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Current and Promising Antivirals Against Chikungunya Virus.

ABSTRACT: Chikungunya virus (CHIKV) is the causative agent of chikungunya fever (CHIKF) and is categorized as a(n) (re)emerging arbovirus. CHIKV has repeatedly been responsible for outbreaks that caused serious economic and public health problems in the affected countries. To date, no vaccine or specific antiviral therapies are available. This review gives a summary on current antivirals that have been investigated as potential therapeutics against CHIKF. The mode of action as well as possible compound targets (viral and host targets) are being addressed. This review hopes to provide critical information on the in vitro efficacies of various compounds and might help researchers in their considerations for future experiments.

SUBMITTER: Hucke FIL

PROVIDER: S-EPMC7769948 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Current and Promising Antivirals Against Chikungunya Virus.

Hucke Friederike I L FIL Bugert Joachim J JJ

Frontiers in public health 20201215

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever (CHIKF) and is categorized as a(n) (re)emerging arbovirus. CHIKV has repeatedly been responsible for outbreaks that caused serious economic and public health problems in the affected countries. To date, no vaccine or specific antiviral therapies are available. This review gives a summary on current antivirals that have been investigated as potential therapeutics against CHIKF. The mode of action as well as possible compound ta ...[more]

PMID: 33384981

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Project description:BACKGROUND:Three different genotypes of chikungunya virus (CHIKV) have been classified: East/Central/South African (ECSA), West African (WA), and Asian. Previously, a rapid immunochromatographic (IC) test detecting CHIKV E1-antigen showed high sensitivity for certain ECSA-genotype viruses, but this test showed poor performance against the Asian-genotype virus that is spreading in the American continents. We found that the reactivity of one monoclonal antibody (MAb) used in the IC rapid diagnostic test (RDT) is affected by a single amino acid substitution in E1. Therefore, we developed new MAbs that exhibited specific recognition of all three genotypes of CHIKV. METHODS:Using a combination of the newly generated MAbs, we developed a novel version of the IC RDT with improved sensitivity to Asian-genotype CHIKV. To evaluate the sensitivity, specificity, and cross-reactivity of the new version of the IC RDT, we first used CHIKV isolates and E1-pseudotyped lentiviral vectors. We then used clinical specimens obtained in Aruba in 2015 and in Bangladesh in 2017 for further evaluation of RDT sensitivity and specificity. Another alphavirus, sindbis virus (SINV), was used to test RDT cross-reactivity. RESULTS:The new version of the RDT detected Asian-genotype CHIKV at titers as low as 10^4 plaque-forming units per mL, a concentration that was below the limit of detection of the old version. The new RDT had sensitivity to the ECSA genotype that was comparable with that of the old version, yielding 92% (92 out of 100) sensitivity (95% confidence interval 85.0-95.9) and 100% (100 out of 100) specificity against a panel of 100 CHIKV-positive and 100 CHIKV-negative patient sera obtained in the 2017 outbreak in Bangladesh. CONCLUSIONS:Our newly developed CHIKV antigen-detecting RDT demonstrated high levels of sensitivity and lacked cross-reactivity against SINV. These results suggested that our new version of the CHIKV E1-antigen RDT is promising for use in areas in which the Asian and ECSA genotypes of CHIKV circulate. Further validation with large numbers of CHIKV-positive and -negative clinical samples is warranted. (323 words).

Project description:Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. Here we describe the development and testing of novel DNA replicon and protein CHIKV vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against CHIKV. We also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed CHIKV vaccine candidates. Immunogenicity and efficacy were studied in a mouse model of CHIKV infection and showed that the DNA replicon and protein antigen were potent vaccine candidates, particularly when used for priming and boosting, respectively. Several prime-boost immunization strategies eliciting unmatched humoral and cellular immune responses were identified. Further characterization by antibody epitope mapping revealed differences in the qualitative immune responses induced by the different vaccine candidates and immunization strategies. Most vaccine modalities resulted in complete protection against wild-type CHIKV infection; however, we did identify circumstances under which certain immunization regimens may lead to enhancement of inflammation upon challenge. These results should help guide the design of CHIKV vaccine studies and will form the basis for further preclinical and clinical evaluation of these vaccine candidates.As of today, there is no licensed vaccine to prevent CHIKV infection. In considering potential new vaccine candidates, a vaccine that could raise long-term protective immunity after a single immunization would be preferable. While humoral immunity seems to be central for protection against CHIKV infection, we do not yet fully understand the correlates of protection. Therefore, in the absence of a functional vaccine, there is a need to evaluate a number of different candidates, assessing their merits when they are used either in a single immunization or in a homologous or heterologous prime-boost modality. Here we show that while single immunization with various vaccine candidates results in potent responses, combined approaches significantly enhance responses, suggesting that such approaches need to be considered in the further development of an efficacious CHIKV vaccine.

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Current and Promising Antivirals Against Chikungunya Virus.

Publications

Current and Promising Antivirals Against Chikungunya Virus.

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