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Heterologous Expression of Recombinant Proteins and Their Derivatives Used as Carriers for Conjugate Vaccines

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Abstract

Carrier proteins that provide an effective and long-term immune response to weak antigens has become a real breakthrough in the disease prevention, making it available to a wider range of patients and making it possible to obtain reliable vaccines against a variety of pathogens. Currently, research is continuing both to identify new peptides, proteins, and their complexes potentially suitable for use as carriers, and to develop new methods for isolation, purification, and conjugation of already known and well-established proteins. The use of recombinant proteins has a number of advantages over isolation from natural sources, such as simpler cultivation of the host organism, the possibility of modifying genetic constructs, use of numerous promoter variants, signal sequences, and other regulatory elements. This review is devoted to the methods of obtaining both traditional and new recombinant proteins and their derivatives already being used or potentially suitable for use as carrier proteins in conjugate vaccines.

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Abbreviations

DT:

diphtheria toxin

CRM197:

non-toxic mutant of diphtheria toxin

GMMA:

generalized modules for membrane antigens

Hib:

Haemophilus influenza type b

OMPC:

outer membrane protein complex

OMV:

outer membrane vesicles

PD:

protein D from Haemophilus influenza

TT:

tetanus toxin

VLP:

virus-like particles

References

  1. Weller, P. F., Smith, A. L., Smith, D. H., and Anderson, P. (1978) Role of immunity in the clearance of bacteremia due to Haemophilus influenzae, J. Infect. Diseases, 138, 427-436, https://doi.org/10.1093/infdis/138.4.427.

    Article  CAS  Google Scholar 

  2. Finlay, B. B., and Falkow, S. (1997) Common themes in microbial pathogenicity revisited, Microbiol. Mol. Biol. Rev., 61, 136-169, https://doi.org/10.1128/mmbr.61.2.136-169.1997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kasper, D. L. (1986) Bacterial capsule – old dogmas and new tricks, J. Infect. Diseases, 153, 407-415, https://doi.org/10.1093/infdis/153.3.407.

    Article  CAS  Google Scholar 

  4. Zimmermann, S., and Lepenies, B. (2015) Glycans as vaccine antigens and adjuvants: immunological considerations, Methods Mol. Biol., 1331, 11-26, https://doi.org/10.1007/978-1-4939-2874-3_2.

    Article  PubMed  Google Scholar 

  5. Hütter, J., and Lepenies, B. (2015) Carbohydrate-based vaccines: an overview, Methods Mol. Biol., 1331, 1-10, https://doi.org/10.1007/978-1-4939-2874-3_1.

    Article  PubMed  Google Scholar 

  6. MacCalman, T. E., Phillips-Jones, M. K., and Harding, S. E. (2019) Glycoconjugate vaccines: some observations on carrier and production methods, Biotechnol. Genet. Engin. Rev., 35, 93-125, https://doi.org/10.1080/02648725.2019.1703614.

    Article  Google Scholar 

  7. Avci, F. Y., and Kasper, D. L. (2010) How bacterial carbohydrates influence the adaptive immune system, Annu. Rev. Immunol., 28, 107-130, https://doi.org/10.1146/annurev-immunol-030409-101159.

    Article  CAS  PubMed  Google Scholar 

  8. Micoli, F., Adamo, R., and Costantino, P. (2018) Protein carriers for glycoconjugate vaccines: history, selection criteria, characterization and new trends, Molecules, 23, 1451, https://doi.org/10.3390/molecules23061451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Möller, J., Kraner, M. E., and Burkovski, A. (2019) More than a toxin: protein inventory of clostridium tetani toxoid vaccines, Proteomes, 7, 15, https://doi.org/10.3390/proteomes7020015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bayart, C., Mularoni, A., Hemmani, N., Kerachni, S., Jose, J., Gouet, P., Paladino, J., and Le Borgne, M. (2022) Tetanus toxin fragment C: structure, drug discovery research and production, Pharmaceuticals, 15, 756, https://doi.org/10.3390/ph15060756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bröker, M., Costantino, P., DeTora, L., McIntosh, E. D., and Rappuoli, R. (2011) Biochemical and biological characteristics of cross-reacting material 197 CRM197, a non-toxic mutant of diphtheria toxin: use as a conjugation protein in vaccines and other potential clinical applications, Biologicals, 39, 195-204, https://doi.org/10.1016/j.biologicals.2011.05.004.

    Article  CAS  PubMed  Google Scholar 

  12. Shinefield, H. R. (2010) Overview of the development and current use of CRM(197) conjugate vaccines for pediatric use, Vaccine, 28, 4335-4339, https://doi.org/10.1016/j.vaccine.2010.04.072.

    Article  CAS  PubMed  Google Scholar 

  13. Forsgren, A., Riesbeck, K., and Janson, H. (2008) Protein D of Haemophilus influenzae: a protective nontypeable H. influenzae antigen and a carrier for pneumococcal conjugate vaccines, Clin. Infect. Dis., 46, 726-731, https://doi.org/10.1086/527396.

