Abstract
Virus-like particles (VLPs) are macromolecular assemblies of recombinant viral structural proteins. Self-assembling with high precision, the repetitive nature of VLPs, their size, and particulate form result in the capacity for effective stimulation of humoral and cellular immune responses. VLP vaccines have achieved commercial success for protection against cognate viruses. However, there is a rich field of research dedicated to harnessing the immune-stimulatory properties of VLPs for the presentation of heterologous antigens for protection and treatment of chronic and infectious diseases. Peptides, proteins, carbohydrates, and small molecules have been converted into effective immunogens via presentation on various VLP platforms. In each case, unique bioengineering challenges must be overcome to allow the recovery, assembly, and structural fidelity of the VLP platform, as well as the immunogenicity of the antigen. This review highlights some of the biomolecular engineering approaches that are being employed to effectively present diverse biological molecules and chemical moieties on VLP platforms and bioprocessing strategies for their efficient recovery from the prokaryotic expression host Escherichia coli.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abbing A, Blaschke UK, Grein S, Kretschmar M, Stark CM, Thies MJ, Walter J, Weigand M, Woith DC, Hess J, Reiser CO (2004) Efficient intracellular delivery of a protein and a low molecular weight substance via recombinant polyomavirus-like particles. J Biol Chem 279(26):27410–27421
Abidin RS, Lua LH, Middelberg AP, Sainsbury F (2015) Insert engineering and solubility screening improves recovery of virus-like particle subunits displaying hydrophobic epitopes. Protein Sci 24(11):1820–1828
Anggraeni MR, Connors NK, Wu Y, Chuan YP, Lua LH, Middelberg AP (2013) Sensitivity of immune response quality to influenza helix 190 antigen structure displayed on a modular virus-like particle. Vaccine 31(40):4428–4435
Babin C, Majeau N, Leclerc D (2013) Engineering of papaya mosaic virus (PapMV) nanoparticles with a CTL epitope derived from influenza NP. J Nanobiotechnol 11:10
Bachmann MF, Jennings GT (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol 10(11):787–796
Bachmann MF, Zinkernagel RM (1997) Neutralizing antiviral B cell responses. Annu Rev Immunol 15:235–270
Barrington R, Zhang M, Fischer M, Carroll MC (2001) The role of complement in inflammation and adaptive immunity. Immunol Rev 180:5–15
Bayer ME, Blumberg BS, Werner B (1968) Particles associated with Australia antigen in the sera of patients with leukaemia, Down’s Syndrome and hepatitis. Nature 218(5146):1057–1059
Bessa J, Jegerlehner A, Hinton HJ, Pumpens P, Saudan P, Schneider P, Bachmann MF (2009) Alveolar macrophages and lung dendritic cells sense RNA and drive mucosal IgA responses. J Immunol 183(6):3788–3799
Blumberg BS, Alter HJ, Visnich S (1965) A "new" antigen in leukemia sera. JAMA 191:541–546
Boura E, Liebl D, Spisek R, Fric J, Marek M, Stokrova J, Holan V, Forstova J (2005) Polyomavirus EGFP-pseudocapsids: analysis of model particles for introduction of proteins and peptides into mammalian cells. FEBS Lett 579(29):6549–6558
Braun H, Boller K, Lower J, Bertling WM, Zimmer A (1999) Oligonucleotide and plasmid DNA packaging into polyoma VP1 virus-like particles expressed in Escherichia coli. Biotechnol Appl Biochem 29:31–43
Brown SD, Fiedler JD, Finn MG (2009) Assembly of hybrid bacteriophage Qbeta virus-like particles. Biochemistry 48(47):11155–11157
Brune KD, Leneghan DB, Brian IJ, Ishizuka AS, Bachmann MF, Draper SJ, Biswas S, Howarth M (2016) Plug-and-display: decoration of virus-like particles via isopeptide bonds for modular immunization. Sci Rep 6:19234
Chackerian B, Lowy DR, Schiller JT (1999) Induction of autoantibodies to mouse CCR5 with recombinant papillomavirus particles. Proc Natl Acad Sci U S A 96(5):2373–2378
