mRNA Vaccine Protects against Zika Virus

Zika virus (ZIKV), a mosquito-borne flavivirus, has recently triggered global concern due to severe health complications. In 2015, a large ZIKV outbreak occurred in the Americas and established a link between ZIKV and microcephaly in newborn babies, spontaneous abortion, persistent viremia, and Guillain–Barré syndrome. While antivirals are being developed and prevention strategies focus on vector control, a safe and effective Zika vaccine remains unavailable. Messenger RNA (mRNA) vaccine technology has arisen as a flexible, simplified, and fast vaccine production platform. Here, we report on an mRNA vaccine candidate that encodes the pre-membrane and envelope (prM–E) glycoproteins of ZIKV strain Brazil SPH2015 and is encapsulated in lipid nanoparticles (LNPs). Our ZIKV prM–E mRNA-LNP vaccine candidate induced antibody responses that protected in AG129 mice deficient in interferon (IFN) alpha/beta/gamma (IFN-α/β/γ) receptors. Notably, a single administration of ZIKV prM–E mRNA-LNP protected against a lethal dose of ZIKV, while a two-dose strategy induced strong protective immunity. E-specific double-positive IFN-γ and TNF-α T-cells were induced in BALB/c mice after immunizations with a two-dose strategy. With the success of mRNA vaccine technology in facing the coronavirus (COVID-19) pandemic, our data support the development of prM–E RNActive® as a promising mRNA vaccine against Zika to counter future epidemics.

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Dengue and Zika Virus Infections Are Enhanced by Live Attenuated Dengue Vaccine but Not by Recombinant DSV4 Vaccine Candidate in Mouse Models

SSRN Electronic Journal ◽

10.2139/ssrn.3572852 ◽

2020 ◽

Author(s):

Rahul Shukla ◽

Julia A. Brown ◽

Hemalatha Beesetti ◽

Richa Ahuja ◽

Viswanathan Ramasamy ◽

...

Keyword(s):

Mouse Models ◽

Zika Virus ◽

Vaccine Candidate ◽

Virus Infections ◽

Dengue Vaccine

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A Chimeric Protein That Functions as both an Anthrax Dual-Target Antitoxin and a Trivalent Vaccine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00640-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4750-4757 ◽

Cited By ~ 6

Author(s):

Gaobing Wu ◽

Yuzhi Hong ◽

Aizhen Guo ◽

Chunfang Feng ◽

Sha Cao ◽

...

Keyword(s):

Protective Antigen ◽

Vaccine Candidate ◽

Lethal Factor ◽

Lethal Dose ◽

Chimeric Protein ◽

Dominant Negative ◽

Lethal Challenge ◽

Edema Factor ◽

Trivalent Vaccine

ABSTRACT Effective measures for the prophylaxis and treatment of anthrax are still required for counteracting the threat posed by inhalation anthrax. In this study, we first demonstrated that the chimeric protein LFn-PA, created by fusing the protective antigen (PA)-binding domain of lethal factor (LFn) to PA, retained the functions of the respective molecules. On the basis of this observation, we attempted to develop an antitoxin that targets the binding of lethal factor (LF) and/or edema factor (EF) to PA and the transportation of LF/EF. Therefore, we replaced PA in LFn-PA with a dominant-negative inhibitory PA (DPA), i.e., PAF427D. In in vitro models of anthrax intoxication, the LFn-DPA chimera showed 3-fold and 2-fold higher potencies than DPA in protecting sensitive cells against anthrax lethal toxin (LeTx) and edema toxin (EdTx), respectively. In animal models, LFn-DPA exhibited strong potency in rescuing mice from lethal challenge with LeTx. We also evaluated the immunogenicity and immunoprotective efficacy of LFn-DPA as an anthrax vaccine candidate. In comparison with recombinant PA, LFn-DPA induced significantly higher levels of the anti-PA immune response. Moreover, LFn-DPA elicited an anti-LF antibody response that could cross-react with EF. Mice immunized with LFn-DPA tolerated a LeTx challenge that was 5 times its 50% lethal dose. Thus, LFn-DPA represents a highly effective trivalent vaccine candidate for both preexposure and postexposure vaccination. Overall, we have developed a novel and dually functional reagent for the prophylaxis and treatment of anthrax.

