Single-shot live-attenuated chikungunya vaccine in healthy adults: a phase 1, randomised controlled trial

Wressnigg, Nina; Hochreiter, Romana; Zoihsl, Oliver; Fritzer, Andrea; Bézay, Nicole; Klingler, Anton; Lingnau, Karen; Schneider, Martina; Lundberg, Urban; Meinke, Andreas; Larcher-Senn, Julian; Čorbic-Ramljak, Irena; Eder-Lingelbach, Susanne; Dubischar, Katrin; Bender, Wolfgang

doi:10.1016/s1473-3099(20)30238-3

Cited by 74 publications

(61 citation statements)

References 24 publications

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“…The alphavirus-based replicon platform technology has been developed as vaccine candidates towards many different infectious diseases, including vaccines for influenza A virus (IAV) 41 , respiratory syncytial virus (RSV) 42,43 , Ebola (EBOV), hepatitis C virus (HCV), chikungunya (CHIKV, now in phase III) 28,44 , HIV (now in phase I), human papilloma virus (HPV, now in therapeutic phase II) 45 . Given the generic design of our platform and that new constructs can be made rapidly with synthetic design of the insert, it can be readily adapted to SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

DNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice

Szurgot

Hanke

Sheward

et al. 2021

Sci Rep

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The outbreak of the SARS-CoV-2 virus and its rapid spread into a global pandemic made the urgent development of scalable vaccines to prevent coronavirus disease (COVID-19) a global health and economic imperative. Here, we characterized and compared the immunogenicity of two alphavirus-based DNA-launched self-replicating (DREP) vaccine candidates encoding either SARS-CoV-2 spike glycoprotein (DREP-S) or a spike ectodomain trimer stabilized in prefusion conformation (DREP-Secto). We observed that the two DREP constructs were immunogenic in mice inducing both binding and neutralizing antibodies as well as T cell responses. Interestingly, the DREP coding for the unmodified spike turned out to be more potent vaccine candidate, eliciting high titers of SARS-CoV-2 specific IgG antibodies that were able to efficiently neutralize pseudotyped virus after a single immunization. In addition, both DREP constructs were able to efficiently prime responses that could be boosted with a heterologous spike protein immunization. These data provide important novel insights into SARS-CoV-2 vaccine design using a rapid response DNA vaccine platform. Moreover, they encourage the use of mixed vaccine modalities as a strategy to combat SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

DNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice

Szurgot

Hanke

Sheward

et al. 2021

Sci Rep

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“…Previously, we have demonstrated that transfection with plasmid-encoded iDNA constructs encoding the Δ5nsP3 deletion generated replicating viruses in cell culture but did not induce viremia in mice 6 . However, we have demonstrated that the Δ5nsP3 virus replicon particles induce viremia in NHPs, which is a more permissive animal model for CHIKV infection 7 , and it was recently shown that vaccination with Δ5nsP3 virus replicon particles also causes viremia in human volunteers 13 . Here, we show that in vitro transcribed iRNA electroporated into BHK-21cells promoted production of viruses able to replicate in cell culture as demonstrated by plaque assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This attenuating deletion has been engineered to be large enough to make reversion to wildtype virus incredibly unlikely, and indeed, serial passaging of viruses carrying these deletions did not reveal any revertants 6 . Moreover, vaccination with the attenuated virus has proved safe and immunogenic in NHP and man 7,13 . Naturally, adverse events is a concern for any live attenuated virus vaccine, and the clinical studies revealed a reactogenicity profile that was considered safe in the high-dose group and well tolerated in the low-and medium-dose groups for this vaccine candidate, which further underlines the clinical potential for an iRNA-based candidate based on this attenuation.…”

Section: Discussionmentioning

confidence: 99%

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Infectious RNA vaccine protects mice against chikungunya virus infection

Szurgot

Ljungberg

Kümmerer

et al. 2020

Sci Rep

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We describe a novel vaccine platform that can generate protective immunity to chikungunya virus (CHIKV) in C57BL/6J mice after a single immunization by employing an infectious RNA (iRNA), which upon introduction into a host cell launches an infectious attenuated virus. We and others have previously reported that an engineered deletion of 183 nucleotides in the nsP3 gene attenuates chikungunya virus (CHIKV) and reduces in vivo viral replication and viremia after challenge in mice, macaques and man. Here, we demonstrated that in vitro transfection of iRNA carrying the nsP3 deletion generated infectious viruses, and after intramuscular injection, the iRNA induced robust antibody responses in mice. The iRNA was superior at eliciting binding and neutralizing antibody responses as compared to a DNA vaccine encoding the same RNA (iDNA) or a non-propagating RNA replicon (RREP) lacking the capsid encoding gene. Subsequent challenge with a high dose of CHIKV demonstrated that the antibody responses induced by this vaccine candidate protected animals from viremia. The iRNA approach constitutes a novel vaccine platform with the potential to impact the spread of CHIKV. Moreover, we believe that this approach is likely applicable also to other positive-strand viruses.

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“…The chikungunya vaccine candidate VLA1553 (Valneva) elicited virus-specific antibodies in all 120 healthy adults enrolled in a randomized, dose-finding Phase 1 study. 2 The immunity lasted for at least one year in all dose cohorts.…”

Section: Chikungunya Vaccine Was Safe and Immunogenic In Early Trialmentioning

confidence: 98%

Human Vaccines & Immunotherapeutics: news

2020

Human Vaccines & Immunotherapeutics

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Single-shot live-attenuated chikungunya vaccine in healthy adults: a phase 1, randomised controlled trial

Cited by 74 publications

References 24 publications

DNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice

DNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice

Infectious RNA vaccine protects mice against chikungunya virus infection

Human Vaccines & Immunotherapeutics: news

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