Highly feasible immunoprotective multicistronic SARS-CoV-2 vaccine candidate blending novel eukaryotic expression and Salmonella bactofection

Jawalagatti, Vijayakumar; Kirthika, Perumalraja; Park, Jiyoung; Hewawaduge, Chamith

doi:10.1016/j.jare.2021.07.007

Cited by 13 publications

(19 citation statements)

References 70 publications

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“…Different vector systems, namely replication-competent viral particles, replication-deficient viral particles, and DNA-launched-mRNA vector approaches, have been exploited for transgene expression (reviewed in 23 , 24 ). DNA-launched-mRNA vectors were engineered by deleting the structural genes from the genome and replacing them with the target genes ( 21 , 25 ). The resulting vector backbone with non-structural proteins (nsp1–4) forms a replicase complex that drives efficient transgene expression by a self-amplifying mechanism ( 21 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]

2022

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The mRNA vaccines from Pfizer/BioNTech and Moderna were granted emergency approval in record time in the history of vaccinology and played an instrumental role in limiting the pandemic caused by SARS-CoV-2. The success of these vaccines resulted from over 3 decades of research from many scientists. However, the development of orally administrable mRNA vaccine development is surprisingly underexplored. Our group specializing in Salmonella-based vaccines explored the possibility of oral mRNA vaccine development. Oral delivery was made possible by the exploitation of the Semliki Forest viral replicon and Salmonella vehicle for transgene amplification and gene delivery, respectively. Herein we highlight the prospect of developing oral replicon-based mRNA vaccines against infectious diseases based on our recent primary studies on SARS-CoV-2. Further, we discuss the potential advantages and limitations of bacterial gene delivery.

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Section: Introductionmentioning

confidence: 99%

Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]

2022

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“…This has necessitated the development of next-generation vaccines to tackle the antigenic diversity. Previously, we developed a Salmonella -mediated multicistronic vaccine targeting the RBD, HR, M, and epitopes of nsp13 of SARS-CoV-2 [ref ( 18 )]. The use of bacteria for gene transfer enables oral delivery of the mRNA vaccine, and to our knowledge, our studies are the first to demonstrate an oral mRNA vaccine to combat infectious diseases ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…The list of bacterial strains, plasmids, and primers used in the present investigation have been listed in Table 1 . We previously reported the design and construction of the vaccine candidate ( 18 ). The vaccine was designed based on the SFV replicon and targets SARS-CoV-2 receptor biding domain (RBD), heptad repeat domain (HR), membrane glycoprotein (M), and epitopes of nsp13.…”

Section: Methodsmentioning

confidence: 99%

“…The sera samples collected in our previous study (Jawalagatti et al., 2021, unpublished) were used to assess the neutralizing antibody response against the parental and delta variants of SARS-CoV-2 ( 18 ). Mice were immunized orally with two doses at two weeks apart and the sera samples were collected at week 3 after final immunization.…”

Section: Methodsmentioning

confidence: 99%

“…We previously developed a multicistronic self-replicating mRNA vaccine candidate against SARS-CoV-2 by exploiting the Semliki Forest Virus replicon ( 18 ). To enable oral delivery of the mRNA vaccine, we exploited the bacteria-mediated gene transfer.…”

Section: Introductionmentioning

confidence: 99%

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A Simplified SARS-CoV-2 Mouse Model Demonstrates Protection by an Oral Replicon-Based mRNA Vaccine

et al. 2022

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A mouse model of SARS-CoV-2 that can be developed in any molecular biology lab with standard facilities will be valuable in evaluating drugs and vaccines. Here we present a simplified SARS-CoV-2 mouse model exploiting the rapid adenoviral purification method. Mice that are sensitive to SARS-CoV-2 infection were generated by transducing human angiotensin-converting enzyme 2 (hACE2) by an adenovirus. The expression kinetics of the hACE2 in transduced mice were assessed by immunohistochemistry, RT-PCR, and qPCR. Further, the ability of the hACE2 to support viral replication was determined in vitro and in vivo. The hACE2 expression in the lungs of mice was observed for at least nine days after transduction. The murine macrophages expressing hACE2 supported viral replication with detection of high viral titers. Next, in vivo studies were carried out to determine viral replication and lung disease following SARS-CoV-2 challenge. The model supported viral replication, and the challenged mouse developed lung disease characteristic of moderate interstitial pneumonia. Further, we illustrated the utility of the system by demonstrating protection using an oral mRNA vaccine. The multicistronic vaccine design enabled by the viral self-cleaving peptides targets receptor binding domain (RBD), heptad repeat domain (HR), membrane glycoprotein (M) and epitopes of nsp13 of parental SARS-CoV-2. Further, Salmonella and Semliki Forest virus replicon were exploited, respectively, for gene delivery and mRNA expression. We recorded potent cross-protective neutralizing antibodies in immunized mice against the SARS-CoV-2 delta variant. The vaccine protected the mice against viral replication and SARS-CoV-2-induced weight loss and lung pathology. The findings support the suitability of the model for preclinical evaluation of anti-SARS-CoV-2 therapies and vaccines. In addition, the findings provide novel insights into mRNA vaccine design against infectious diseases not limiting to SARS-CoV-2.

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Advancement of Engineered Bacteria for Orally Delivered Therapeutics

Guo

Wang

Yue

et al. 2023

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The use of bacteria and their biotic components as therapeutics has shown great potential in the treatment of diseases. Orally delivered bacteria improve patient compliance compared with injection‐administered bacteria and are considered the preferred mode. However, due to the harsh gastrointestinal environment, the viability and therapeutic efficacy of orally delivered bacteria are significantly reduced in vivo. In recent years, with the rapid development of synthetic biology and nanotechnology, bacteria and biotic components have been engineered to achieve directed genetic reprogramming for construction and precise spatiotemporal control in the gastrointestinal tract, which can improve viability and therapeutic efficiency. Herein, a state‐of‐the‐art review on the current progress of engineered bacterial systems for oral delivery is provided. The different types of bacterial and biotic components for oral administration are first summarized. The engineering strategies of these bacteria and biotic components and their treatment of diseases are next systematically summarized. Finally, the current challenges and prospects of these bacterial therapeutics are highlighted that will contribute to the development of next‐generation orally delivered bacteriotherapy.

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Highly feasible immunoprotective multicistronic SARS-CoV-2 vaccine candidate blending novel eukaryotic expression and Salmonella bactofection

Cited by 13 publications

References 70 publications

Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]

Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]

A Simplified SARS-CoV-2 Mouse Model Demonstrates Protection by an Oral Replicon-Based mRNA Vaccine

Advancement of Engineered Bacteria for Orally Delivered Therapeutics

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