DNA vaccine against the non-structural 1 protein (NS1) of dengue 2 virus

Costa, Simoni Furtado da; Freire, Marcos S.; Alves, Ada M. B.

doi:10.1016/j.vaccine.2005.08.022

Cited by 58 publications

(38 citation statements)

References 10 publications

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“…Consistent with our results, a recent study also reported the utility of LNP-encapsulated mRNA encoding the prM and E genes as a candidate vaccine for ZIKV infection . The flexibility of this platform allows for the future inclusion of additional mRNA encoding other flavivirus proteins (e.g., NS1) that could augment protective responses (Costa et al, 2007;Costa et al, 2006) or immunodominant helper CD4 T cell epitopes (Hung et al, 2007). Future studies will be directed on evaluating the immunogenicity and protective efficacy of these mRNA vaccines in pregnant mice, nonhuman primates, and ultimately, humans.…”

Section: Discussionmentioning

confidence: 99%

Modified mRNA Vaccines Protect against Zika Virus Infection

Richner¹,

Himansu²,

Dowd³

et al. 2017

Cell

215

188

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SUMMARYThe emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (~ 1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. eTOC A modified mRNA vaccine induces sterilizing immunity against Zika virus while avoiding the generation of cross-reactive antibodies that may enhance dengue infection. AUTHOR CONTRIBUTION HHS Public Access

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Section: Discussionmentioning

confidence: 99%

Modified mRNA Vaccines Protect against Zika Virus Infection

Richner¹,

Himansu²,

Dowd³

et al. 2017

Cell

215

188

View full text Add to dashboard Cite

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“…Conversely, active or passive immunization with NS1 promotes the survival of DENVchallenged mice, making it an attractive target for vaccine development (15)(16)(17). However, only a few studies have succeeded in determining its function during replication.…”

mentioning

confidence: 99%

Dengue Virus NS1 Protein Modulates Cellular Energy Metabolism by Increasing Glyceraldehyde-3-Phosphate Dehydrogenase Activity

Allonso

Andrade

Conde

et al. 2015

J Virol

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Dengue is one of the main public health concerns worldwide. Recent estimates indicate that over 390 million people are infected annually with the dengue virus (DENV), resulting in thousands of deaths. Among the DENV nonstructural proteins, the NS1 protein is the only one whose function during replication is still unknown. NS1 is a 46-to 55-kDa glycoprotein commonly found as both a membrane-associated homodimer and a soluble hexameric barrel-shaped lipoprotein. Despite its role in the pathogenic process, NS1 is essential for proper RNA accumulation and virus production. In the present study, we identified that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with intracellular NS1. Molecular docking revealed that this interaction occurs through the hydrophobic protrusion of NS1 and the hydrophobic residues located at the opposite side of the catalytic site. Moreover, addition of purified recombinant NS1 enhanced the glycolytic activity of GAPDH in vitro. Interestingly, we observed that DENV infection promoted the relocalization of GAPDH to the perinuclear region, where NS1 is commonly found. Both DENV infection and expression of NS1 itself resulted in increased GAPDH activity. Our findings indicate that the NS1 protein acts to increase glycolytic flux and, consequently, energy production, which is consistent with the recent finding that DENV induces and requires glycolysis for proper replication. This is the first report to propose that NS1 is an important modulator of cellular energy metabolism. The data presented here provide new insights that may be useful for further drug design and the development of alternative antiviral therapies against DENV. IMPORTANCE Dengue represents a serious public health problem worldwide and is caused by infection with dengue virus (DENV).Estimates indicate that half of the global population is at risk of infection, with almost 400 million cases occurring per year. The NS1 glycoprotein is found in both the intracellular and the extracellular milieus. Despite the fact that NS1 has been commonly associated with DENV pathogenesis, it plays a pivotal but unknown role in the replication process. In an effort to understand the role of intracellular NS1, we demonstrate that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with NS1. Our results indicate that NS1 increases the glycolytic activity of GAPDH in vitro. Interestingly, the GAPDH activity was increased during DENV infection, and NS1 expression alone was sufficient to enhance intracellular GAPDH activity in BHK-21 cells. Overall, our findings suggest that NS1 is an important modulator of cellular energy metabolism by increasing glycolytic flux. Dengue is one of the major health problems in tropical regions. It is estimated that over 390 million people are infected annually with one of the four dengue virus (DENV) serotypes (1). The absence of both an effective tetravalent vaccine and therapeutic agents worsens the impact of the dengue burden. DENV, the most threatening member of the Flaviviridae family,...

