Dengue viruses and promising envelope protein domain III-based vaccines

Fahimi, Hossein; Mohammadipour, Mahshid; Kashani, Hamed Haddad; Parvini, Farshid; Sadeghizadeh, Majid

doi:10.1007/s00253-018-8822-y

Cited by 55 publications

(41 citation statements)

References 161 publications

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“…In contrast, most quaternary epitope directed neutralizing antibodies have been isolated from people infected with wild type flaviviruses 7,14-17 . In fact, recent studies demonstrate that neutralizing antibodies in people exposed to flavivirus infections or effective live attenuated vaccines predominantly recognize quaternary epitopes, with simple EDIII epitopes accounting for only a minor fraction of neutralizing antibodies 18-22 . To compare levels of EDIII directed antibodies in animals immunized with rE M or rE D , we used recombinant ZIKV-EDIII conjugated to magnetic beads to deplete mouse immune sera of EDIII binding antibodies ( Fig.3A ).…”

Section: Resultsmentioning

confidence: 99%

Oligomeric state of the ZIKV E protein defines protective immune responses

Metz

Thomas

Brackbill

et al. 2019

Preprint

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8The current leading Zika vaccine candidates in clinical testing are based on live or killed virus 9 platforms, which have safety issues, especially in pregnant women. Zika subunit vaccines, 10 however, have shown poor performance in preclinical studies. We hypothesized that Zika 11Envelope (E) protein subunit vaccines have performed poorly because the antigens tested have 12been recombinant E monomers that do not display critical quaternary structure epitopes present 13on Zika E protein homodimers that cover the surface of the virus. To test this hypothesis, we 14 engineered and produced stable recombinant E protein homodimers. Unlike the E monomer, the 15 dimer was recognized by strongly neutralizing monoclonal antibodies isolated from Zika-immune 16 individuals. In a mouse model of vaccination, the dimeric antigen stimulated strongly neutralizing 17 antibodies that targeted epitopes that were similar to epitopes recognized by human antibodies 18 following natural Zika virus infection. In contrast, the monomer antigen stimulated lower levels of 19 neutralizing antibodies directed to simple epitopes on domain III of E protein. In a mouse model 20 of ZIKV challenge, only E dimer antigen stimulated protective antibodies, not the 21 monomer. These results highlight the importance of mimicking the highly structured flavivirus 22 surface when designing subunit vaccines. The flavivirus field has a long history of using E 23 monomers as vaccine antigens with limited success. These results are applicable to developing 24 second generation subunit vaccines against Zika as well as other medically important flaviviruses 25 such as dengue and yellow fever viruses. 26 130 Figure 3: ZIKV rE D stimulates antibodies that target complex epitopes on the virion. A) Method for 131 depleting EDIII binding antibodies from mouse immune sera. Recombinant ZIKV EDIII (His-tagged) was 132 coupled to nickel beads i then incubated with immune sera ii . Magnetic pull down removes nickel beads and 133 EDIII binding antibodies iii , leaving leavind sera depleted from EDIII binding antibodies iv . B) The level of 134 EDIII-binding antibodies in the serum of mice immunized with the indicated antigens is shown as a 135 percentage of the total level of ZIKV specific IgG, as measured by ELISA of EDIII-depleted and control-136 depleted serum. C) The neutralizing activity of EDIII-depleted and undepleted sera was determined and 137 expressed as the dilution at which 50% of the virus was neutralized (Neut50). D) A blockade of binding 138 (BOB) assay was used to evaluate if mice immunized with rE M or rE D developed antibodies that blocked 139 the binding of A9E, G9E and EDE C10 human mAbs. Data points represent individual mice. Statistical140differences were determined by one-way ANOVA followed by a Tukey's test (p<0.05).

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Section: Resultsmentioning

confidence: 99%

Oligomeric state of the ZIKV E protein defines protective immune responses

Metz

Thomas

Brackbill

et al. 2019

Preprint

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“…Multiple tetravalent vaccine candidates are being developed. These include live-attenuated vaccines, whole virus inactivated vaccines, protein-based vaccines, chimeric vaccines, and mRNA-based and synthetic virus-like particle vaccines [137][138][139][140][141][142]. Among these vaccines, Dengvaxia (also called CYD-TDV), developed by Sanofi Pasteur, is the only one licensed for use in about 20 dengue-endemic countries in Asia, Latin America, and Oceania as well as in Europe.…”

