the temperature of viral replicative shutoff and mouse neurovirulence were reduced. Three DEN-4 strains showed similar late-passage biologic marker changes. The observations made, although not exhaustive, provide laboratory correlates for virus strains that have shown reduced virulence but retained immunogenicity in humans. Candidate human vaccines have been prepared from five of the studied strains: DEN-1 (16007) at PDK 13, DEN-2 (16681 and S-16803) at PDK 50 or above, and DEN-4 (1036 and 341750) at PDK 48 and 20, respectively.

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“…4 Even though promising preliminary results were reported by Vaughn and others, 5 attempts to produce cell culture derived live attenuated or recombinant protein subunit dengue vaccines have had limited success to date. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] A potential problem associated with the development of an effective vaccine to protect against dengue virus infections is the occurrence of DHF and DSS predominantly in people who have had a previous dengue infection or in infants born to dengue-immune mothers. 2,20 A person who has experienced a single dengue virus infection remains susceptible to the other 3 serotypes of dengue virus.…”

Section: Introductionmentioning

confidence: 99%

Characterization of antibody responses to combinations of a dengue-2 DNA and dengue-2 recombinant subunit vaccine.

Simmons¹,

Murphy²,

Kochel³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. A dengue-2 (DEN-2) DNA vaccine coding for the premembrane and envelope (E) proteins and a recombinant fusion protein containing the B domain of the DEN-2 E protein fused to the maltose-binding protein (MBP) of Escherichia coli both elicited neutralizing antibody in mice. In order to achieve more rapid protective immunity as well as to increase the persistence of neutralizing antibody, we primed mice with the DNA vaccine (D), the recombinant MBP protein (R), or both (RD) given simultaneously, and then boosted twice with either the R ( (40), and the D/R/R group had a slightly higher titer (156) than these 2 groups. The predominant antibody subclass for the D/D/D mice was immunoglobulin (Ig) G2a, similar to mice infected with live virus. The R/R/R mice showed an exclusive IgG1 antibody response, and the RD/RD/RD response also was predominantly IgG1. The antibody subclass pattern of the R/D/D and D/R/R mice showed a more balanced distribution of both IgG1 and IgG2a. Investigating the neutralizing capacity of antibody subclasses suggested that both IgG1 and IgG2a could neutralize DEN-2 virus. Our observations indicate that the combination RD prime-boost regimen warrants further investigation as a vaccine strategy to prevent dengue infection.

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Preparation of an Attenuated Dengue 4 (341750 Carib) Virus Vaccine

Cited by 50 publications

References 0 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

Biologic Properties of Dengue Viruses Following Serial Passage in Primary Dog Kidney Cells: Studies at the University of Hawaii

Characterization of antibody responses to combinations of a dengue-2 DNA and dengue-2 recombinant subunit vaccine.

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