DOI QR코드

DOI QR Code

Strategic construction of mRNA vaccine derived from conserved and experimentally validated epitopes of avian influenza type A virus: a reverse vaccinology approach

  • Leana Rich Herrera-Ong (Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila)
  • Received : 2023.01.22
  • Accepted : 2023.03.31
  • Published : 2023.04.30

Abstract

Purpose: The development of vaccines that confer protection against multiple avian influenza A (AIA) virus strains is necessary to prevent the emergence of highly infectious strains that may result in more severe outbreaks. Thus, this study applied reverse vaccinology approach in strategically constructing messenger RNA (mRNA) vaccine construct against avian influenza A (mVAIA) to induce cross-protection while targeting diverse AIA virulence factors. Materials and Methods: Immunoinformatics tools and databases were utilized to identify conserved experimentally validated AIA epitopes. CD8+ epitopes were docked with dominant chicken major histocompatibility complexes (MHCs) to evaluate complex formation. Conserved epitopes were adjoined in the optimized mVAIA sequence for efficient expression in Gallus gallus. Signal sequence for targeted secretory expression was included. Physicochemical properties, antigenicity, toxicity, and potential cross-reactivity were assessed. The tertiary structure of its protein sequence was modeled and validated in silico to investigate the accessibility of adjoined B-cell epitope. Potential immune responses were also simulated in C-ImmSim. Results: Eighteen experimentally validated epitopes were found conserved (Shannon index <2.0) in the study. These include one B-cell (SLLTEVETPIRNEWGCR) and 17 CD8+ epitopes, adjoined in a single mRNA construct. The CD8+ epitopes docked favorably with MHC peptidebinding groove, which were further supported by the acceptable ∆Gbind (-28.45 to -40.59 kJ/mol) and Kd (<1.00) values. The incorporated Sec/SPI (secretory/signal peptidase I) cleavage site was also recognized with a high probability (0.964814). Adjoined B-cell epitope was found within the disordered and accessible regions of the vaccine. Immune simulation results projected cytokine production, lymphocyte activation, and memory cell generation after the 1st dose of mVAIA. Conclusion: Results suggest that mVAIA possesses stability, safety, and immunogenicity. In vitro and in vivo confirmation in subsequent studies are anticipated.

