A VLP vaccine for epidemic Chikungunya virus protects non-human primates against infection

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Nature medicine (Impact Factor: 27.36). 03/2010; 16(3):334-8. DOI: 10.1038/nm.2105
Source: PubMed


Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.

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    • "Likewise, in CHIKV-infected animals, high titers of neutralizing CHIKV-specific antibodies were produced after infection and their epitopes within the E2 glycoprotein has been mapped (Table 1). Furthermore, the virus-like particle (VLP) vaccine was demonstrated to induce the production of neutralizing antibodies in vaccinated non-human primates that protected the animals against challenge (Akahata et al., 2010). Likewise, a measles virus-based vaccine, which expresses CHIKV VLPs, protected susceptible mice from lethal challenge (Brandler et al., 2013). "
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    ABSTRACT: Chikungunya virus (CHIKV) is an arthropod-borne virus that causes chikungunya fever, a disease characterized by the onset of fever and rashes, with arthralgia as its hallmark symptom. CHIKV has re-emerged over the past decade, causing numerous outbreaks around the world. Since late 2013, CHIKV has reached the shores of the Americas, causing more than a million cases of infection. Despite concentrated efforts to understand the pathogenesis of the disease, further outbreaks remain a threat. This review highlights important findings regarding CHIKV-associated immunopathogenesis and offers important insights into future directions. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World." Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 06/2015; 120. DOI:10.1016/j.antiviral.2015.06.009 · 3.94 Impact Factor
    • "Geographical expansion of the Aedes albopictus mosquito's distribution has allowed for the first autochthonous CHIKV infections in Italy and France, in 2007 and 2010, respectively (Rezza et al., 2007; Angelini et al., 2008; Grandadam et al., treatment of rheumatic disease caused by CHIKV currently involves the use of painkillers and/or non-steroidal anti-inflammatory drugs. Presently, there are no licensed human vaccines available although CHIKV vaccines are in development (Akahata et al., 2010; Wang et al., 2011; Brandler et al., 2013; Metz et al., 2013; Powers, 2014). "
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    ABSTRACT: Chikungunya fever (CHIKF) has re-emerged as an arboviral disease that mimics clinical symptoms of other diseases such as dengue, malaria, as well as other alphavirus-related illnesses leading to problems with definitive diagnosis of the infection. Herein we describe the development and evaluation of a sensitive epitope-blocking ELISA (EB-ELISA) capable of specifically detecting anti-chikungunya virus (CHIKV) antibodies in clinical samples. The assay uses a monoclonal antibody (mAb) that binds an epitope on the E2 protein of CHIKV and does not exhibit cross-reactivity to other related alphaviruses. We also demonstrated the use of recombinant CHIK virus-like particles (VLPs) as a safe alternative antigen to infectious virions in the assay. Based on testing of 60 serum samples from patients in the acute or convalescent phase of CHIKV infection, the EB-ELISA provided us with 100% sensitivity, and exhibited 98.5% specificity when Ross River virus (RRV)- or Barmah Forest virus (BFV)-immune serum samples were included. This assay meets the public health demands of a rapid, robust, sensitive and specific, yet simple assay for specifically diagnosing CHIK-infections in humans. Copyright © 2015. Published by Elsevier B.V.
    Journal of virological methods 05/2015; 222. DOI:10.1016/j.jviromet.2015.05.011 · 1.78 Impact Factor
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    • "The CHIKV VLPs expressed with mammalian cells [15] and baculovirus/insect cells [28] have been shown to elicit neutralizing antibodies that protect experimental animals from CHIKV challenge. However, the VLPs produced using insect cells showed better immunogenicity than those produced in mammalian cells, and this was likely due to the difference in glycosylation between these cells [28]. "
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    ABSTRACT: Chikungunya virus (CHIKV) is becoming a global concern due to the increasing number of outbreaks throughout the world and the absence of any CHIKV-specific vaccine or treatment. Virus-like particles (VLPs) are multistructured proteins that mimic the organization and conformation of native viruses but lack the viral genome. They are noninfectious and potentially safer vaccine candidates. Recent studies demonstrated that the yield of CHIKV VLPs varies depending on the strains, despite the 95% amino acid similarity of the strains. This might be due to the codon usage, since protein expression is differently controlled by different organisms. We optimized the region encoding CHIKV structural proteins, C-E3-E2-6k-E1, inserted it into a mammalian expression vector, and used the resulting construct to transfect 293 cells. We detected 50-kDa proteins corresponding to E1 and/or E2 in the cell lysate and the supernatant. Transmission electron microscopy revealed spherical particles with a 50- to 60-nm diameter in the supernatant that resembled the native CHIKV virions. The buoyant density of the VLPs was 1.23 g/mL, and the yield was 20 µg purified VLPs per 108 cells. The VLPs aggregated when mixed with convalescent sera from chikungunya patients, indicating that their antigenicity is similar to that of native CHIKV. Antibodies elicited with the VLPs were capable of detecting native CHIKV, demonstrating that the VLPs retain immunogenicity similar to that of the native virion. These results indicated that CHIKV VLPs are morphologically, antigenically, and immunologically similar to the native CHIKV, suggesting that they have potential for use in chikungunya vaccines.
    PLoS ONE 09/2014; 9(9):e108169. DOI:10.1371/journal.pone.0108169 · 3.23 Impact Factor
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