Dengue-2 Vaccine: Oral Infection, Transmission, and Lack of Evidence for Reversion in the Mosquito, Aedes aegypti *

Br, Miller; Bj, Beaty; Th, Aitken; Kh, Eckels; Pk, Russell

doi:10.4269/ajtmh.1982.31.1232

Cited by 27 publications

(22 citation statements)

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“…This was similar to the results of our previous study on DEN-2 PDK53 9 and to the results of other investigators on DEN-2 PR159/S-1 15 and DEN-4 PDKTD3FRhLp3 vaccines. 16 A possible explanation is that the vaccine viruses had been modified during serial passages in unnatural hosts (PDK, PGMK, or FRhL cells), which affected the ability to infect mosquitoes.…”

Section: Discussionsupporting

confidence: 82%

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Dynamics of susceptibility and transmissibility of the live, attenuated, candidate vaccines dengue-1 PDK13, dengue-3 PGMK30F3, and dengue-4 PDK48 after oral infection in Aedes aegypti.

Jirakanjanakit¹,

Khin²,

Yoksan³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Dengue-1 virus PDK13 and isolates from vaccinees (dengue-1 Ib1 and dengue-1 Ib 10), dengue-3 PGMK30F3, and dengue-4 PDK48 were studied for their abilities to infect, disseminate, and replicate in Aedes aegypti mosquitoes by the oral route. In general, infection and dissemination rates were poorer for the vaccine compared with the parent viruses. The transmissibility was also lower for dengue-1 PDK13 than the parent virus, whereas it was not detected for isolates from vaccinees and dengue-3 PGMK30F3. Transmissibility of dengue-4 PDK48 was not determined because no dissemination occurred. Replication rates of vaccine strains were also found to be less efficient than the parent viruses. These imply that vaccination with the candidate vaccine is safe. Moreover, vector attenuation of vaccine viruses was consistent with its phenotypic markers of attenuation, which remained stable after a mosquito passage or after human and mosquito passage.Dengue (DEN) is a global disease of the tropics and one of the most important emerging diseases, with half of the world population at risk.1 Since the 1940s, an approach of disease prevention has been directed towards a search for a vaccine.2,3 Live, attenuated, candidate DEN-1 PDK13, DEN-2, PDK53, DEN-3 PGMK30F3, and DEN-4 PDK48 vaccine viruses were developed by the Center for Vaccine Development at Mahidol University (Nakornpathom, Thailand). [4][5][6][7] The DEN-1 PDK13, DEN-2 PDK53, and DEN-4 PDK48 candidate vaccine viruses were derived from serially passages of the parent viruses DEN-1 16007, DEN-2 16681 and DEN-4 1036 in primary dog kidney (PDK) cell cultures (National Institute of Public Health and Environment Protection, Bilthoyen, The Netherlands). 4,8 The DEN-3 PGMK30F3 vaccine was derived from serial passages of DEN-3 16562 virus in primary green monkey kidney (PGMK) cells for 30 consecutive passages and an additional 3 passages in certified fetal rhesus lung (FRhL) cells (American Type Culture Collection, Rockville, MD). These DEN virus candidate vaccines have met the appropriate requirements of biologic attenuation. 4 However, during phase 1 and phase 2 clinical evaluations of DEN candidate vaccines, some volunteers experienced a transient period of viremia, during which dengue viruses were recovered. 5 The possibility of the vector Aedes aegypti feeding on a viremic individual exists, especially when immunization programs are conducted. This concern has provoked an investigation of the stability of the biologic characteristics of DEN candidate vaccines after oral infection into Ae. aegypti. It is expected that the vaccine should not infect mosquito by oral route. However, if it does, the vaccine virus should infect the mosquito poorly and be inefficiently transmitted. Moreover, the vaccine virus should not revert to a virulent form, so that immunization with the vaccine will not disseminate pathogenic dengue virus in nature. Therefore, vector attenuation is an important consideration for a dengue candidate vaccine.Our previous study on DEN-2 PDK53 candidate v...

