Viremia and Immunogenicity in Nonhuman Primates of a Tetravalent Yellow Fever–Dengue Chimeric Vaccine: Genetic Reconstructions, Dose Adjustment, and Antibody Responses against Wild-type Dengue Virus Isolates

Guirakhoo, Farshad; Пугачев, К. В.; Arroyo, Juan; Miller, Catherine M.; Zhang, Z.-X.; Weltzin, Richard; Georgakopoulos, K.; Catalan, John; Ocran, Simeon W.; Draper, Ken; Monath, Thomas P.

doi:10.1006/viro.2002.1462

Cited by 136 publications

(84 citation statements)

References 22 publications

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“…The lower dose (3.0 log 10 PFU) was selected based on preclinical data in nonhuman primates: a tetravalent formulation containing all 4 chimeric viruses required a 3-log dose of ChimeriVax™-DEN2 and a higher dose of the other 3 viruses to avoid possible interference effects. 9 Adverse events were anticipated to resemble those associated with ChimeriVax™-JE. Data from Phase 1 and 2 trials of this vaccine indicated that it was well tolerated and highly immunogenic at all dose levels tested (5.8 to 1.8 log 10 PFU).…”

Section: Discussionmentioning

confidence: 99%

“…7 ChimeriVax™-DEN2 is a live, attenuated, genetically engineered virus prepared by replacing the genes encoding the two structural proteins, premembrane (prM) and envelope (E), of the YF 17D vaccine virus with the corresponding genes of the DEN2 virus (strain PUO-218, isolated from a case of classical DF, Bangkok, Thailand). 8 It is a monovalent component of a tetravalent vaccine formulation 9 currently being investigated in a Phase 2 study. Preclinical studies have demonstrated that the ChimeriVax™-DEN2 virus was is not neurovirulent when administered to adult mice via the intracerebral (IC) route, is genetically stable in cell culture, induces low levels of viremia, and protects 100% of monkeys against wt DEN2 heterologous challenge upon a single SC immunization.…”

Section: Introductionmentioning

confidence: 99%

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Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Guirakhoo

Kitchener²,

Morrison³

et al. 2006

Human Vaccines

187

136

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A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax™-DEN2) in comparison to that of YF vaccine (YF-VAX ® ). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX ® by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax TM -DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX ® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log 10 PFU of ChimeriVax TM -DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX ® seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX ® . In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax™-DEN2 vaccine is consistent with that of YF-VAX ® , and (2) preimmunity to YF virus does not interfere with ChimeriVax TM -DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Guirakhoo

Kitchener²,

Morrison³

et al. 2006

Human Vaccines

187

136

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“…Improved molecular virology techniques and an improved understanding of the genomic structure of DENV have permitted a more rapid approach based on engineering of attenuating mutations into infectious cDNA clones of each of the four DENV serotypes, with the added theoretical advantage of a lower possibility of reversion to virulence (18)(19)(20). Another molecular approach being utilized is the creation of four separate infectious chimeric flaviviruses, each of which contains the pre-M and E genes of one of the four DENV serotypes in a single "backbone" containing the C and NS proteins of an attenuated flavivirus, either the yellow fever vaccine strain or an attenuated DENV strain (21,22). DNA vaccines consisting of plasmids expressing one or a few proteins from each DENV serotype are in an earlier stage of development, as are subunit vaccines based on purified recombinant DENV proteins (23,24).…”

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confidence: 99%

Dengue: defining protective versus pathologic immunity

Rothman¹

2004

J. Clin. Invest.

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Nonstandard abbreviations used: antibody-dependent enhancement of infection (ADE); core (C); dengue fever (DF); dengue hemorrhagic fever (DHF); dengue virus (DENV); envelope (E); membrane (M); nonstructural (NS). Conflict of interest:The author has declared that no conflict of interest exists. Among scientists in the developed world, there has been a recent resurgence of interest in exotic diseases, with the aim of protecting the global population from emerging infectious disease threats. The renewed commitment of effort and resources has welcome implications for the developing world, whose population faces the greatest part of these threats. Among the biological threats considered most serious are the viral hemorrhagic fevers. Although this term usually brings to mind the deadly outbreaks of Ebola virus, in reality over 99% of the cases of viral hemorrhagic fever reported worldwide are related instead to dengue hemorrhagic fever (DHF) (1).DHF is caused by the dengue viruses (DENVs), members of the Flaviviridae family of small enveloped viruses (2). The flaviviruses carry a single-stranded RNA genome of relatively simple organization. A single open reading frame in the RNA directs the synthesis of a long polyprotein that is processed by viral and host cell proteases to produce the ten viral proteins, including three structural proteins (core [C]; membrane [M], produced as a precursor protein; and envelope [E]) and seven nonstructural (NS) proteins (Figure 1). The DENV complex encompasses four closely related serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. All four DENV serotypes are transmitted between humans in nature by mosquitoes of the genus Aedes, principally Aedes aegypti, which is highly domesticated and has a preference for biting humans.It has been estimated that over 50 million DENV infections occur globally each year (3). Most of these infections are clinically inapparent. Among symptomatic cases, the majority of subjects experience uncomplicated dengue fever (DF), an acute febrile illness typically lasting 3-7 days, accompanied by headache, myalgias, and, less often, a maculopapular rash. The headache and myalgias may be quite debilitating, which originated the name "break-bone fever" that was recorded prior to the 1900s (4). Laboratory findings in patients with DF include leukopenia thrombocytopenia, and mild elevations in serum hepatic transaminases (5). Fatigue may be prolonged for months after resolution of fever, but patients eventually recover without sequelae. None of these features is sufficiently specific for accurate clinical diagnosis of DF. Laboratory support for detection of IgM antibody or virus (by RT-PCR or virus isolation) is therefore important for recognition of outbreaks.DHF represents the severe clinical manifestation of DENV infection, which occurs in no more than 3% of infected individuals (6). Fever, headache, and myalgias are prominent symptoms in DHF, as they are in DF. DHF is distinguished from DF on clinical grounds, with the three primary criteria being the occurrence of a...

