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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
mRNA vaccine design targeting Merkel cell polyomavirus for immunotherapy of Merkel cell carcinoma
Akmal Zubair1, Faisal Ahmad2, Muhammad Yaqoob Shahani3
1Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan. akmalkhattk1994@gmail.com.
Abstract:
The pathogenesis of Merkel cell polyomavirus (MCPyV) is characterized by ubiquitous and most likely silent childhood infection that may cause Merkel cell carcinoma (MCC). This mRNA vaccine includes the capsid proteins VP1 and VP2, as well as the Large T antigen and small T antigen, which are highly immunogenic. This has led to the development of mRNA vaccines against these T and Capsid peptides. Different computational methods was used to identify the epitopes of helper CD4 + lymphocytes and CD8 + lymphocytes. All of selected epitopes was analyzed for their toxicity, allergenicity, and immunogenicity. The MD simulation was carried out in an orthorhombic TIP3P water box with a buffer region of 10 Å, and Na+/Cl- counter ions at a physiological amount of salt (150 mM) were added to neutralize the system. Once the NVT and NPT aggregates were equilibrated, a 100 ns manufacturing run at 310 K and 1 atm was performed. Our vaccine has 19 epitopes in the vaccine construct, including HTLs and CTLs. The vaccine was found to have an increased hydrophilicity, and the average hydropathicity score was - 8.95. The Ramachandran plot revealed potential stability, 94.6% of the amino acid units were found in the allowed region. The vaccine showed potentially high affinity with the TLR3 receptor as the docking score was - 318.56 KJ/mol, and the confidence score was 0.9668. After codon optimization, there was a knowing improvement in the expression in E. coli vectors that produced vaccines, as indicated by the increase in GC content to 53.41. MM-GBSA analysis showed that there was a uniform binding affinity of TLR3 between - 1500 and - 2000 kcal/mol. Our vaccine construct against MCPyV showed potential immune responses and should be advanced to in vitro and in vivo clinical experiments.
Insights
A novel mRNA vaccine targeting Merkel cell polyomavirus (MCPyV) has been developed using computational methods to identify key epitopes. This vaccine shows potential for eliciting immune responses against MCPyV and Merkel cell carcinoma (MCC).
Area of Science:
- Immunology and Virology
- Vaccine Development
- Computational Biology
Background:
- Merkel cell polyomavirus (MCPyV) causes Merkel cell carcinoma (MCC) following childhood infection.
- Current therapeutic strategies for MCC are limited, necessitating novel vaccine approaches.
- MCPyV encodes immunogenic viral proteins, including capsid proteins (VP1, VP2) and T antigens (Large T, small T).
Purpose of the Study:
- To design and computationally evaluate an mRNA vaccine construct targeting MCPyV.
- To identify and analyze potential T-cell epitopes for vaccine development.
- To assess the vaccine construct's stability, immunogenicity, and binding affinity to immune receptors.
Main Methods:
- In silico epitope prediction for CD4+ helper T lymphocytes (HTLs) and CD8+ cytotoxic T lymphocytes (CTLs).
- Analysis of predicted epitopes for toxicity, allergenicity, and immunogenicity.
- Molecular dynamics (MD) simulations, docking studies with TLR3, and MM-GBSA for binding affinity assessment.
- Codon optimization for enhanced expression in E. coli vectors.
Main Results:
- A vaccine construct comprising 19 validated epitopes (HTLs and CTLs) was designed.
- The vaccine construct exhibited favorable physicochemical properties, including increased hydrophilicity (score -8.95) and structural stability (94.6% in allowed Ramachandran regions).
- High binding affinity to the TLR3 receptor was predicted (docking score -318.56 KJ/mol, confidence 0.9668; MM-GBSA -1500 to -2000 kcal/mol).
- Codon optimization improved expression potential, evidenced by increased GC content (53.41%).
Conclusions:
- The computationally designed mRNA vaccine construct shows significant potential for inducing immune responses against MCPyV.
- The predicted stability, immunogenicity, and receptor binding suggest the vaccine is a promising candidate for further preclinical development.
- The study supports advancing this MCPyV vaccine candidate to in vitro and in vivo clinical trials.
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