Section: Importance For Vaccine Developmentmentioning

confidence: 99%

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

et al. 2019

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With 40% of the world population at risk, infections with dengue virus (DENV) constitute a serious threat to public health. While there is no antiviral therapy available against this potentially lethal disease, the efficacy of the only approved vaccine is not optimal and its safety has been recently questioned. In order to develop better vaccines based on attenuated and/or chimeric viruses, one must consider how the human immune system is engaged during DENV infection. The activation of the innate immunity through the detection of viruses by cellular sensors is the first line of defence against those pathogens. This triggers a cascade of events which establishes an antiviral state at the cell level and leads to a global immunological response. However, DENV has evolved to interfere with the innate immune signalling at multiple levels, hence dampening antiviral responses and favouring viral replication and dissemination. This review elaborates on the interplay between DENV and the innate immune system. A special focus is given on the viral countermeasure mechanisms reported over the last decade which should be taken into consideration during vaccine development.Vaccines 2019, 7, 145 2 of 21 serotypes (1-4) in one given restricted geographic area [4,5]. While there is an unmet medical need regarding strategies against dengue, the incidence of this disease is expected to geographically expand in the future considering that the arthropod vector is colonizing northern European and American territories with temperate climates. Clinical ManifestationDENV infection is characterized by a mixed clinical presentation that ranges from an asymptomatic disease to a mild febrile prodrome all the way to a severe hemorrhagic fever and shock syndrome. All infected individuals, asymptomatic or not, can transmit DENV to Aedes mosquitoes during a blood meal, making it difficult to precisely estimate the actual size of the reservoir at any given time. DENV infection severity is classified according to the World Health Organization (WHO) 1997 and 2009 guidelines [6]. Dengue "without warning signs" (or dengue fever) regroups at-risk individuals with fever and at least two of the following signs and symptoms: nausea/vomiting, rash, headaches, eye pain, muscle aches, joint pain, leukopenia, or positivity at the tourniquet test. Dengue "with warning signs of severe infection" (or dengue hemorrhagic fever) includes in addition to the previous signs and symptoms abdominal pain, persistent vomiting, ascites, pleural effusion, mucosal bleeding, lethargy or restlessness, hepatomegaly, and an increase in hematocrit paired with rapid decrease in platelet count. Lastly, severe dengue (or dengue shock) occurs when the infection leads to severe plasma leakage, massive bleeding, and multiple organ failures. As of now, the therapeutic arsenal against DENV infection is fairly limited and only consists of supportive care and intravenous fluid therapy.From a host-pathogen interaction point of view, it is interesting to note that, in the majority of DENV-...

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“…Dengue is a wide-spread disease caused by the dengue virus (DENV), a member of the Flaviviridae family [1]. The virus infects human, transmitted by Aedes aegypti and Aedes albopictus mosquitoes as the vector [2].…”

Section: Introductionmentioning

confidence: 99%

“…E protein is composed of three domains (domain I, II, and II). Domain III of the E protein (EDIII) plays a role in receptor binding for viral entry and inducing protective immunity against the virus [1]. Domain III is able to trigger receptor binding that will lead to the virus entry and replication of virus in the host [14].…”

Section: Introductionmentioning

confidence: 99%

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Computational Design of Ancestral and Consensus Asian Dengue Envelope Protein for Vaccine Candidate

Kemal

Ivan

Sandjaja

et al. 2020

KLS

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Dengue is a mosquito-borne viral disease of which incidence has rapidly increased in the last few years. Despite the recent development of a licensed dengue vaccine, safer and more efficacious dengue vaccine still needs to be developed. Dengue virus has four antigenically and genetically distinct serotypes. Ancestral sequence reconstruction (ASR) and consensus sequence (CS) might be able to overcome antigenic distinction between those four serotypes. Envelope (E) protein is responsible for a wide range of dengue virus biological activities. Domain III of the E protein (EDIII) plays a role in receptor binding for viral entry and inducing protective immunity against the dengue virus. We utilised bioinformatics software to computationally design ancestral and consensus sequences of Asian dengue E protein. E protein sequences of 987 DENV strains and 5 outgroups were retrieved from GenBank. We constructed ancestral and consensus sequences for each serotype. For ASR, ancestral sequences were gradually designed to construct ancestral sequence for all serotypes using MEGA X. For CS, all four consensus sequences were directly used to construct consensus sequence for all serotypes using UGENE 1.32. Phylogenetic tree consisting existing dengue sequences as well as ancestral and consensus sequences were visualised using FigTree 1.4.4. All ancestral and consensus sequences were analysed for conserved motifs, especially in domain III region. ASR sequences were closer to the centre of phylogenetic tree branches while consensus sequences were located among natural isolates. Further CD4 T cell immunogenicity prediction on domain III (EDIII) showed that both ASR and consensus EDIII have the two-highest combined immunogenicity scores. These sequences are potential for further in vitro and in vivo studies as dengue vaccine candidate. Keywords: ancestral sequence, consensus, dengue, envelope protein, vaccine

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Dengue viruses and promising envelope protein domain III-based vaccines

Cited by 55 publications

References 161 publications

Oligomeric state of the ZIKV E protein defines protective immune responses

Oligomeric state of the ZIKV E protein defines protective immune responses

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

Computational Design of Ancestral and Consensus Asian Dengue Envelope Protein for Vaccine Candidate

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