Cheong WS, Reiseger J, Turner SJ, Boyd R, Netter HJ (2009) Chimeric virus-like particles for the delivery of an inserted conserved influenza A-specific CTL epitope. Antivir Res 81(2):113–122
Chuan YP, Fan YY, Lua LH, Middelberg AP (2010) Virus assembly occurs following a pH- or Ca2+−triggered switch in the thermodynamic attraction between structural protein capsomeres. J R Soc Interface 7(44):409–421
Chuan YP, Lua LH, Middelberg AP (2008) High-level expression of soluble viral structural protein in Escherichia coli. J Biotechnol 134(1–2):64–71
Chuan YP, Wibowo N, Lua LHL, Middelberg APJ (2014) The economics of virus-like particle and capsomere vaccines. Biochem Eng J 90:255
Dashti NH, Abidin RS, Sainsbury F (2018) Programmable in vitro coencapsidation of guest proteins for intracellular delivery by virus-like particles. ACS Nano 12(5):4615–4623
Eriksson M, Andreasson K, Weidmann J, Lundberg K, Tegerstedt K, Dalianis T, Ramqvist T (2011) Murine polyomavirus virus-like particles carrying full-length human PSA protect BALB/c mice from outgrowth of a PSA expressing tumor. PLoS One 6(8):e23828
Glasgow J, Tullman-Ercek D (2014) Production and applications of engineered viral capsids. Appl Microbiol Biotechnol 98(13):5847–5858
Hagensee ME, Yaegashi N, Galloway DA (1993) Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J Virol 67(1):315–322
Janitzek CM, Matondo S, Thrane S, Nielsen MA, Kavishe R, Mwakalinga SB, Theander TG, Salanti A, Sander AF (2016) Bacterial superglue generates a full-length circumsporozoite protein virus-like particle vaccine capable of inducing high and durable antibody responses. Malar J 15(1):545
Jegerlehner A, Storni T, Lipowsky G, Schmid M, Pumpens P, Bachmann MF (2002) Regulation of IgG antibody responses by epitope density and CD21-mediated costimulation. Eur J Immunol 32(11):3305–3314
Kawano M, Morikawa K, Suda T, Ohno N, Matsushita S, Akatsuka T, Handa H, Matsui M (2014) Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza a virus without the need of adjuvants. Virology 448:159–167
Khan F, Porter M, Schwenk R, DeBot M, Saudan P, Dutta S (2015) Head-to-head comparison of soluble vs. Qβ VLP circumsporozoite protein vaccines reveals selective enhancement of NANP repeat responses. PLoS One 10(11):e0142035
Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT (1992) Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 89(24):12180–12184
Kushnir N, Streatfield SJ, Yusibov V (2012) Virus-like particles as a highly efficient vaccine platform: diversity of targets and production systems and advances in clinical development. Vaccine 31(1):58–83
Ladd Effio C, Baumann P, Weigel C, Vormittag P, Middelberg A, Hubbuch J (2016a) High-throughput process development of an alternative platform for the production of virus-like particles in Escherichia coli. J Biotechnol 219:7–19
Ladd Effio C, Oelmeier SA, Hubbuch J (2016b) High-throughput characterization of virus-like particles by interlaced size-exclusion chromatography. Vaccine 34(10):1259–1267
Lee KL, Twyman RM, Fiering S, Steinmetz NF (2016) Virus-based nanoparticles as platform technologies for modern vaccines. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8(4):554–578
Li L, Fierer JO, Rapoport TA, Howarth M (2014) Structural analysis and optimization of the covalent association between SpyCatcher and a peptide tag. J Mol Biol 426(2):309–317
Li M, Cripe TP, Estes PA, Lyon MK, Rose RC, Garcea RL (1997) Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Virol 71(4):2988–2995
Li W, Jing Z, Wang S, Li Q, Xing Y, Shi H, Li S, Hong Z (2021) P22 virus-like particles as an effective antigen delivery nanoplatform for cancer immunotherapy. Biomaterials 271:120726
Liew MW, Rajendran A, Middelberg AP (2010) Microbial production of virus-like particle vaccine protein at gram-per-litre levels. J Biotechnol 150(2):224–231
Liew MWO, Chuan YP, Middelberg APJ (2012a) Reactive diafiltration for assembly and formulation of virus-like particles. Biochem Eng J 68:120–128
