Lack of Attenuation of a Candidate Dengue 1 Vaccine (45AZ5) in Human Volunteers

Kt, McKee; Wh, Bancroft; Kh, Eckels; Rr, Redfield; Pl, Summers; Pk, Russell

doi:10.4269/ajtmh.1987.36.435

Cited by 78 publications

(46 citation statements)

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“…In fact, both volunteers who received the 45AZ5 PDK-0 vaccine strain of DEN-1 not only developed unmodified DEN fever, but developed uncharacteristically long viraemias beginning on day one postinoculation and lasting 12-19 days (McKee et al, 1987). However, the additional 25 nucleotide point mutations resulting in 11 amino acid changes that occurred between 45AZ5 PDK-0 and 45AZ5 PDK-27 did result in attenuation since none of the volunteers inoculated with the passage level 27 vaccine strain developed fever or viraemia, and only 4 out of 10 seroconverted for DEN-1 neutralizing antibody (Edelman et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of dengue virus attenuation after serial passage in primary dog kidney cells.

Puri

Nelson

Henchal

et al. 1997

Journal of General Virology

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The complete nucleotide sequences of the genomes of dengue-1 virus virulent 45AZ5 PDK-0 and attenuated vaccine candidate strain 45AZ5 PDK-27 have been determined and compared with the dengue-1 virus Western Pacific (West Pac) 74 parent strain from which 45AZ5 PDK-0 was derived. Twenty-five (0n23 %) nucleotide and 10 (0n29 %) amino acid substitutions occurred between parent strain dengue-1 virus West Pac 74 and virulent strain 45AZ5 PDK-0, which was derived from the parent by serial passage in diploid foetal rhesus lung (FRhL-2) and mutagenized with 5-azacytidine.

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Section: Discussionmentioning

confidence: 99%

Molecular analysis of dengue virus attenuation after serial passage in primary dog kidney cells.

Puri

Nelson

Henchal

et al. 1997

Journal of General Virology

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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

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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“…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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Lack of Attenuation of a Candidate Dengue 1 Vaccine (45AZ5) in Human Volunteers

Cited by 78 publications

References 0 publications

Molecular analysis of dengue virus attenuation after serial passage in primary dog kidney cells.

Molecular analysis of dengue virus attenuation after serial passage in primary dog kidney cells.

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

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

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