A systematic approach to the development of a safe live attenuated Zika vaccine

Kwek, Swee Sen; Watanabe, Sumio; Chan, Kap Luk; Ong, Eugenia Z.; Tan, Hwee Cheng; Ng, Wendy; Nguyen, Mien T. X.; Gan, Esther S.; Zhang, Summer L.; Chan, Kitti Wing Ki; Tan, Jun; Sessions, October M.; Manuel, Menchie; Pompon, Julien; Chua, Camillus; Hazirah, Sharifah Nur; Tryggvason, Karl; Vasudevan, Subhash G.; Ooi, Eng Eong

doi:10.1038/s41467-018-03337-2

Cited by 35 publications

(42 citation statements)

References 64 publications

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“…To compare infection phenotypes and immune responses induced by different ZIKV variants in adults, and safety of potential vaccine candidates in adults during pregnancy, we used the pregnancy model (22,40). Eight-to 10 weeks-old BALB/c female mice were mated to 12 week-old males in our animal facilities.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…To compare infection phenotypes in adult animals, we used the mouse pregnancy model (22,40); maternal inoculation results in congenital infection and pregnancy pathology providing a sensitive experimental model to compare infection phenotypes caused by different strains or mutants. At E5, 8to 10-weeks-old immunocompetent, bred dams were injected IP with 2 mg of anti-IFNAR1 Abs; at E6, mice were inoculated SC with 10 4 TCID 50 of WT, E+102CpG, or E/NS1+176CpG ZIKV variants or control virus-free media, and at E18, mice were sampled.…”

Section: Zikv Variants With the Increased Cpg Content Cause Attenuatementioning

confidence: 99%

“…One of the potential perspectives for the CpG recoding vaccine approach is in combination with established LAV strategies; for example, CpG recoding can serve as an additional safety level for viruses bearing attenuating amino acid mutations. Often, virus attenuation in efficient LAVs is determined by single or several amino acid mutations-e.g., a systemic approach to the development of interferon-restricted ZIKV variants with properties similar to yellow fever 17D LAV resulted in a promising vaccine candidate with only several amino acid mutations (40). Another example is poliovirus vaccine Sabin strains with only a single mutation critical for attenuation (18).…”

Section: Implications For Cpg Recoding Vaccine Approachmentioning

confidence: 99%

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CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

et al. 2020

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Experimental increase of CpG dinucleotides in an RNA virus genome impairs infection providing a promising approach for vaccine development. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo. For example, infection phenotypes, immunogenicity, and protective efficacy induced by CpG-recoded viruses in different age groups were not studied yet. This is important, because attenuation of infection phenotypes caused by recoded viruses may depend on the population-based expression of cellular components targeting viral CpG dinucleotides. In the present study, we generated several Zika virus (ZIKV) variants with the increasing CpG content and compared infection in neonatal and adult mice. Increasing the CpG content caused host-age-dependent attenuation of infection with considerable attenuation in neonates and high attenuation in adults. Expression of the zinc-finger antiviral protein (ZAP)-the host protein targeting viral CpG dinucleotides-was also age-dependent. Similar to the wild-type virus, ZIKV variants with the increased CpG content evoked robust cellular and humoral immune responses and protection against lethal challenge. Collectively, the host age should be accounted for in future studies on mechanisms targeting viral CpG dinucleotides, development of safe dinucleotide recoding strategies, and applications of CpG-recoded vaccines.

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Section: Animal Experimentsmentioning

confidence: 99%

Section: Zikv Variants With the Increased Cpg Content Cause Attenuatementioning

confidence: 99%

Section: Implications For Cpg Recoding Vaccine Approachmentioning

confidence: 99%

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CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

et al. 2020

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“…São várias linhas de estudo em andamento ao mesmo tempo, a maioria focando a proteína do envelope do vírus. Recentemente, alguns pesquisadores focaram o desenvolvimento da vacina através da proteína NS1 e outros tentam desenvolver uma semelhante à vacina da febre amarela, com o vírus atenuado (KWEK et al, 2018).…”

