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Published on: January 7, 2019
Reverse Vaccinology Approach in Constructing a Multi-Epitope Vaccine Against Cancer-Testis Antigens Expressed in
1Department of Physical Sciences, College of Science, Polytechnic University of the Philippines, Manila City, Philippines.
Background:
The 5-year survival rate of non-small cell lung cancer (NSCLC) patients has not significantly improved despite advancements in the currently applied treatments. Thus, efforts are put forth in developing novel immunotherapeutic agents targeting cancer-testis antigens (CTA) in NSCLC. This work utilized reverse vaccinology approach in designing a novel multi-epitope vaccine targeting melanoma-associated antigen 3 (MAGEA3), MAGEA4, New York esophageal squamous cell carcinoma-1 (NY-ESO-1), and Kita-Kyushu lung cancer antigen 1 (KK-LC1), being the most frequently expressed CTAs in NSCLC.
Methods:
Epitopes were mapped from the sequences of CTAs. The population coverage (PC) of identified CD4+ and CD8+ epitopes were estimated. Candidate linear B cell (BL), CD4+, and CD8+ epitopes were adjoined in a multi-epitope construct (Mvax) with flagellin domain as an adjuvant. Antigenicity, and cross-reactivity of Mvax were examined. The tertiary structure of Mvax was modelled, and validated. All epitopes included in the vaccine were docked with their human leukocyte antigen (HLA) binders. The immunogenicity of epitopes in Mvax was validated through molecular dynamics analysis.
Results:
Mvax contains 22 epitopes from MAGEA3, MAGEA4, NY-ESO-1, and KK-LC1. It is classified as antigenic, non-allergen, non-toxic, and possesses physicochemical stability. Epitopes have no significant hits with other human proteins, except for 2 other CTAs frequently expressed in NSCLC. The stretch of BL epitopes in Mvax confers flexibility, and accessibility emphasizing its antigenicity. The tertiary structure analysis showed that Mvax model has good structural quality. All epitopes included in the vaccine are highly immunogenic as indicated by favorable binding affinity, low binding energy, and acceptable root-mean-square deviation (RMSD). CD4+ and CD8+ epitopes have global PC of 81.81%, and 84.15%, respectively.
Conclusion:
Overall, in silico evaluations show that Mvax is a potential immunotherapeutic agent against NSCLC.
Insights
A novel multi-epitope vaccine, Mvax, was designed using reverse vaccinology for non-small cell lung cancer (NSCLC). In silico analysis indicates Mvax is a promising immunotherapeutic agent targeting cancer-testis antigens (CTAs) in NSCLC patients.
Area of Science:
- Immunology and Cancer Therapeutics
- Bioinformatics and Vaccine Design
Background:
- Non-small cell lung cancer (NSCLC) survival rates remain suboptimal despite current treatments.
- Novel immunotherapeutic strategies targeting cancer-testis antigens (CTAs) are crucial for NSCLC treatment.
- This study focuses on CTAs frequently expressed in NSCLC, including MAGEA3, MAGEA4, NY-ESO-1, and KK-LC1.
Purpose of the Study:
- To design a novel multi-epitope vaccine (Mvax) against NSCLC using a reverse vaccinology approach.
- To target specific cancer-testis antigens (CTAs) highly prevalent in NSCLC.
- To evaluate the immunogenicity and structural properties of the designed vaccine candidate.
Main Methods:
- Epitope mapping from selected CTAs (MAGEA3, MAGEA4, NY-ESO-1, KK-LC1).
- Design of a multi-epitope construct (Mvax) incorporating B cell (BL), CD4+, and CD8+ epitopes with a flagellin adjuvant.
- In silico analysis including antigenicity, cross-reactivity, tertiary structure modeling, molecular dynamics, and population coverage (PC) estimation.
Main Results:
- Mvax comprises 22 epitopes from targeted CTAs, exhibiting favorable antigenic, non-allergenic, and non-toxic properties.
- Tertiary structure modeling confirmed good structural quality, and molecular dynamics analysis indicated high immunogenicity with favorable binding affinities.
- The vaccine construct demonstrated significant population coverage for both CD4+ (81.81%) and CD8+ (84.15%) T cell epitopes.
Conclusions:
- In silico evaluations suggest Mvax is a potent and viable immunotherapeutic candidate for NSCLC.
- The designed vaccine shows potential for broad applicability due to high population coverage.
- Further experimental validation is warranted to confirm Mvax efficacy in NSCLC treatment.
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