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Section: Discussionsupporting

confidence: 82%

“…aegypti orally infected with DEN-2 PR159/S1 vaccine virus. 15 They proposed that virus replicated in the midgut of the mosquito but was unable to mature and escape into the hemocoel, or to attach and replicate in secondary organ systems. Kuberski suggested that dissemination of viruses could occur via the hemolymph.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of susceptibility and transmissibility of the live, attenuated, candidate vaccines dengue-1 PDK13, dengue-3 PGMK30F3, and dengue-4 PDK48 after oral infection in Aedes aegypti.

Jirakanjanakit¹,

Khin²,

Yoksan³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The PR-159 strain of DEN-2 virus was isolated from the serum of a patient with dengue fever in Puerto Rico in 1969. 19 A confluent 75-cm 2 tissue culture flask of A. albopictus C6/36 cells was infected at a multiplicity of infection of 0.01-0.1, and the flask was brought to a total volume of 10 ml with L-15 medium, 2% fetal bovine serum (FBS), 100 U/ml of penicillin, and 100 g/ml of streptomycin (P/ S). After seven days incubation at 28ЊC, cells were scraped into the medium and this suspension was the source of virus for infectious blood meals.…”

Section: Methodsmentioning

confidence: 99%

Quantitative genetics of vector competence for dengue-2 virus in Aedes aegypti.

Bosio

Beaty²,

Th³

1998

The American Journal of Tropical Medicine and Hygiene

182

217

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Abstract. A quantitative genetic study of the ability of Aedes aegypti to propagate dengue-2 (DEN-2) virus in the midgut and in a disseminated infection in the head was conducted with a standard half-sib breeding design. Aedes aegypti aegypti and A. aegypti formosus differ markedly in oral susceptibility to DEN-2 virus. Mosquitoes were orally infected and, after an extrinsic incubation period of 14 days, virus titer (by tissue culture infectious dose, 50% endpoint) was determined in the midgut (MT) and head (HT). Body size as measured by wing length was not significantly different between infected and uninfected mosquitoes and was not correlated with MT or HT. The heritability for MT in both subspecies was 0.41 and was 0.39 for HT in A. aegypti formosus. In A. aegypti aegypti, HT appeared to be controlled by dominant alleles. The MT was not correlated with HT nor did MT determine whether virus disseminated out of the midgut. These results suggest that it is the barriers to infection and dissemination, independent of virus titer, that determine vector competence for DEN-2 virus.The four serotypes of dengue (DEN) virus are a major public health concern for many tropical regions, each year causing hundreds of thousands of cases of dengue fever and dengue hemorrhagic fever. 1,2 The primary vector of DEN viruses is the mosquito Aedes aegypti. Subspecies and strains of A. aegypti have been shown to vary phenotypically in their susceptibility to DEN viruses. 3 Aedes aegypti aegypti has a broad geographic distribution, and many studies have shown that it is a more competent vector of flaviviruses than A. aegypti formosus, which is distributed only in sylvan and rural areas of West Africa. 3,4 In a study of the vector competence of A. aegypti for yellow fever (YF) virus, patterns of susceptibility among different populations were correlated with genetic groupings identified by allozyme analysis, suggesting a genetic basis for this variation. 4 Similar phenotypic variation has been seen for DEN viruses in another important vector, A. albopictus. 5 When a mosquito takes a viremic blood meal, the virus encounters several barriers to infection. First, virus must establish an infection in the midgut by overcoming a midgut infection barrier (MIB). Following replication in midgut epithelium, virus must pass through a midgut escape barrier (MEB) and replicate in other tissues (disseminated infection). Finally, virus must infect the salivary glands and be shed in saliva to be transmitted to the next vertebrate host.The genetics of MIB, MEB, and disseminated infection in A. aegypti for DEN virus and other flaviviruses are not well understood. Genetic studies of vector competence to date have primarily used selection protocols to produce susceptible and resistant lines, followed by crossing these lines to analyze the phenotype in F 1 offspring and in some studies, monitoring of susceptibility in F 2 and backcross generations. Miller and Mitchell 6 selected lines of A. aegypti that were completely refractory or highly susceptible to...

