Chikungunya Virus Host Range E2 Transmembrane Deletion Mutants Induce Protective Immunity against Challenge in C57BL/6J Mice

Piper, Amanda; Ribeiro, Mariana; Smith, Katherine; Briggs, Caitlin M.; Huitt, Emerson; Nanda, Kavita; Spears, Carla J.; Quiles, Michelle; Cullen, John M.; Thomas, Malcolm E.; Brown, Dennis T.; Hernandez, Raquel

doi:10.1128/jvi.03357-12

Cited by 27 publications

(16 citation statements)

References 63 publications

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“…Moreover, an attenuated CHIKV vaccine can easily be produced at biosafety level 2 (BSL-2). The attenuated CHIKV vaccine candidates developed to date rely on a small number of attenuating mutations (11)(12)(13) and are at risk of being unstable or even sensitive to reversion. We therefore aimed for a more stable attenuation strategy, choosing to replace a 61-aa region of nsP3 (⌬5nsP3) with a short linker or to delete the entire 6K (⌬6K).…”

Section: Discussionmentioning

confidence: 99%

“…This vaccine has, however, not been further pursued due to virus passaging in uncertified cell cultures during development, and a more recent study indicated that 181/clone25 is attenuated by only two point mutations (27) and is at risk of reversion to pathogenic CHIKV. Similarly, other attenuated CHIKV vaccine candidates also rely on a small number of attenuating mutations (11)(12)(13).…”

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confidence: 99%

“…A number of CHIKV vaccine candidates have been described, including attenuated (11)(12)(13) or inactivated (14,15) CHIKV, alphavirus chimeras (16), and subunit (17)(18)(19)(20) and genetic (21)(22)(23)(24) vaccines. Since inactivated, subunit, and genetic vaccines typically require several immunizations to confer immunity and are expensive to produce, live-attenuated viruses are usually the most potent vaccines because of their ability to infect cells and stimulate both innate and adaptive immune responses, usually without the need for a booster immunization (25).…”

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confidence: 99%

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Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice

Holzmann

Kakoulidou

Lulla

et al. 2014

J Virol

154

132

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Chikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that has caused severe epidemics in Africa and Asia and occasionally in Europe. As of today, there is no licensed vaccine available to prevent CHIKV infection. Here we describe the development and evaluation of novel CHIKV vaccine candidates that were attenuated by deleting a large part of the gene encoding nsP3 or the entire gene encoding 6K and were administered as viral particles or infectious genomes launched by DNA. The resulting attenuated mutants were genetically stable and elicited high magnitudes of binding and neutralizing antibodies as well as strong T cell responses after a single immunization in C57BL/6 mice. Subsequent challenge with a high dose of CHIKV demonstrated that the induced antibody responses protected the animals from viremia and joint swelling. The protective antibody response was long-lived, and a second homologous immunization further enhanced immune responses. In summary, this report demonstrates a straightforward means of constructing stable and efficient attenuated CHIKV vaccine candidates that can be administered either as viral particles or as infectious genomes launched by DNA. IMPORTANCESimilar to other infectious diseases, the best means of preventing CHIKV infection would be by vaccination using an attenuated vaccine platform which preferably raises protective immunity after a single immunization. However, the attenuated CHIKV vaccine candidates developed to date rely on a small number of attenuating point mutations and are at risk of being unstable or even sensitive to reversion. We report here the construction and preclinical evaluation of novel CHIKV vaccine candidates that have been attenuated by introducing large deletions. The resulting mutants proved to be genetically stable, attenuated, highly immunogenic, and able to confer durable immunity after a single immunization. Moreover, these mutants can be administered either as viral particles or as DNA-launched infectious genomes, enabling evaluation of the most feasible vaccine modality for a certain setting. These CHIKV mutants could represent stable and efficient vaccine candidates against CHIKV.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice

Holzmann

Kakoulidou

Lulla

et al. 2014

J Virol

154

132

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“…We apologize to all whose work could not be referenced because of formatting and length restrictions. Other live-attenuated CHIKV vaccine strategies include deletions in viral genes (187,188), modification of glycosaminoglycan binding (138), alphavirus chimeras (189,190), and codon alteration (191). As reversion is a major safety concern with live-attenuated vaccines, a CHIKV vaccine containing a combination of attenuation strategies could diminish reversion and pathogenicity.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

Silva¹,

Dermody²

2017

Journal of Clinical Investigation

324

338

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“…Several CHIKV vaccine candidates are under development (9), including attenuated (10)(11)(12)(13)(14)(15)(16) or inactivated (17)(18)(19) CHIKV, alphavirus chimeras (20)(21)(22), and subunit (23)(24)(25)(26)(27) and genetic (21,(28)(29)(30)(31) vaccines. Moreover, we have reported previously on the construction and preclinical evaluation of novel CHIKV vaccine candidates, based on attenuated CHIKV (12) or recombinant modified vaccinia virus Ankara (MVA) expressing CHIKV antigens (MVA-CHIKV) (29), that were able to induce strong immunogenicity and efficacy in a mouse model.…”

Section: Hikungunya Virus (Chikv) Is An Alphavirus Of the Familymentioning

confidence: 99%

Prime-Boost Immunization Strategies against Chikungunya Virus

Holzmann

Lum

Kümmerer

et al. 2014

J Virol

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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. IMPORTANCE As of today, there is no licensed vaccine to prevent CHIKV infection. In considering potential new vaccine candidates, a vaccinethat 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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Chikungunya Virus Host Range E2 Transmembrane Deletion Mutants Induce Protective Immunity against Challenge in C57BL/6J Mice

Cited by 27 publications

References 63 publications

Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice

Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

Prime-Boost Immunization Strategies against Chikungunya Virus

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