    Article  CAS  PubMed  Google Scholar 

  14. Holst, J., Martin, D., Arnold, R., Huergo, C. C., Oster, P., O’Hallahan, J., and Rosenqvist, E. (2009) Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis, Vaccine, 27 Suppl 2, B3-B12, https://doi.org/10.1016/j.vaccine.2009.04.071.

    Article  CAS  PubMed  Google Scholar 

  15. Rossi, O., Citiulo, F., and Mancini, F. (2021) Outer membrane vesicles: moving within the intricate labyrinth of assays that can predict risks of reactogenicity in humans, Human Vaccines Immunother., 17, 601-613, https://doi.org/10.1080/21645515.2020.1780092.

    Article  CAS  Google Scholar 

  16. Bröker, M., Berti, F., Schneider, J., and Vojtek, I. (2017) Polysaccharide conjugate vaccine protein carriers as a “neglected valency” – potential and limitations, Vaccine, 35, 3286-3294, https://doi.org/10.1016/j.vaccine.2017.04.078.

    Article  CAS  PubMed  Google Scholar 

  17. Dagan, R., Poolman, J., and Siegrist, C. A. (2010) Glycoconjugate vaccines and immune interference: a review, Vaccine, 28, 5513-5523, https://doi.org/10.1016/j.vaccine.2010.06.026.

    Article  CAS  PubMed  Google Scholar 

  18. Pichichero, M. E. (2013) Protein carriers of conjugate vaccines: characteristics, development, and clinical trials, Human Vaccines Immunother., 9, 2505-2523, https://doi.org/10.4161/hv.26109.

    Article  CAS  Google Scholar 

  19. Van der Put, R. M. F., Metz, B., and Pieters, R. J. (2023) Carriers and antigens: new developments in glycoconjugate vaccines, Vaccines, 11, 219, https://doi.org/10.3390/vaccines11020219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kay, E., Cuccui, J., and Wren, B. W. (2019) Recent advances in the production of recombinant glycoconjugate vaccines, NPJ Vaccines, 4, 16, https://doi.org/10.1038/s41541-019-0110-z.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Choe, S., Bennett, M. J., Fujii, G., Curmi, P. M., Kantardjieff, K. A., Collier, R. J., and Eisenberg, D. (1992) The crystal structure of diphtheria toxin, Nature, 357, 216-222, https://doi.org/10.1038/357216a0.

    Article  CAS  PubMed  Google Scholar 

  22. Rappuoli, R. (1990) New and Improved Vaccines against Diphtheria and Tetanus, 2nd Edn., Marcel Dekker, New York.

  23. Brodzik, R., Spitsin, S., Pogrebnyak, N., Bandurska, K., Portocarrero, C., Andryszak, K., Koprowski, H., and Golovkin, M. (2009) Generation of plant-derived recombinant DTP subunit vaccine, Vaccine, 27, 3730-3734, https://doi.org/10.1016/j.vaccine.2009.03.084.

    Article  CAS  PubMed  Google Scholar 

  24. Greenfield, L., Bjorn, M. J., Horn, G., Fong, D., Buck, G. A., Collier, R. J., and Kaplan, D. A. (1983) Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage beta, Proc. Natl. Acad. Sci. USA, 80, 6853-6857, https://doi.org/10.1073/pnas.80.22.6853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Malito, E., Bursulaya, B., Chen, C., Lo Surdo, P., Picchianti, M., Balducci, E., Biancucci, M., Brock, A., Berti, F., Bottomley, M. J., Nissum, M., Costantino, P., Rappuoli, R., and Spraggon, G. (2012) Structural basis for lack of toxicity of the diphtheria toxin mutant CRM197, Proc. Natl. Acad. Sci. USA, 109, 5229-5234, https://doi.org/10.1073/pnas.1201964109.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ratti, G., Rappuoli, R., and Giannini, G. (1983) The complete nucleotide sequence of the gene coding for diphtheria toxin in the corynephage omega (tox+) genome, Nucleic Acids Res., 11, 6589-6595, https://doi.org/10.1093/nar/11.19.6589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Uchida, T., Pappenheimer, A. M., Jr., and Greany, R. (1973) Diphtheria toxin and related proteins. I. Isolation and properties of mutant proteins serologically related to diphtheria toxin, J. Biol. Chem., 248, 3838-3844, https://doi.org/10.1016/S0021-9258(19)43810-6.

    Article  CAS  PubMed  Google Scholar 

  28. Hu, V. W., and Holmes, R. K. (1987) Single mutation in the A domain of diphtheria toxin results in a protein with altered membrane insertion behavior, Biochim. Biophys. Acta, 902, 24-30, https://doi.org/10.1016/0005-2736(87)90132-5.

