Dataset Information

Insights from the Construction of Adenovirus-Based Vaccine Candidates against SARS-CoV-2: Expecting the Unexpected.

ABSTRACT: To contain the spread of the SARS-CoV-2 pandemic, rapid development of vaccines was required in 2020. Rational design, international efforts, and a lot of hard work yielded the market approval of novel SARS-CoV-2 vaccines based on diverse platforms such as mRNA or adenovirus vectors. The great success of these technologies, in fact, contributed significantly to control the pandemic. Consequently, most scientific literature available in the public domain discloses the results of clinical trials and reveals data of efficaciousness. However, a description of processes and rationales that led to specific vaccine design is only partially available, in particular for adenovirus vectors, even though it could prove helpful for future developments. Here, we disclose our insights from the endeavors to design compatible functional adenoviral vector platform expression cassettes for the SARS-CoV-2 spike protein. We observed that contextualizing genes from an ssRNA virus into a DNA virus provides significant challenges. Besides affecting physical titers, expression cassette design of adenoviral vaccine candidates can affect viral propagation and spike protein expression. Splicing of mRNAs was affected, and fusogenicity of the spike protein in ACE2-overexpressing cells was enhanced when the ER retention signal was deleted.

SUBMITTER: Weklak D

PROVIDER: S-EPMC10675337 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Insights from the Construction of Adenovirus-Based Vaccine Candidates against SARS-CoV-2: Expecting the Unexpected.

Weklak Denice D Tisborn Julian J Mangold Maurin Helen MH Scheu Raphael R Wodrich Harald H Hagedorn Claudia C Jönsson Franziska F Kreppel Florian F

Viruses 20231025 11

To contain the spread of the SARS-CoV-2 pandemic, rapid development of vaccines was required in 2020. Rational design, international efforts, and a lot of hard work yielded the market approval of novel SARS-CoV-2 vaccines based on diverse platforms such as mRNA or adenovirus vectors. The great success of these technologies, in fact, contributed significantly to control the pandemic. Consequently, most scientific literature available in the public domain discloses the results of clinical trials a ...[more]

PMID: 38005833

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Project description:New universal prophylactic vaccine platforms are needed to prevent or reduce the impact of future respiratory viral infections. While the attribute of T memory cells is particularly attractive in the context of vaccine design for viral infection, the efficiency of T and B memory cell-mediated protection generated under the adenoviral vector was tested. We studied the mechanism using the platform/ immunological factor combination (AdV1+rRBD): adenovirus AdV1 (adjuvant) armed with inducible co-stimulator ICOS and CD40 ligand in combination with recombinant spike protein rRBD (antigen) to promote the differentiation of memory T and B cells. Additionally, adenovirus AdV2 (adjuvant) without ICOS and CD40 ligand in combination with rRBD was tested. Investigating ex vivo T cell responses to the platform-specific stimuli, we found higher frequencies of CD8+ than CD4+ platform-specific T cells vs mock. The cytometric analysis showed that T cells confer protection against SARS-CoV-2 via elevated T cell subsets: CD8+TEMRA (57.6% ± SD 3.3 vs mock 39.6% ± SD 4.83) and CD4+TNAÏVE (59.6% ± SD 0.4 vs mock 50.8% ± SD 1.9). We found that CD8+TEM, CD8+TSCM, and CD8+TCM are antigen-experienced subpopulations generated via the platform after 7 days. When stimulated with the immunological factors, B cells changed from the production of IgM and IgD to isotype IgG. The CD40 gene was significantly expressed (RT-qPCR) in VERO E6 after stimulation with the platform. RNA-seq profiling identified Th1, Th2, and Th17 cell differentiation gene expression patterns that effectively protect against different pathogens. RNA-seq analysis determined signaling pathways that control immunological mechanisms by which the platform induces protective immunity: MAPK cascade, adipocytokine, cAMP, TNF, and Toll-like receptor (TLR) signaling pathway. The formulation (AdV1+rRBD) increased the production of IL-6, IL-8, and TNF vs the mock (P<0.0001). The whole-genome sequencing of VERO E6 showed differences in the expression of apoptosis gene stimulated with the platforms vs mock. Moreover, apoptotic hallmarks were identified and quantified using flow cytometry. We proved that immunogenic factors compromised plasma membrane integrity (RNA-seq). To sum up, the proposed adenoviral platform generated innate and adaptive immunity for the complex and robust regulatory system to prevent SARS-CoV-2 infections.

Project description:Introduction: The current incidence of the novel coronavirus disease has shown only small reductions of cases and has become a major public health challenge. Development of effective vaccines against the virus is still being encouraged such as multi-epitope vaccines designed from the components of SARS-CoV-2 including its spike, nucleocapsid and ORF1a proteins. Since the addition of adjuvants including HABA protein and L7/L12 ribosomal are considered helpful to increase the effectiveness of the designed vaccine, we proposed to design multiepitope vaccines by two different adjuvants. Methods: We used the IEDB server to predict BCL and TCL epitopes that were characterized using online tools including VaxiJen, AllPred and IL-10 Prediction. The selected epitopes were further constructed into multiepitope vaccines. We also added two different adjuvants to the vaccine components in order to increase the effectiveness of the vaccines. The 3D-structured vaccines were built using trRosetta. They were further docked with different Toll-like-receptors (TLR 3, 4 and 8) and the entry receptor of SARS-CoV-2, ACE2 using ClusPro, PatchDock and refined by FireDock. All structures were visualized by USCF Chimera and PyMOL. Results: In this study, we succeeded in designing two different candidate vaccines by the addition of HABA protein and L7/L12 ribosomal as adjuvants. The two vaccines were almost equally good in terms of their physicochemical properties and characteristics. Likewise, their strong interactions with TLR3 4, 8 and ACE2 show the lowest energy level of both was estimated at more than -1,000. Interactions of vaccines with ACE2 and TLRs are essential for activation of immune responses and production of antibodies. Conclusion: The two designed and constructed multiepitope vaccine have good characteristics and may have the potential to activate humoral and cellular immune responses against SARS-CoV-2. Further research is worth considering to confirm the findings of this study.

Dataset Information

Insights from the Construction of Adenovirus-Based Vaccine Candidates against SARS-CoV-2: Expecting the Unexpected.

Publications

Insights from the Construction of Adenovirus-Based Vaccine Candidates against SARS-CoV-2: Expecting the Unexpected.

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