Section: Infecção Pelo Zika Vírusunclassified

Aspectos Relevantes Sobre O Diagnóstico Do Zika Vírus

Licínio¹,

Ayres²

2018

Enci Bio

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RESUMO O Zika vírus é um RNA vírus envelopado, em sentido positivo e de fita simples. Pertence ao gênero Flavivirus, assim como a Dengue e a Febre Amarela, sendo também classificado como arbovírus devido à transmissão via mosquitos do gênero Aedes. São conhecidas duas linhagens do vírus, a linhagem africana e a linhagem asiática. A doença ficou bastante conhecida depois do surto brasileiro em 2015. Até essa data, apenas dois outros surtos eram conhecidos: em 2007 na ilha Yap e em 2013 na Polinésia Francesa. As consequências mais graves da infecção pelo Zika vírus são a Síndrome de Guillain-Barré e a Síndrome Congênita da Zika, que causou vários casos de microcefalia em neonatos no surto brasileiro. A linhagem encontrada neste surto é a asiática e provavelmente chegou ao país através de imigrantes ilegais e/ou soldados em missão de paz, ambos vindos do Haiti. O diagnóstico da doença é realizado pelos métodos tradicionais de laboratório clínico, como a RT-PCR, PCR em tempo real, os métodos sorológicos e PRTN (Teste de neutralização por redução de placa). As reações cruzadas com os demais Flavivirus é bastante comum, devido à semelhança genética entre os vírus, principalmente com o vírus da Dengue. A RT-PCR, PCR em tempo real e PRTN são realizados durante a fase aguda da doença. Os testes sorológicos são realizados tanto na fase aguda (anticorpos do tipo IgM) quanto na fase de convalescência (anticorpo do tipo IgG).

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“…Fortunately, working vaccines have been developed for both YFV and JEV and are currently being widely implemented to control the spread of these diseases. Recent outbreaks of ZIKV, which has been demonstrated to cause microcephaly in infants born to infected mothers, have fast tracked efforts to develop effective vaccines to prevent its spread (Sen Kwek et al, 2018;. Unlike the case of YFV and JEV, there exists no commercially implemented vaccine for WNV.…”

Section: Flavivirusesmentioning

confidence: 99%

Investigating the role of microRNAs in Wolbachia-Aedes aegypti-dengue virus interactions

Osei-Amo¹

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More than a third of the world's population is at risk of infection from various arboviruses transmitted by mosquitoes. One particularly destructive example of these is dengue virus (DENV), which is the causative agent of dengue haemorrhagic fever and is responsible for as many as 390 million infections annually across the tropical and sub-tropical regions of the world.Unfortunately, there has been limited effectiveness of vaccines against DENV to date and preventative efforts have focused largely on vector control through the use of pesticides. There exist several drawbacks to such strategies including possible off-target effects of pesticides as well as the potential for development of resistant insects. These challenges have necessitated novel approaches to restricting the prevalence of DENV such as the use of biocontrol agents. Recent research efforts in this field have successfully demonstrated that the endosymbiotic bacterium Wolbachia pipientis holds the potential to inhibit the ability of several viral pathogens to replicate in their insect hosts.Infecting up to two thirds of all insect species, this Gram-negative bacterium encompasses several distinct strains that produce a diverse array of impacts on their respective hosts physiology. In some cases, these effects are pathogenic, such as male killing, reduced lifespan, and reduced fecundity, and yet others are less so, such as increased resistance to particular pathogens and cytoplasmic incompatibility. When a non-native strain of Wolbachia (wMelPop-CLA) was introduced into the DENV vector Aedes aegypti, it had the impact of drastically restricting the ability of several viruses, including DENV, to successfully replicate and disseminate through the mosquito tissues. Despite this impactful discovery, very little is known about the physiological and molecular mechanisms that mediate this ability of Wolbachia to impinge DENV success in its host. One demonstrable effect of Wolbachia colonisation of its mosquito host is the marked induction of the key transcription factor GATA4.This versatile transcription factor has a wide array of tissue specific developmental functions in mammals including effects on ovary and teste development. This activity in ovarian development is at least partially conserved in Ae. aegypti as GATA4 has been shown to induce vitellogenesis in response iii to blood meal and thus play a key role in embryo development. Our observations of GATA4s behaviour in response to Wolbachia led us to investigate potential genes under GATA4 regulatory control. We determine two genes, Blastoderm specific gene 25D (BSG25D) and Imaginal disc growth factor (disc) expressed in the ovaries, to be transcriptionally repressed in vitro by GATA4. When we reproduced this suppression of the disc gene in vivo it led to delayed emergence of eggs giving some insight into the effects Wolbachia may produce by suppressing this gene.Despite this work and the work of others, the mechanism of GATA4 induction as well as several other transcriptional changes induced by Wolb...

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A systematic approach to the development of a safe live attenuated Zika vaccine

Cited by 35 publications

References 64 publications

CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

Aspectos Relevantes Sobre O Diagnóstico Do Zika Vírus

Investigating the role of microRNAs in Wolbachia-Aedes aegypti-dengue virus interactions

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