Modified mRNA Vaccines Protect against Zika Virus Infection

Richner, Justin M.; Himansu, Sunny; Dowd, Kimberly A.; Butler, Scott L.; Salazar, Vanessa; Fox, Julie M.; Julander, Justin G.; Tang, William W.; Shresta, Sujan; Pierson, Theodore C.; Ciaramella, Giuseppe; Diamond, Michael S.

doi:10.1016/j.cell.2017.03.016

Cited by 228 publications

(200 citation statements)

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“…These include conventional approaches, such as the use of purified inactivated virus (PIV) (20,21), DNA (20)(21)(22), and adenovirus-based subunit vaccines incorporating the prM-E or M-E region of ZIKV (20,23), as well as the use of lipid nanoparticle (LNP)-encapsulated RNA or modified mRNA as a vaccine candidate (24)(25)(26). These studies have demonstrated effective neutralizing antibody responses capable of protecting against ZIKV infection in various animal models.…”

Section: Discussionmentioning

confidence: 99%

“…These encompass the use of established approaches, such as purified inactivated virus (PIV) (20,21), to more advanced approaches, such as DNA (prM-E) (20)(21)(22), subunit (E) (23), and recombinant adenovirus (20,23) platforms, along with the recent development of RNA nanoparticle technology (24) or modified mRNA (prM-E) (25,26), as vaccine candidates. Studies have demonstrated an effective neutralizing antibody response capable of protecting against ZIKV infection in both mice and nonhuman primates (20)(21)(22), leading to several clinical trials that are under way (ClinicalTrials.gov identifiers NCT02963909, NCT02840487, NCT02887482, NCT02809443, and NCT02952833).…”

mentioning

confidence: 99%

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Development of Virus-Like-Particle Vaccine and Reporter Assay for Zika Virus

Garg

Sedano

Plata

et al. 2017

J Virol

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Recent worldwide outbreaks of Zika virus (ZIKV) infection and the lack of an approved vaccine raise serious concerns regarding preparedness to combat this emerging virus. We used a virus-like particle (VLP)-based approach to develop a vaccine and a microneutralization assay for ZIKV. A synthetic capsid-premembrane-envelope (CprM-E) gene construct of ZIKV was used to generate reporter virus particles (RVPs) that package a green fluorescent protein (GFP) reporter-expressing West Nile virus (WNV) replicon. The assay was adapted to a 96-well format, similar to the plaque reduction neutralization test (PRNT), and showed high reproducibility with specific detection of ZIKV neutralizing antibodies. Furthermore, C-prM-E and prM-E VLPs were tested as vaccine candidates in mice and compared to DNA vaccination. While the ZIKV prM-E construct alone was sufficient for generating VLPs, efficient VLP production from the C-prM-E construct could be achieved in the presence of the WNV NS2B-3 protease, which cleaves C from prM, allowing virus release. Immunization studies in mice showed that VLPs generated higher neutralizing antibody titers than those with the DNA vaccines, with C-prM-E VLPs giving slightly higher titers than those with prM-E VLPs. The superiority of C-prM-E VLPs suggests that inclusion of capsid may have benefits for ZIKV and other flaviviral VLP vaccines. To facilitate the VLP platform, we generated a stable cell line expressing high levels of ZIKV prM-E proteins that constitutively produce VLPs as well as a cell line expressing ZIKV C-prM-E proteins for RVP production. While several vaccine platforms have been proposed for ZIKV, this study describes a safe, effective, and economical VLP-based vaccine against ZIKV.IMPORTANCE To address the growing Zika virus epidemic, we undertook this study with two objectives: first, to develop a safe, effective, and economical vaccine for ZIKV, and second, to develop a rapid and versatile assay to detect the anti-ZIKV immune response. We generated a cell line stably expressing ZIKV prM-E that produces large amounts of VLPs in the supernatant and a ZIKV C-prM-E cell line that produces reporter virus particles upon transfection with a GFP replicon plasmid. The prM-E VLPs induced a strong neutralizing antibody response in mice that was better when the capsid was included. VLP-based vaccines showed significantly better neutralizing antibody responses than those with their DNA counterparts. The RVP-based microneutralization assay worked similarly to the PRNT assay, with a rapid GFP readout in a 96-well format. Our VLP-based platform provides a source for a ZIKV vaccine and diagnosis that can rapidly be adapted to current outbreaks.KEYWORDS C-prM-E, diagnostics, microneutralization, neutralization, PRNT, reporter, reporter virus particles, vaccine, Zika, prM-E S ince the identification of Zika virus (ZIKV) from a rhesus monkey in Uganda in 1947 (1, 2) until 2010, the virus predominantly circulated between Aedes mosquitoes and nonhuman primates. Periodic episodes were inde...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Development of Virus-Like-Particle Vaccine and Reporter Assay for Zika Virus

