Use of Human Monoclonal Antibodies to Treat Chikungunya Virus Infection

Frič, Jan; Bertin-Maghit, Sebastien; Wang, Cheng‐I; Nardin, Alessandra; Warter, Lucile

doi:10.1093/infdis/jis674

Cited by 78 publications

(64 citation statements)

References 14 publications

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“…In addition, natural antibodies present in the sera of uninfected C57BL/6 mice were able to partially inhibit CHIKV (75). Furthermore, therapies based on passively transferred anti-CHIKV neutralizing antibodies conferred protection to A129 mice (42,44,45,70,71,73,(76)(77)(78) and nonhuman primates (37) against CHIKV and protection to mice against more distantly related arthrogenic alphaviruses (43,93,96), establishing the key role of humoral immunity in the control of CHIKV replication. Interestingly, complete protection from CHIKV challenge can be obtained using adoptive transfer of antibodies induced by immunization with a CHIKV/IRES vaccine candidate and occurs in the absence of CD4 ϩ /CD8 ϩ T cells (42); a titer of 35 for neutralizing antibodies was sufficient to protect mice from a challenge with 100 PFU of CHIKV (42).…”

Section: Discussionmentioning

confidence: 98%

“…Antibodies against CHIKV are crucial to control CHIKV infection (37,42,44,45,(70)(71)(72)(73)(74)(75)(76)(77)(78). Thus, to study the ability of MVA-CHIKV to elicit humoral immune responses against CHIKV, we analyzed the levels of CHIKV envelope-specific antibodies present in the sera of C57BL/6 mice immunized with one or two doses of MVA-CHIKV (see Materials and Methods).…”

Section: Mva-wt and Mva-chikv Induce Similar Magnitudes And Polyfunctmentioning

confidence: 99%

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A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

García-Arriaza

Cepeda

Holzmann

et al. 2014

J Virol

111

127

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There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-␤), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKVspecific CD8؉ T cell responses were elicited. The CHIKV-specific CD8 ؉ T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8؉ memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. IMPORTANCEWe have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.

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Section: Discussionmentioning

confidence: 98%

Section: Mva-wt and Mva-chikv Induce Similar Magnitudes And Polyfunctmentioning

confidence: 99%

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

García-Arriaza

Cepeda

Holzmann

et al. 2014

J Virol

111

127

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“…Thus, it was of importance to assess the individual merits of new CHIKV vaccine platforms in a more stringent animal model that more closely resembles a clinical setting. Antibody responses are known to correlate with protection against CHIKV (29)(30)(31)(32)(33)(34)(35)(36), but CD4 T cell responses may also be important (37)(38)(39). Thus, it was of importance to determine the potential immunological differences that our vaccine candidate might display.…”

Section: Discussionmentioning

confidence: 99%

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

et al. 2017

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“…Bindarit, a macrophage chemoattractant protein-1 (MCP-1) inhibitor, ameliorates inflammatory disease in mouse models of RRV and CHIKV, and may be a candidate for treatment of acute disease in humans (Rulli, Guglielmotti et al 2009, Rulli, Rolph et al 2011. Studies of neutralising monoclonal anti-CHIKV antibodies have demonstrated effective attenuation of viraemia and disease in knockout and neonatal mouse models of CHIKV (Couderc, Khandoudi et al 2009, Fric, Bertin-Maghit et al 2013, Pal, Dowd et al 2013). This therapy may prove useful for prevention of peri-natal maternal transfer (Gould, Coutard et al 2010, (Warter, Lee et al 2011, Fric, Bertin-Maghit et al 2013).…”

Section: Treatment Of Chikv Diseasementioning

confidence: 99%

“…Studies of neutralising monoclonal anti-CHIKV antibodies have demonstrated effective attenuation of viraemia and disease in knockout and neonatal mouse models of CHIKV (Couderc, Khandoudi et al 2009, Fric, Bertin-Maghit et al 2013, Pal, Dowd et al 2013). This therapy may prove useful for prevention of peri-natal maternal transfer (Gould, Coutard et al 2010, (Warter, Lee et al 2011, Fric, Bertin-Maghit et al 2013). …”

Section: Treatment Of Chikv Diseasementioning

confidence: 99%

The role of type I interferon in the immunobiology of chikungunya virus

Wilson¹

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause explosive outbreaks of a febrile, arthritic/arthralgic disease usually lasting weeks to months, and in rare cases, more than a year. In 2004, the largest ever CHIKV outbreak began in Kenya, spreading to islands of the Indian Ocean, India, South East Asia and major outbreaks have recently occurred in the South Pacific Islands and the Caribbean.The host type I interferon (IFN) response is crucial for effective control of CHIKV infection.Herein, the dynamics, source and responses generated by the type I IFNs following CHIKV infection were investigated. RNASeq was undertaken to examine, in detail, the nature of the type I IFN responses generated in the feet and inguinal lymph nodes of mice following CHIKV infection at days 2 and 7 post-infection. High quality sequencing data was generated from III host and viral poly-adenylated RNA, permitting investigation of low level gene transcription from both sources, and the identification of novel genes/transcripts, in addition to analysis of differential gene expression.Investigation of host transcriptional activity revealed a type I IFN dominated immune response, in spite of a low induction of type I IFN mRNA transcripts at day 2 and an absence of type I IFN mRNA induction on day 7. Many type I IFN-regulated genes, including IRF7, remained up-regulated in the feet at day 7, suggesting type I IFNindependent mechanisms for maintenance of type I IFN-regulated gene expression. Six novel IRF3 isoforms and a potentially novel protein coding gene were also identified.RNA-Seq analysis of CHIKV transcriptional activity reflected the known CHIKV replication kinetics, in which virus replicates in the joints, and spreads to the draining lymph nodes, with viral titres peaking at day 2 and largely resolving at day 7. Assessment of mutations within the CHIKV genome showed an accumulation with time, with error accumulation higher in the lymph nodes than in the feet. These studies represent the first deep sequencing analysis of CHIKV genomes in tissues.The findings in this thesis substantially add to our knowledge of the role and function of the immune response after CHIKV, illustrating for the first time that type I IFNs protect against haemorrhagic shock and that expression of type I IFN inducible genes is maintained well after type I IFN induction has waned.

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Use of Human Monoclonal Antibodies to Treat Chikungunya Virus Infection

Cited by 78 publications

References 14 publications

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

The role of type I interferon in the immunobiology of chikungunya virus

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