Keywords

References

  1. Horwood PF. Avian influenza H5N1: still a pandemic threat? Microbiol Aust 2021;42:152-5. https://doi.org/10.1071/MA21044
  2. Yamamoto Y, Nakamura K, Mase M. Survival of highly pathogenic avian influenza H5N1 virus in tissues derived from experimentally infected chickens. Appl Environ Microbiol 2017;83:e00604-17. https://doi.org/10.1128/AEM.00604-17
  3. Beerens N, Heutink R, Harders F, Bossers A, Koch G, Peeters B. Emergence and selection of a highly pathogenic avian influenza H7N3 virus. J Virol 2020;94:e01818-9. https://doi.org/10.1128/JVI.01818-19
  4. Taubenberger JK, Kash JC, Morens DM. The 1918 influenza pandemic: 100 years of questions answered and unanswered. Sci Transl Med 2019;11:eaau5485.
  5. Bellini S, Scaburri A, Colella EM, et al. Epidemiological features of the highly pathogenic avian influenza virus H5N1 in a densely populated area of Lombardy (Italy) during the epidemic season 2021-2022. Viruses 2022;14:1890.
  6. Wappes J. H5N1 avian flu now affecting more than two thirds of states [Internet]. Minneapolis (MN): Center for Infectious Disease Research and Policy; 2022 [cited 2023 Jan 3]. Available from: https://www.cidrap.umn.edu/h5n1-avian-flu-now-affecting-more-two-thirds-states
  7. Jocson LM. Bird flu detected in 9 provinces in Luzon, 1 in Mindanao. BusinessWorld [Internet]. 2022 Oct 6 [cited 2023 Jan 3]. Available from: https://www.bworldonline.com/the-nation/2022/10/06/479144/bird-flu-detectedin-9-provinces-in-luzon-1-in-mindanao/
  8. Guyonnet V, Peters AR. Are current avian influenza vaccines a solution for smallholder poultry farmers? Gates Open Res 2020;4:122.
  9. Jain S, Venkataraman A, Wechsler ME, Peppas NA. Messenger RNA-based vaccines: past, present, and future directions in the context of the COVID-19 pandemic. Adv Drug Deliv Rev 2021;179:114000.
  10. Yu L, Pan J, Cao G, et al. AIV polyantigen epitope expressed by recombinant baculovirus induces a systemic immune response in chicken and mouse models. Virol J 2020;17:121.
  11. James CM, Foong YY, Mansfield JP, Fenwick SG, Ellis TM. Use of tetanus toxoid as a differentiating infected from vaccinated animals (DIVA) strategy for sero-surveillance of avian influenza virus vaccination in poultry. Vaccine 2007;25:5892-901. https://doi.org/10.1016/j.vaccine.2007.05.023
  12. Li J, Helal ZH, Karch CP, et al. A self-adjuvanted nanoparticle based vaccine against infectious bronchitis virus. PLoS One 2018;13:e0203771.
  13. Palmer E, Migalska M, Wise D, Tregaskes C, Kaufman J. Transport studies with the polymorphic TAP molecules in chickens. Mol Immunol 2022;150:28.
  14. Halabi S, Ghosh M, Stevanovic S, et al. The dominantly expressed class II molecule from a resistant MHC haplotype presents only a few Marek's disease virus peptides by using an unprecedented binding motif. PLoS Biol 2021; 19:e3001057.
  15. Diatroptov ME. Changes in body temperature of small mammals and birds in a few minutes range as reflection of environmental influences. Bull Exp Biol Med 2021;171:388-92. https://doi.org/10.1007/s10517-021-05234-z
  16. Dhungel P, Cao S, Yang Z. The 5'-poly(A) leader of poxvirus mRNA confers a translational advantage that can be achieved in cells with impaired cap-dependent translation. PLoS Pathog 2017;13:e1006602.
  17. Kaczmarek JC, Kowalski PS, Anderson DG. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med 2017;9:60.
  18. Rohner E, Yang R, Foo KS, Goedel A, Chien KR. Unlocking the promise of mRNA therapeutics. Nat Biotechnol 2022;40:1586-600. https://doi.org/10.1038/s41587-022-01491-z
  19. Dimitrov I, Flower DR, Doytchinova I. AllerTOP: a server for in silico prediction of allergens. BMC Bioinformatics 2013;14 Suppl 6(Suppl 6):S4.
  20. Ponomarenko J, Bui HH, Li W, et al. ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinformatics 2008;9:514.
  21. Castiglione F, Duca K, Jarrah A, Laubenbacher R, Hochberg D, Thorley-Lawson D. Simulating Epstein-Barr virus infection with C-ImmSim. Bioinformatics 2007;23:1371-7. https://doi.org/10.1093/bioinformatics/btm044
  22. Baldazzi V, Castiglione F, Bernaschi M. An enhanced agent based model of the immune system response. Cell Immunol 2006;244:77-9. https://doi.org/10.1016/j.cellimm.2006.12.006
  23. Mohammadin S, Edger PP, Pires JC, Schranz ME. Positionally-conserved but sequence-diverged: identification of long non-coding RNAs in the Brassicaceae and Cleomaceae. BMC Plant Biol 2015;15:217.
  24. Georgakopoulos-Soares I, Parada GE, Hemberg M. Secondary structures in RNA synthesis, splicing and translation. Comput Struct Biotechnol J 2022;20:2871-84. https://doi.org/10.1016/j.csbj.2022.05.041
  25. Guruprasad K, Reddy BV, Pandit MW. Correlation between stability of a protein and its dipeptide composition: a novel approach for predicting in vivo stability of a protein from its primary sequence. Protein Eng 1990;4:155-61. https://doi.org/10.1093/protein/4.2.155
  26. Hema K, Ahamad S, Joon HK, Pandey R, Gupta D. Atomic resolution homology models and molecular dynamics simulations of Plasmodium falciparum tubulins. ACS Omega 2021;6:17510-22. https://doi.org/10.1021/acsomega.1c01988
  27. Mora Lagares L, Minovski N, Caballero Alfonso AY, et al. Homology modeling of the human P-glycoprotein (ABCB1) and insights into ligand binding through molecular docking studies. Int J Mol Sci 2020;21:4058.
  28. Litwin S, Jores R. Shannon information as a measure of amino acid diversity. In: Perelson AS, Weisbuch G, editors. Theoretical and experimental insights into immunology. Berlin: Springer-Verlag; 1992. p. 279-87.
  29. Lisowska E. Antigenic properties of human glycophorins: an update. Adv Exp Med Biol 2001;491:155-69. https://doi.org/10.1007/978-1-4615-1267-7_12
  30. Saito Y, Peterson PA, Matsumura M. Quantitation of peptide anchor residue contributions to class I major histocompatibility complex molecule binding. J Biol Chem 1993;268:21309-17. https://doi.org/10.1016/S0021-9258(19)36925-X
  31. Reich Z, Altman JD, Boniface JJ, et al. Stability of empty and peptide-loaded class II major histocompatibility complex molecules at neutral and endosomal pH: comparison to class I proteins. Proc Natl Acad Sci U S A 1997;94:2495-500. https://doi.org/10.1073/pnas.94.6.2495
  32. Hanke T, Ondondo B, Abdul-Jawad S, Roshorm Y, Bridgeman A. Vector delivery-dependant effect of human tissue plasminogen activator signal peptide on vaccine induction of T cells. J HIV AIDS 2016;2:1-8.
  33. Reche PA. Potential cross-reactive immunity to SARSCoV-2 from common human pathogens and vaccines. Front Immunol 2020;11:586984.
  34. Drazkowska K, Tomecki R, Warminski M, et al. 2'-O-Methylation of the second transcribed nucleotide within the mRNA 5' cap impacts the protein production level in a cell-specific manner and contributes to RNA immune evasion. Nucleic Acids Res 2022;50:9051-71. https://doi.org/10.1093/nar/gkac722
  35. Andrews RJ, Baber L, Moss WN. Mapping the RNA structural landscape of viral genomes. Methods 2020;183:57-67. https://doi.org/10.1016/j.ymeth.2019.11.001
  36. Kim SC, Sekhon SS, Shin WR, et al. Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency. Mol Cell Toxicol 2022;18:1-8. https://doi.org/10.1007/s13273-021-00171-4
  37. Magdeldin S, Yoshida Y, Li H, et al. Murine colon proteome and characterization of the protein pathways. BioData Min 2012;5:11.