Liew MWO, Chuan YP, Middelberg APJ (2012b) High-yield and scalable cell-free assembly of virus-like particles by dilution. Biochem Eng J 67:88–96
Lipin DI, Raj A, Lua LH, Middelberg AP (2009) Affinity purification of viral protein having heterogeneous quaternary structure: modeling the impact of soluble aggregates on chromatographic performance. J Chromatogr A 1216(30):5696–5708
Lua LH, Connors NK, Sainsbury F, Chuan YP, Wibowo N, Middelberg AP (2014) Bioengineering virus-like particles as vaccines. Biotechnol Bioeng 111(3):425–440
Marusic C, Rizza P, Lattanzi L, Mancini C, Spada M, Belardelli F, Benvenuto E, Capone I (2001) Chimeric plant virus particles as immunogens for inducing murine and human immune responses against human immunodeficiency virus type 1. J Virol 75(18):8434–8439
Maurer P, Jennings GT, Willers J, Rohner F, Lindman Y, Roubicek K, Renner WA, Muller P, Bachmann MF (2005) A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity. Eur J Immunol 35(7):2031–2040
Middelberg AP, Rivera-Hernandez T, Wibowo N, Lua LH, Fan Y, Magor G, Chang C, Chuan YP, Good MF, Batzloff MR (2011) A microbial platform for rapid and low-cost virus-like particle and capsomere vaccines. Vaccine 29(41):7154–7162
Mitic NS, Pavlovic MD, Jandrlic DR (2014) Epitope distribution in ordered and disordered protein regions - part a. T-cell epitope frequency, affinity and hydropathy. J Immunol Methods 406:83–103
Murphy K, Travers P, Walport M, Janeway C (2008) Janeway's Immunobiology, 7th edn. Garland Science, New York
Oussoren C, Zuidema J, Crommelin DJ, Storm G (1997) Lymphatic uptake and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid composition and lipid dose. Biochim Biophys Acta 1328(2):261–272
Pastori C, Tudor D, Diomede L, Drillet AS, Jegerlehner A, Rohn TA, Bomsel M, Lopalco L (2012) Virus like particle based strategy to elicit HIV-protective antibodies to the alpha-helic regions of gp41. Virology 431(1–2):1–11
Pattinson DJ, Apte SH, Wibowo N, Chuan YP, Rivera-Hernandez T, Groves PL, Lua LH, Middelberg APJ, Doolan DL (2019) Chimeric murine polyomavirus virus-like particles induce plasmodium antigen-specific CD8+ T cell and antibody responses. Front Cell Infect Microbiol 9:215
Pleckaityte M, Bremer CM, Gedvilaite A, Kucinskaite-Kodze I, Glebe D, Zvirbliene A (2015) Construction of polyomavirus-derived pseudotype virus-like particles displaying a functionally active neutralizing antibody against hepatitis B virus surface antigen. BMC Biotechnol 15:85
Pokorski JK, Hovlid ML, Finn MG (2011) Cell targeting with hybrid Qbeta virus-like particles displaying epidermal growth factor. Chembiochem 12(16):2441–2447
Pokorski JK, Steinmetz NF (2011) The art of engineering viral nanoparticles. Mol Pharm 8(1):29–43
Reddy ST, Rehor A, Schmoekel HG, Hubbell JA, Swartz MA (2006) In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J Control Release 112(1):26–34
Rivera-Hernandez T, Hartas J, Wu Y, Chuan YP, Lua LH, Good M, Batzloff MR, Middelberg AP (2013) Self-adjuvanting modular virus-like particles for mucosal vaccination against group a streptococcus (GAS). Vaccine 31(15):1950–1955
Rodriguez-Limas WA, Sekar K, Tyo KE (2013) Virus-like particles: the future of microbial factories and cell-free systems as platforms for vaccine development. Curr Opin Biotechnol 24(6):1089–1093
Salunke DM, Caspar DL, Garcea RL (1986) Self-assembly of purified polyomavirus capsid protein VP1. Cell 46(6):895–904
Schiller J, Chackerian B (2014) Why HIV virions have low numbers of envelope spikes: implications for vaccine development. PLoS Pathog 10(8):e1004254
Schwarz B, Morabito KM, Ruckwardt TJ, Patterson DP, Avera J, Miettinen HM, Graham BS, Douglas T (2016) Virus like particles encapsidating respiratory syncytial virus M and M2 proteins induce robust T cell responses. ACS Biomaterials Sci Eng 2(12):2324–2332
