rDEN4Δ30, a Live Attenuated Dengue Virus Type 4 Vaccine Candidate, Is Safe, Immunogenic, and Highly Infectious in Healthy Adult Volunteers

Durbin, Anna P.; Whitehead, Stephen S.; McArthur, J. C.; Perreault, John R.; Blaney, Joseph E.; Thumar, Bhavin; Murphy, Brian R.; Karron, Ruth A.

doi:10.1086/427780

Cited by 118 publications

(117 citation statements)

References 44 publications

(59 reference statements)

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“…The clinical reactogenicity observed in recipients of the LGT/DEN4 vaccine was less than that observed in recipients of a similar dose of a previously reported live attenuated dengue DEN4 vaccine [32]. Rash and neutropenia were observed in some recipients of the previously tested DEN4 vaccine candidate, but not in LGT/DEN4 vaccinees.…”

Section: Discussioncontrasting

confidence: 57%

“…This interpretation is offered with the caveat that the replication of the wild-type DEN4 parent has not been evaluated directly in humans. However, LGT/DEN4 induced viremia much less frequently in healthy adult volunteers than that observed for live attenuated DEN4Δ30 vaccine candidate derived from the same DEN4 parent and administered at the same dose [32].…”

Section: Discussionmentioning

confidence: 80%

“…YF/JE-N [28,29], St. Louis encephalitis/DEN4 (A.G. Pletnev; unpublished data), intertypic DEN1/DEN4 [30], or intertypic JE virus chimeras [31] do not appear to be satisfactorily attenuated in mice or monkeys. All chimeric viruses evaluated to date involved a parent virus that contained one or more attenuating mutations [32,33]. Since the current human study was the first to evaluate a chimeric flavivirus generated from two unmodified parent viruses, this permitted an evaluation of the independent effect of chimerization on virus attenuation for humans.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

Wright

Ankrah

Henderson

et al. 2008

Vaccine

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With the steady rise in tick-borne encephalitis virus (TBEV) infections in Europe, development of a live attenuated vaccine that will generate long-lasting immunity would be of considerable benefit. A chimeric flavivirus, designated LGT/DEN4, was previously constructed to have a genome containing the prM and E protein genes of Langat virus (LGT), a naturally attenuated member of the TBEV complex, and the remaining genetic sequences derived from dengue 4 virus (DEN4).LGT/ DEN4 was highly attenuated in rodents and non-human primates, and clinical trials in humans were initiated. Twenty-eight healthy seronegative adult volunteers were randomly assigned in a 4:1 ratio to receive 10 3 PFU of LGT/DEN4 or placebo. Volunteers were closely monitored for clinical responses and for blood chemistry and hematological changes, and the level of viremia and the magnitude and duration of the neutralizing antibody response were determined. The LGT/DEN4 vaccine was safe and viremia was seen in only one vaccinee. Infection induced a neutralizing antibody response to wild-type LGT in 80% of volunteers with a geometric mean titer (GMT) of 1:63 present on day 42 post-immunization; however the antibody response against TBEV was both much less frequent (35%) and lower in magnitude (GMT = 1:9). To assess the response to a booster dose, 21 of the original 28 volunteers were re-randomized to receive a second dose of either 10 3 PFU of vaccine or placebo given 6 to 18 months after the first dose. The immunogenicity against either LGT or TBEV was not significantly enhanced after the second dose of vaccine. Thus, chimerization of LGT with DEN4 yielded a vaccine virus that was highly attenuated yet infectious in humans. The level of replication was sufficiently restricted to induce only a weak cross-reactive antibody response to TBEV. To provide a sufficient level of immunity to widely prevalent, highly neurovirulent strains of TBEV in humans, vaccine candidates will likely need to be based on the TBEV structural protein genes.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

Wright

Ankrah

Henderson

et al. 2008

Vaccine

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“…Because of the important role of neutralizing antibodies as surrogates of protection, the validation of neutralization tests is a priority 128 . Current approaches to vaccine development involve using live attenuated viruses, inactivated viruses, subunit vaccines, DNA vaccines, cloned engineered viruses and chimeric viruses using yellow fever vaccine and attenuated dengue viruses as backbones [129][130][131][132][133][134] . TABLE 1 summarizes the most advanced vaccine candidates.…”

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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“…First, reverse genetics has been used to introduce an attenuating 30 nucleotide (nt) deletion (Δ30) mutation into the 3'-UTR of cDNA clones of each DENV serotype [16][17][18][19][20][21]. In initial studies, the rDEN4Δ30 vaccine candidate was found to be attenuated in rhesus monkeys and phase I/II clinical trials in humans have demonstrated that infection with vaccine virus results in low viremia, is strongly immunogenic, and exhibits minimal reactogenicity without serious adverse events [20,22]. Recently, the rDEN1Δ30 vaccine candidate, which was also attenuated in rhesus monkeys, has been found to share a similar set of properties in clinical trials as that observed for rDEN4Δ30: low viremia, strong immunogenicity, and minimal reactogenicity in 20 volunteers [21].…”

Section: Introductionmentioning

confidence: 99%

Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

Blaney

Sathe

Goddard

et al. 2008

Vaccine

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The dengue virus type 3 (DENV-3) vaccine candidate, rDEN3Δ30, was previously found to be underattenuated in both SCID-HuH-7 mice and rhesus monkeys. Herein, two strategies have been employed to generate attenuated rDEN3 vaccine candidates which retain the full complement of structural and nonstructural proteins of DENV-3 and thus are able to induce humoral or cellular immunity to each of the DENV-3 proteins. First, using the predicted secondary structure of the 3' untranslated region (3'-UTR) of DENV-3 to design novel deletions, nine deletion mutant viruses were engineered and found to be viable. Four of nine deletion mutants replicated efficiently in Vero cells and were genetically stable. Second, chimeric rDENV-3 viruses were generated by replacement of the 3'-UTR of the rDENV-3 cDNA clone with that of rDENV-4 or rDEN4Δ30 yielding the rDEN3-3'D4 and rDEN3-3'D4Δ30 viruses, respectively. Immunization of rhesus monkeys with either of two deletion mutant viruses, rDEN3Δ30/31 and rDEN3Δ86, or with rDEN3-3'D4Δ30 resulted in infection without detectable viremia, with each virus inducing a strong neutralizing antibody response capable of conferring protection from DENV-3 challenge. The rDEN3Δ30/31 virus showed a strong host range restriction phenotype with complete loss of replication in C6/36 mosquito cells despite robust replication in Vero cells. In addition, rDEN3Δ30/31 had reduced replication in Toxorynchites mosquitoes following intrathoracic inoculation. The results are discussed in the context of vaccine development and the physical structure of the DENV 3'-UTR.

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rDEN4Δ30, a Live Attenuated Dengue Virus Type 4 Vaccine Candidate, Is Safe, Immunogenic, and Highly Infectious in Healthy Adult Volunteers

Abstract: The rDEN4 Delta 30 vaccine is safe and induced an antibody response that was broadly neutralizing against genotypically diverse DEN-4 viruses. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.

Cited by 118 publications

References 44 publications

Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers

Dengue: a continuing global threat

Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

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