Garg

Sedano

Plata

et al. 2017

J Virol

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“…The mRNA molecules were encapsulated in optimized lipid nano particles (LPN) and delivered via intramuscular injection to mice. [28] Data were encouraging as the vaccine generated high neutralizing antibody titers. To minimize the risk of ADE, Richner et al, created another modified mRNA vaccine or mutant vaccine deficient in 'Fusion Loop' sequence in DII domain of E protein.…”

Section: Zika Virus Vaccinesmentioning

confidence: 99%

“…The brain and uterus are primary target organs to be protected by ZV infection due to its neurological and pregnancy related complication. [28] Pardi et al, Designed another modified mRNA vaccine that also encoded pre-membrane and envelope (prM-Env) glycol proteins of ZV H/PF/2013 strain. The vaccine molecules were encapsulated in LNP and the vaccine was delivered through intra dermal injection in a single dose of 50µg to C57BL/6 mice [26].…”

Section: Zika Virus Vaccinesmentioning

confidence: 99%

Recent Advances in Zika Virus Vaccine Development

Shafique¹

2017

IJVR

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Figure 1: Three different mechanisms of ADE (Antibody-dependent enhancement):A-receptors on virus particles bound by cross-reactive antibody get conformational change in structure that results in high affinity with the corresponding receptor on the host cell membrane. The corresponding receptor was not able to recognize the viral receptor before this conformational change. B-The cross-reactive antibody binds to viral and host cell membrane receptors at the same time bringing the viral particle near to the host cell. C-The Fc component of the cross-reactive antibody is recognized by the corresponding receptor on host cell membrane being the predominant mechanism of ADE phenomenon. [DENV], are the primary focus for the current vaccine and therapeutic research against ZV. Zika virus spreads by a mosquito, Anopheles Aegypti. [16] In addition to the mosquito bite, the vertical transmission, from mother to baby during pregnancy, and the sexual transmission have also been reported. Transmission[25] ZV infection is characterized by mild rash and fever.[22] However, where it infects the cells of nervous system may result in severe non-reversible complications. The neurological complications include Guillain-Barre (GB) syndrome characterized by neuromuscular paralysis .[24] ZV infection during pregnancy causes Congenital Zika Virus syndrome (CZS) which is a defined set of congenital conditions in newborns. CZS consists of microcephaly, decreased brain tissue, damage to the back of the eye, joints with limited movement and increased muscle tone . [7] Microcephaly, where the head circumference of newborn is less than thirty-two cms, has been the hallmark of the teratogenicity of ZV maternal infection.[2] ZV infection in pregnancy complicated with the microcephalic baby is a major cause of the anxiety and depression among the reproductive age women of ZV endemic area.[10] In adult men, ZV keeps on shedding in semen for more than two months after infection and damages spermatogonia in male reproductive organs resulting in male infertility.[19] Therefore, the consequences of ZV epidemic are affecting next human generations.The phenomenon of Antibody Dependent Enhancement of infection (ADE) is an important risk for the sample selection in clinical trials for monoclonal antibodies. Antibody Dependent Enhancement of infection is the phenomenon that results in magnifying the host cell infection by the viruses of same family due to the presence of cross-reactive antibodies. The respective antibodies recognize the receptors on the viral particle and the host cell membrane. These antibodies may be produced against one type of virus, for example Dengue Virus and can cross-react with the same epitopes present on the Zika Virus (ZV). There are three proposed mechanisms of ' ADE, the first one being recognition of the receptor on the surface of virus particle, inducing a conformational change in the structure of the receptor that increases its affinity for a corresponding receptor on the host cell membrane (Figure 1 A). In the second me...

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“…Two recent reports describing the successful testing of experimental ZIKV vaccines in animal models -one by Pardi et al 1 and another by Richner et al 2 -are welcome news. Both groups engineered messenger RNAs (mRNAs) with sequences encoding the ZIKV precursor membrane (prM) glycoprotein and envelope (E) glycoprotein.…”

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confidence: 99%

Zika Virus Vaccines — A Full Field and Looking for the Closers

Thomas

2017

N Engl J Med

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Modified mRNA Vaccines Protect against Zika Virus Infection

Cited by 228 publications

References 56 publications

Development of Virus-Like-Particle Vaccine and Reporter Assay for Zika Virus

Development of Virus-Like-Particle Vaccine and Reporter Assay for Zika Virus

Recent Advances in Zika Virus Vaccine Development

Zika Virus Vaccines — A Full Field and Looking for the Closers

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