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Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

mBio ◽

10.1128/mbio.01683-18 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 31

Author(s):

Qi Chen ◽

Jin Wu ◽

Qing Ye ◽

Feng Ma ◽

Qian Zhu ◽

...

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Zika Virus ◽

Vaccine Candidate ◽

Cell Subpopulation ◽

Glioma Stem Cells ◽

Intracerebral Injection ◽

Potential Candidate ◽

Orthotopic Model ◽

Human Gbm

ABSTRACT Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy. IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.

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Expression of High Mobility Group Box Chromosomal Protein 1 and Its Modulating Effects on Downstream Cytokines in Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.090663 ◽

2010 ◽

Vol 37 (4) ◽

pp. 766-775 ◽

Cited By ~ 58

Author(s):

JIE LI ◽

HONGFU XIE ◽

TING WEN ◽

HONGBO LIU ◽

WU ZHU ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Messenger Rna ◽

Activity Index ◽

High Mobility ◽

High Mobility Group ◽

Chromosomal Protein ◽

Systemic Lupus ◽

Tnf Α

Objective.To compare the expression of high mobility group box chromosomal protein 1 (HMGB1) and the modulating effects on its downstream cytokines in patients with systemic lupus erythematosus (SLE) and healthy controls.Methods.HMGB1 concentrations in serum from SLE patients and controls were measured by immunoblot analysis. HMGB1 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) was detected by real-time reverse transcription–polymerase chain reaction. Immunofluorescence assay was employed to examine the translocation of HMGB1 in monocytes after endotoxin stimulation. Release of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) by PBMC after rHMGB1 stimulation was also measured.Results.Serum HMGB1 levels and HMGB1 mRNA expressions in PBMC were elevated in SLE patients compared with controls. A positive correlation was demonstrated between HMGB1 concentrations and SLE Disease Activity Index. There was an inverse correlation between HMGB1 levels and C4 and C3 concentrations in SLE patients. HMGB1 concentrations were higher in patients with vasculitis and myositis. Lipopolysaccharide stimulated a temporarily elevated release of HMGB1 in SLE patients compared with controls. The pattern and localization of HMGB1 staining in monocytes were similar in both groups. After stimulation with rHMGB1, TNF-α level decreased but IL-6 level increased in SLE patients compared with controls.Conclusion.Our findings suggest that increased serum levels of HMGB1 in SLE may be associated with lupus disease activity. The altered production of TNF-α and IL-6 in response to rHMGB1 stimulation may participate in the disruption of cytokine homeostasis in SLE.

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Target cell-directed rapid degradation of TNF-α messenger RNA in human cytotoxic T cells

Immunology Letters ◽

10.1016/0165-2478(94)90203-8 ◽

1994 ◽

Vol 40 (1) ◽

pp. 37-42 ◽

Cited By ~ 1

Author(s):

Markian R. Bochan ◽

Zacharie Brahmi

Keyword(s):

T Cells ◽

Target Cell ◽

Messenger Rna ◽

Cytotoxic T Cells ◽

Rapid Degradation ◽

Tnf Α

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Maternal immunization with a DNA vaccine candidate elicits specific passive protection against post-natal Zika virus infection in immunocompetent BALB/c mice

Vaccine ◽

10.1016/j.vaccine.2018.04.051 ◽

2018 ◽

Vol 36 (24) ◽

pp. 3522-3532 ◽

Cited By ~ 14

Author(s):

Ran Wang ◽

Xianzheng Liao ◽

Dongying Fan ◽

Lei Wang ◽

Ji Song ◽

...

Keyword(s):

Virus Infection ◽

Dna Vaccine ◽

Zika Virus ◽

Vaccine Candidate ◽

Passive Protection ◽

Maternal Immunization ◽

Zika Virus Infection

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Immunogenicity and Efficacy of Zika Virus Envelope Domain III in DNA, Protein, and ChAdOx1 Adenoviral-Vectored Vaccines

Vaccines ◽

10.3390/vaccines8020307 ◽

2020 ◽

Vol 8 (2) ◽

pp. 307 ◽

Cited By ~ 3

Author(s):

César López-Camacho ◽

Giuditta De Lorenzo ◽

Jose Luis Slon-Campos ◽

Stuart Dowall ◽

Peter Abbink ◽

...