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“…These potential complications have delayed significantly the development and the release of an efficient anti-DENV vaccine. The use of DENV structural proteins as vaccine targets may be attributed to the difficulties faced by the most studied anti-DENV vaccine candidate to achieve higher protective levels in clinical trials carried out in several countries (26)(27)(28).DENV nonstructural proteins (NSs) have been shown to be promising vaccine antigen candidates in monovalent formulations by inducing T cell-based immune responses (17, 18,(29)(30)(31)(32). In addition, NSs are highly conserved among serotypes and are not known to be involved in the ADE phenomenon (33).…”

mentioning

confidence: 99%

“…DENV nonstructural proteins (NSs) have been shown to be promising vaccine antigen candidates in monovalent formulations by inducing T cell-based immune responses (17,18,(29)(30)(31)(32). In addition, NSs are highly conserved among serotypes and are not known to be involved in the ADE phenomenon (33).…”

mentioning

confidence: 99%

Production of a Recombinant Dengue Virus 2 NS5 Protein and Potential Use as a Vaccine Antigen

Alves

Pereira

Fabris

et al. 2016

Clin Vaccine Immunol

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Dengue fever is caused by any of the four known dengue virus serotypes (DENV1 to DENV4) that affect millions of people worldwide, causing a significant number of deaths. There are vaccines based on chimeric viruses, but they still are not in clinical use. Anti-DENV vaccine strategies based on nonstructural proteins are promising alternatives to those based on whole virus or structural proteins. The DENV nonstructural protein 5 (NS5) is the main target of anti-DENV T cell-based immune responses in humans. In this study, we purified a soluble recombinant form of DENV2 NS5 expressed in Escherichia coli at large amounts and high purity after optimization of expression conditions and purification steps. The purified DENV2 NS5 was recognized by serum from DENV1-, DENV2-, DENV3-, or DENV4-infected patients in an epitope-conformation-dependent manner. In addition, immunization of BALB/c mice with NS5 induced high levels of NS5-specific antibodies and expansion of gamma interferon-and tumor necrosis factor alpha-producing T cells. Moreover, mice immunized with purified NS5 were partially protected from lethal challenges with the DENV2 NGC strain and with a clinical isolate (JHA1). These results indicate that the recombinant NS5 protein preserves immunological determinants of the native protein and is a promising vaccine antigen capable of inducing protective immune responses. Dengue fever is an acute disease caused by dengue virus (DENV), an arbovirus belonging to the Flaviviridae family, transmitted by Aedes mosquitoes (1, 2). In urban settings, DENV is found as four immunologically distinct types (serotypes), DENV1 to DENV4, which have approximately 30% divergence in their genomic nucleotide sequences (3-7). The disease may present with different degrees of manifestations that are classified by the WHO as dengue fever, dengue with warning signs, and severe dengue (8). A recent study showed that, annually, an average of 96 million DENV-infected people develop symptoms with severity sufficient to change their routines (1); according to previous studies, about 500,000 cases develop into severe forms of disease, which may include hemorrhage and shock syndrome (9). The mortality rate in this group reaches 10% in hospitalized patients, increasing to 30% in nontreated DENV-infected patients (9-11). Despite the high epidemiological importance of dengue fever, no effective anti-DENV drug or vaccine formulation is in clinical use for treatment or prevention of the disease.Several strategies have been explored, aiming toward the development of an effective dengue vaccine (12-21). Nonetheless, a tetravalent vaccine formulation requires a neutralizing response to all four serotypes (22)(23)(24)(25). A poor vaccine-induced response to structural proteins of any of the four serotypes may pose a risk of the onset of antibody-dependent enhancement (ADE) of virus replication upon infection by a subneutralized serotype (22-25). Moreover, protection based on the induction of neutralizing antibodies targeting structural proteins may be neg...

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DNA vaccine against the non-structural 1 protein (NS1) of dengue 2 virus

Cited by 58 publications

References 10 publications

Modified mRNA Vaccines Protect against Zika Virus Infection

Modified mRNA Vaccines Protect against Zika Virus Infection

Dengue Virus NS1 Protein Modulates Cellular Energy Metabolism by Increasing Glyceraldehyde-3-Phosphate Dehydrogenase Activity

Production of a Recombinant Dengue Virus 2 NS5 Protein and Potential Use as a Vaccine Antigen

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