Swartz MA (2001) The physiology of the lymphatic system. Adv Drug Deliv Rev 50(1–2):3–20
Tegerstedt K, Franzen A, Ramqvist T, Dalianis T (2007) Dendritic cells loaded with polyomavirus VP1/VP2Her2 virus-like particles efficiently prevent outgrowth of a Her2/neu expressing tumor. Cancer Immunol Immunother 56(9):1335–1344
Tekewe A, Connors NK, Sainsbury F, Wibowo N, Lua LH, Middelberg APJ (2015) A rapid and simple screening method to identify conditions for enhanced stability of modular vaccine candidates. Biochem Eng J 100:50–58
Tekewe A, Fan Y, Tan E, Middelberg AP, Lua LH (2017) Integrated molecular and bioprocess engineering for bacterially produced immunogenic modular virus-like particle vaccine displaying 18 kDa rotavirus antigen. Biotechnol Bioeng 114(2):397–406
Teunissen EA, de Raad M, Mastrobattista E (2013) Production and biomedical applications of virus-like particles derived from polyomaviruses. J Control Release 172(1):305–321
Thrane S, Janitzek CM, Matondo S, Resende M, Gustavsson T, de Jongh WA, Clemmensen S, Roeffen W, van de Vegte-Bolmer M, van Gemert GJ, Sauerwein R, Schiller JT, Nielsen MA, Theander TG, Salanti A, Sander AF (2016) Bacterial superglue enables easy development of efficient virus-like particle based vaccines. J Nanobiotechnol 14:30
Tumban E, Peabody J, Peabody DS, Chackerian B (2011) A pan-HPV vaccine based on bacteriophage PP7 VLPs displaying broadly cross-neutralizing epitopes from the HPV minor capsid protein, L2. PLoS One 6(8):e23310
Tumban E, Peabody J, Tyler M, Peabody DS, Chackerian B (2012) VLPs displaying a single L2 epitope induce broadly cross-neutralizing antibodies against human papillomavirus. PLoS One 7(11):e49751
Tyler M, Tumban E, Peabody DS, Chackerian B (2014) The use of hybrid virus-like particles to enhance the immunogenicity of a broadly protective HPV vaccine. Biotechnol Bioeng 111(12):2398–2406
Wibowo N, Chuan YP, Lua LH, Middelberg AP (2012) Modular engineering of a microbially-produced viral capsomere vaccine. Chem Eng Sci 103:12–20
Wibowo N, Wu Y, Fan Y, Meers J, Lua LH, Middelberg AP (2015) Non-chromatographic preparation of a bacterially produced single-shot modular virus-like particle capsomere vaccine for avian influenza. Vaccine 33(44):5960–5965
Yan D, Wei YQ, Guo HC, Sun SQ (2015) The application of virus-like particles as vaccines and biological vehicles. Appl Microbiol Biotechnol 99(24):10415–10432
Yin Z, Comellas-Aragones M, Chowdhury S, Bentley P, Kaczanowska K, Benmohamed L, Gildersleeve JC, Finn MG, Huang X (2013) Boosting immunity to small tumor-associated carbohydrates with bacteriophage qbeta capsids. ACS Chem Biol 8(6):1253–1262
Yusibov V, Modelska A, Steplewski K, Agadjanyan M, Weiner D, Hooper DC, Koprowski H (1997) Antigens produced in plants by infection with chimeric plant viruses immunize against rabies virus and HIV-1. Proc Natl Acad Sci U S A 94(11):5784–5788
Zakeri B, Fierer JO, Celik E, Chittock EC, Schwarz-Linek U, Moy VT, Howarth M (2012) Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin. Proc Natl Acad Sci U S A 109(12):E690–E697
Zamora E, Handisurya A, Shafti-Keramat S, Borchelt D, Rudow G, Conant K, Cox C, Troncoso JC, Kirnbauer R (2006) Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice. J Immunol 177(4):2662–2670
Zeltins A (2013) Construction and characterization of virus-like particles: a review. Mol Biotechnol 53(1):92–107
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Abidin, R.S., Sainsbury, F. (2022). Bioengineering and Bioprocessing of Virus-Like Particle Vaccines in Escherichia coli. In: Rehm, B.H.A., Wibowo, D. (eds) Microbial Production of High-Value Products. Microbiology Monographs, vol 37. Springer, Cham. https://doi.org/10.1007/978-3-031-06600-9_10
Download citation
DOI: https://doi.org/10.1007/978-3-031-06600-9_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-06599-6
Online ISBN: 978-3-031-06600-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)