Keyword(s):

Immune Responses ◽

Dengue Virus ◽

Zika Virus ◽

Neutralizing Antibodies ◽

Vaccine Candidate ◽

Protein Domain ◽

Virus Envelope ◽

Zikv Infection ◽

Domain Iii ◽

Open Question

The flavivirus envelope protein domain III (EDIII) was an effective immunogen against dengue virus (DENV) and other related flaviviruses. Whether this can be applied to the Zika virus (ZIKV) vaccinology remains an open question. Here, we tested the efficacy of ZIKV-EDIII against ZIKV infection, using several vaccine platforms that present the antigen in various ways. We provide data demonstrating that mice vaccinated with a ZIKV-EDIII as DNA or protein-based vaccines failed to raise fully neutralizing antibodies and did not control viremia, following a ZIKV challenge, despite eliciting robust antibody responses. Furthermore, we showed that ZIKV-EDIII encoded in replication-deficient Chimpanzee adenovirus (ChAdOx1-EDIII) elicited anti-ZIKV envelope antibodies in vaccinated mice but also provided limited protection against ZIKV in two physiologically different mouse challenge models. Taken together, our data indicate that contrary to what was shown for other flaviviruses like the dengue virus, which has close similarities with ZIKV-EDIII, this antigen might not be a suitable vaccine candidate for the correct induction of protective immune responses against ZIKV.

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Dynamic production of tumour necrosis factor‐α (TNF‐α) messenger RNA, intracellular and extracellular TNF‐α by murine macrophages and possible association with protein tyrosine phosphorylation of STAT1α and ERK2 as an early signal

Immunology ◽

10.1046/j.1365-2567.1996.513591.x ◽

1996 ◽

Vol 87 (4) ◽

pp. 544-550 ◽

Cited By ~ 16

Author(s):

Z. M. ZHENG ◽

S. SPECTER

Keyword(s):

Tyrosine Phosphorylation ◽

Tumour Necrosis Factor ◽

Messenger Rna ◽

Tumour Necrosis ◽

Protein Tyrosine Phosphorylation ◽

Tumour Necrosis Factor Α ◽

Early Signal ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

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Zederone, a Sesquiterpene from Curcuma elata Roxb, is Hepatotoxic in Mice

International Journal of Toxicology ◽

10.1177/1091581813504595 ◽

2013 ◽

Vol 32 (6) ◽

pp. 454-462 ◽

Cited By ~ 8

Author(s):

Prapapan Pimkaew ◽

Kanoknetr Suksen ◽

Koravit Somkid ◽

Ratchanaporn Chokchaisiri ◽

Surawat Jariyawat ◽

...

Keyword(s):

Mrna Expression ◽

Messenger Rna ◽

Lethal Dose ◽

Related Factor ◽

Metabolizing Enzymes ◽

Centrilobular Necrosis ◽

Cytokine Tumor Necrosis Factor ◽

Antioxidant Gene Expression ◽

Liver Enlargement ◽

Factor Α

The present study aimed to investigate the hepatotoxicity of zederone isolated from Curcuma elata in mice. Adult male mice were intraperitoneally injected with a single dose of zederone (50-300 mg/kg body weight [BW]). Twenty-four hours after the injection, zederone induced liver enlargement with scattered white foci over the organ. The medium lethal dose (LD50) value at 24 hours of zederone was approximately 223 mg/kg BW. Hepatic centrilobular necrosis with marked increases in plasma alanine transaminase activity and total bilirubin levels was observed. Zederone at a dose of 200 mg/kg BW markedly decreased the activity of superoxide dismutase and the hepatic glutathione content, whereas the activity of catalase was not altered. The compound at this dose also increased the messenger RNA (mRNA) expression of Cyp2b10 and Cyp3a11, which are the main drug-metabolizing enzymes in the liver. The mRNA expression of proinflammatory cytokine tumor necrosis factor α was increased. The nuclear factor-E2-related factor 2 protein, which is the transcription factor regulating the antioxidant gene expression, was decreased. The histopathology of massive hepatic centrilobular necrosis with an increase in the expression of cytochrome P450 (Cyp) suggests that the possible potentiation of zederone-induced hepatotoxicity implicated the induction of Cyps, which leads to the formation of biological reactive metabolites and that cause the oxidative stress and liver cell injuries.

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