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“…Most of these chimeric viruses are derived from the infectious clone of YF17D (44). YF17D has been used as a "vector" for engineering new vaccines against other flaviviruses (e.g., the ChimeriVax vaccines ChimeriVax-JE [9,37] and ChimeriVax-DEN1, -2, -3, and -4 [13][14][15][16] and other chi-meras, i.e., WN/YF17D [34,35] and DEN2/YF17D, that are based on other dengue type 2 virus strains than the one used for ChimeriVax-DEN2 [5,49]). …”

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confidence: 99%

Exchanging the Yellow Fever Virus Envelope Proteins with Modoc Virus prM and E Proteins Results in a Chimeric Virus That Is Neuroinvasive in SCID Mice

Charlier

Molenkamp

Leyssen

et al. 2004

J Virol

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A chimeric flavivirus infectious cDNA was constructed by exchanging the premembrane (prM) and envelope (E) genes of the yellow fever virus vaccine strain 17D (YF17D) with the corresponding genes of Modoc virus (MOD). This latter virus belongs to the cluster of the "not-known vector" flaviviruses and is, unlike YF17D, neuroinvasive in SCID mice. Replication of in vitro-transcribed RNA from this chimeric flavivirus was shown by [ 3 H]uridine labeling and RNA analysis. Expression of the MOD prM and E proteins was monitored by radioimmunoprecipitation and revealed that the MOD proteins were correctly and efficiently produced from the chimeric precursor protein. The MOD E protein was shown to be N-linked glycosylated, whereas prM, as predicted from the genome sequence, did not contain N-linked carbohydrates. In Vero cells, the chimeric virus replicated with a similar efficiency as the parental viruses, although it formed smaller plaques than YF17D and MOD. In SCID mice that had been infected intraperitoneally with the chimeric virus, the viral load increased steadily until death. The MOD/YF virus, like MOD from which it had acquired the prM and E structural proteins, but unlike YF, proved neuroinvasive in SCID mice. Animals developed neurological symptoms about 15 days after inoculation and died shortly thereafter. The distribution of MOD/YF RNA in the brain of infected mice was similar to that observed in MOD-infected mice. The observations provide compelling evidence that the determinants of neuroinvasiveness of flaviviruses are entirely located in the envelope proteins prM and E.The flaviviruses (family Flaviviridae) consist of nearly 80 viruses that are distributed worldwide. These small, enveloped viruses contain a single positive-strand RNA genome of ca. 11 kb. Translation of the genome results in the synthesis of a single polyprotein precursor that is co-and posttranslationally processed by cellular proteases and a virus-encoded protease into capsid (C), premembrane (prM) and envelope (E) proteins and the nonstructural (NS) proteins NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 (36). Many flaviviruses are neurotropic, exhibiting various degrees of neuroinvasiveness and neurovirulence in experimentally infected rodents and primates. Both host-and virus-related factors are believed to influence the course of the infection (4).Yellow fever 17D virus (YF17D), considered to be one of the most effective and safest vaccines available, is neurovirulent, but not neuroinvasive, in adult (SCID) mice. Several studies suggest that the E protein, in particular, plays a dominant role as a determinant of flavivirus neurovirulence, since single amino acid substitutions in the E protein were shown to cause major effects on neurovirulence (reviewed in reference 29). It is not well understood, however, how these various mutations alter the functional properties of the flavivirus E protein and thus increase the particular characteristics of neurovirulence (29).The mechanisms and determinants underlying the neuroinvasiveness of flavivi...

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Viremia and Immunogenicity in Nonhuman Primates of a Tetravalent Yellow Fever–Dengue Chimeric Vaccine: Genetic Reconstructions, Dose Adjustment, and Antibody Responses against Wild-type Dengue Virus Isolates

Cited by 136 publications

References 22 publications

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax™-DEN2) Vaccine: Phase I Clinical Trial for Safety and Immunogenicity: Effect of Yellow Fever Pre-immunity in Induction of Cross Neutralizing Antibody Responses to All

Dengue: defining protective versus pathologic immunity

Exchanging the Yellow Fever Virus Envelope Proteins with Modoc Virus prM and E Proteins Results in a Chimeric Virus That Is Neuroinvasive in SCID Mice

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