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“…In this and previous studies (10,25) (2,3,15,34,45). A DEN-4 deletion mutant that failed to produce plaques in C6/36 cells was also replication defective in A. albopictus mosquitoes (11).…”

Section: Vol 74 2000mentioning

confidence: 99%

Chimeric Dengue Type 2 (Vaccine Strain PDK-53)/Dengue Type 1 Virus as a Potential Candidate Dengue Type 1 Virus Vaccine

Huang

Butrapet

Pierro

et al. 2000

J Virol

165

162

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We constructed chimeric dengue type 2/type 1 (DEN-2/DEN-1) viruses containing the nonstructural genes of DEN-2 16681 virus or its vaccine derivative, strain PDK-53, and the structural genes (encoding capsid protein, premembrane protein, and envelope glycoprotein) of DEN-1 16007 virus or its vaccine derivative, strain PDK-13. We previously reported that attenuation markers of DEN-2 PDK-53 virus were encoded by genetic loci The viral structural proteins, C, prM/M, and E, and the nonstructural proteins, NS1 to NS5, are translated as a single polyprotein and processed by cellular and viral proteases (12,49).Transmitted by Aedes aegypti mosquitoes to humans, DEN viruses cause tens of millions of cases, ranging from dengue fever to the sometimes fatal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in tropical and subtropical regions of the world every year (42). Epidemiologic studies have shown that individuals who experience a secondary infection with a DEN virus serotype that differs from that of the previous infection are at higher risk of developing DHF/DSS (21). Therefore, an efficacious tetravalent vaccine is needed to provide solid and long-term immunity against all four DEN virus serotypes. Four parental DEN virus serotypes (DEN-1 16007, DEN-2 16681, DEN-3 16562, and DEN-4 1036) were passaged in cell cultures to obtain attenuated vaccine candidates at Mahidol University, Bangkok, Thailand (51). Human clinical trials have been conducted in Thailand and the United States (4-6, 17, 48). These attenuated viruses are currently the most promising DEN virus vaccine candidates in terms of immunogenicity and safety in humans. The Mahidol vaccine candidates DEN-1 PDK-13, DEN-2 PDK-53, DEN-3 PGMK-30/FRhL-3, and DEN-4 PDK-48 viruses have 50% minimum infectious dose values of 10 4 , 5, 3,500, and 150 PFU, respectively, in humans (4). The candidate DEN-2 PDK-53 virus vaccine, which has the lowest infectious dose in humans, is strongly immunogenic and has produced no untoward clinical symptoms. The DEN-1 PDK-13 virus vaccine, on the other hand, has a high infectious dose and has resulted in minimal reactogenicity with lower seroconversion rate in human trials (4). While only one immunization with DEN-2 PDK-53 virus was required to achieve 100% seroconversion, a DEN-1 PDK-13 virus booster was needed to achieve the same seroconversion rate.An understanding of the attenuation markers of the candidate DEN-2 PDK-53 virus vaccine should permit engineering of improved DEN virus vaccines. For this purpose, infectious cDNA clones of DEN-2 16681 and PDK-53 viruses (25), as well as recombinant DEN-2 16681/PDK-53 viruses (10), have been constructed. The uncloned PDK-53 virus vaccine contains a mixture of two genotypic variants (25), designated PDK53-E and PDK53-V in this report. The PDK53-V variant contains all nine PDK-53 virus vaccine-specific nucleotide mutations, including the Glu-to-Val mutation at amino acid position NS3-250. The PDK53-E variant contains eight of the nine mutations of the PDK-53 vaccine and the NS3-250-...

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Dengue-2 Vaccine: Oral Infection, Transmission, and Lack of Evidence for Reversion in the Mosquito, Aedes aegypti *

Cited by 27 publications

References 0 publications

Dynamics of susceptibility and transmissibility of the live, attenuated, candidate vaccines dengue-1 PDK13, dengue-3 PGMK30F3, and dengue-4 PDK48 after oral infection in Aedes aegypti.

Dynamics of susceptibility and transmissibility of the live, attenuated, candidate vaccines dengue-1 PDK13, dengue-3 PGMK30F3, and dengue-4 PDK48 after oral infection in Aedes aegypti.

Quantitative genetics of vector competence for dengue-2 virus in Aedes aegypti.

Chimeric Dengue Type 2 (Vaccine Strain PDK-53)/Dengue Type 1 Virus as a Potential Candidate Dengue Type 1 Virus Vaccine

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