A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection

Akahata, Wataru; Yang, Zhiyong; Andersen, Hanné; Sun, Siyang; Holdaway, Heather A.; Kong, Wing-Pui; Lewis, Mark G.; Higgs, Stephen; Rossmann, Michael G.; Rao, Srinivas S.; Nabel, Gary J.

doi:10.1038/nm.2105

Cited by 409 publications

(438 citation statements)

References 35 publications

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“…Expression of the virus structural proteins resulted in a VLP that resembled the structure of live alphaviruses. 38 This VLP was shown to elicit a robust antibody response and protection against Chikungunya virus.…”

Section: Recent Progress To Trivalent Weev Eeev and Veev Vaccinesmentioning

confidence: 99%

Current Strategic Thinking for the Development of a Trivalent Alphavirus Vaccine for Human Use

Wolfe

Heppner

Gardner

et al. 2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Vaccinations against the encephalitic alphaviruses (western, eastern, and Venezuelan equine encephalitis virus) are of significant interest to biological defense, public health, and agricultural communities alike. Although vaccines licensed for veterinary applications are used in the Western Hemisphere and attenuated or inactivated viruses have been used under Investigational New Drug status to protect at-risk personnel, there are currently no licensed vaccines for use in humans. Here, we will discuss the need for a trivalent vaccine that can protect humans against all three viruses, recent progress to such a vaccine, and a strategy to continue development to Food and Drug Administration licensure.

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Section: Recent Progress To Trivalent Weev Eeev and Veev Vaccinesmentioning

confidence: 99%

Current Strategic Thinking for the Development of a Trivalent Alphavirus Vaccine for Human Use

Wolfe

Heppner

Gardner

et al. 2014

The American Journal of Tropical Medicine and Hygiene

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“…In the future, viral entry could be easily monitored in a BSL-2 containment laboratory by using pseudotyped lentiviral vectors that assemble into virus-like particles. 16 The screening assay developed in our laboratory monitors the cellular shutoff induced by CHIKV nsP2 in a BSL-2 containment. CHIKV, as previously described for other Old World alphaviruses, induces a cellular shutoff at both transcriptional and translational levels and blocks interferon-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

A Phenotypic Assay to Identify Chikungunya Virus Inhibitors Targeting the Nonstructural Protein nsP2

et al. 2013

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These authors contributed equally to this work. AbstractChikungunya virus (CHIKV) is a mosquito-transmitted pathogen responsible for an acute infection of abrupt onset, characterized by high fever, polyarthralgia, myalgia, headaches, chills, and rash. In 2006, CHIKV was responsible for an epidemic outbreak of unprecedented magnitude in the Indian Ocean, stressing the need for therapeutic approaches. Since then, we have acquired a better understanding of CHIKV biology, but we are still missing active molecules against this reemerging pathogen. We recently reported that the nonstructural nsP2 protein of CHIKV induces a transcriptional shutoff that allows the virus to block cellular antiviral response. This was demonstrated using various luciferase-based reporter gene assays, including a trans-reporter system where Gal4 DNA binding domain is fused to Fos transcription factor. Here, we turned this assay into a high-throughput screening system to identify small molecules targeting nsP2-mediated shutoff. Among 3040 molecules tested, we identified one natural compound that partially blocks nsP2 activity and inhibits CHIKV replication in vitro. This proof of concept suggests that similar functional assays could be developed to target other viral proteins mediating a cellular shutoff and identify innovative therapeutic molecules.

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“…The CHIKV VLPs were prepared in PBS (pH 7.4) at a concentration of 2 mg/mL following previously described procedures (20). The human mAbs were purified from the supernatants of cultured human hybridoma cells secreting mAbs, as described previously (35).…”

Section: Methodsmentioning

confidence: 99%

“…VLP-based vaccines are currently commercialized for hepatitis B virus and human papillomavirus (19). Indeed, a VLP-based vaccine against CHIKV is immunogenic and protective (20) and has advanced through phase 1 clinical trials in humans (21).…”

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confidence: 99%

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

Long

Fong

Austin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes. chikungunya virus-antibody complexes | cryo-electron microscopy structure | neutralizing mechanism | viral fusion inhibition C hikungunya virus (CHIKV) is an enveloped, positive-stranded RNA virus that belongs to the alphavirus genus of the Togaviridae family (1, 2). CHIKV is transmitted to humans by Aedes species mosquitoes and causes a debilitating febrile illness associated with acute and chronic arthritis (3, 4). Since the first human CHIKV infection was reported in East Africa in 1952 (5), epidemics of CHIKV have occurred in Africa, Asia, and Europe (6, 7). A CHIKV outbreak in the Caribbean area in late 2013 spread through the Americas and caused about 1.4 million infections (8). Despite its global disease burden and risk of spread, there is no available vaccine or effective antiviral drug for CHIKV.The genome of CHIKV is ∼11.8 kb long and encodes nine viral proteins, five of which are structural (capsid, E3, E2, 6K, and E1) (2). These structural proteins are translated as a single polyprotein, which is then cleaved into the capsid, p62, 6K, and E1 proteins by cellular and viral proteases. During maturation, p62 is cleaved to release E3, which protects the fusion loop in the immature virus. The virus consists of a central core with diameter of ∼400 Å with the icosahedrally organized capsid proteins surrounding the viral genome. The nucleocapsid core is enveloped by a lipid membrane into which the E1 and E2 glycoproteins are inserted (9). The mature CHIKV particle has a diameter of 700 Å. The E2 glycoprotein binds to uncharacterized cellular receptors to initiate virus entry into host cells, whereas E1 glycoprotein participates in virus-host cell membrane fusion (10, 11). Although the E3 and 6K proteins contribute to virus assembly and maturation, they are released during the format...

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A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection

Cited by 409 publications

References 35 publications

Current Strategic Thinking for the Development of a Trivalent Alphavirus Vaccine for Human Use

Current Strategic Thinking for the Development of a Trivalent Alphavirus Vaccine for Human Use

A Phenotypic Assay to Identify Chikungunya Virus Inhibitors Targeting the Nonstructural Protein nsP2

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

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