    Article  CAS  PubMed  Google Scholar 

  29. Khatuntseva, E. A., and Nifantiev, N. E. (2022) Cross reacting material (CRM197) as a carrier protein for carbohydrate conjugate vaccines targeted at bacterial and fungal pathogens, Int. J. Biol. Macromol., 218, 775-798, https://doi.org/10.1016/j.ijbiomac.2022.07.137.

    Article  CAS  PubMed  Google Scholar 

  30. Sundaran, B., Rao, Y. U., and Boopathy, R. (2001) Process optimization for enhanced production of diphtheria toxin by submerged cultivation, J. Biosci. Bioengin., 91, 123-128, https://doi.org/10.1263/jbb.91.123.

    Article  CAS  Google Scholar 

  31. Suwanpatcharakul, M., Pakdeecharoen, C., Visuttitewin, S., Pesirikan, N., Chauvatcharin, S., and Pongtharangkul, T. (2016) Process optimization for an industrial-scale production of Diphtheria toxin by Corynebacterium diphtheriae PW8, Biologicals, 44, 534-539, https://doi.org/10.1016/j.biologicals.2016.08.002.

    Article  CAS  PubMed  Google Scholar 

  32. Tchorbanov, A. I., Dimitrov, J. D., and Vassilev, T. L. (2004) Optimization of casein-based semisynthetic medium for growing of toxigenic Corinebacterium diphtheriae in a fermenter, Can. J. Microbiol., 50, 821-826, https://doi.org/10.1139/w04-061.

    Article  CAS  PubMed  Google Scholar 

  33. Rappuoli, R., Perugini, M., Marsili, I., and Fabbiani, S. (1983) Rapid purification of diphtheria toxin by phenyl sepharose and DEAE-cellulose chromatography, J. Chromatogr., 268, 543-548, https://doi.org/10.1016/S0021-9673(01)95457-3.

    Article  CAS  Google Scholar 

  34. Zhou, J., and Petracca, R. (1999) Secretory expression of recombinant diphtheria toxin mutants in B. subtilis, J. Tongji Med. Univ., 19, 253-256, https://doi.org/10.1007/bf02886955.

    Article  CAS  PubMed  Google Scholar 

  35. Orr, N., Galen, J. E., and Levine, M. M. (1999) Expression and immunogenicity of a mutant diphtheria toxin molecule, CRM(197), and its fragments in Salmonella typhi vaccine strain CVD 908-htrA, Infect. Immun., 67, 4290-4294, https://doi.org/10.1128/iai.67.8.4290-4294.1999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stefan, A., Conti, M., Rubboli, D., Ravagli, L., Presta, E., and Hochkoeppler, A. (2011) Overexpression and purification of the recombinant diphtheria toxin variant CRM197 in Escherichia coli, J. Biotechnol., 156, 245-252, https://doi.org/10.1016/j.jbiotec.2011.08.024.

    Article  CAS  PubMed  Google Scholar 

  37. Mahamad, P., Boonchird, C., and Panbangred, W. (2016) High level accumulation of soluble diphtheria toxin mutant (CRM197) with co-expression of chaperones in recombinant Escherichia coli, Appl. Microbiol. Biotechnol., 100, 6319-6330, https://doi.org/10.1007/s00253-016-7453-4.

    Article  CAS  PubMed  Google Scholar 

  38. Xu, L., Zhang, J., Yu, R., and Su, Z. (2017) Expression of CRM197 in E. coli system and its application in universal influenza vaccine, Chin. J. Process Eng., 17, 1054-1058.

    Google Scholar 

  39. Goffin, P., Dewerchin, M., De Rop, P., Blais, N., and Dehottay, P. (2017) High-yield production of recombinant CRM197, a non-toxic mutant of diphtheria toxin, in the periplasm of Escherichia coli, Biotechnol. J., 12, 1700168, https://doi.org/10.1002/biot.201700168.

    Article  CAS  Google Scholar 

  40. Roth, R., van Zyl, P., Tsekoa, T., Stoychev, S., Mamputha, S., Buthelezi, S., and Crampton, M. (2017) Co-expression of sulphydryl oxidase and protein disulphide isomerase in Escherichia coli allows for production of soluble CRM(197), J. Appl. Microbiol., 122, 1402-1411, https://doi.org/10.1111/jam.13441.

    Article  CAS  PubMed  Google Scholar 

  41. Mishra, R. P. N., Yadav, R. S. P., Jones, C., Nocadello, S., Minasov, G., Shuvalova, L. A., Anderson, W. F., and Goel, A. (2018) Structural and immunological characterization of E. coli derived recombinant CRM(197) protein used as carrier in conjugate vaccines, Biosci. Rep., 38, BSR20180238, https://doi.org/10.1042/bsr20180238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Park, A. R., Jang, S. W., Kim, J. S., Park, Y. G., Koo, B. S., and Lee, H. C. (2018) Efficient recovery of recombinant CRM197 expressed as inclusion bodies in E. coli, PLoS One, 13, e0201060, https://doi.org/10.1371/journal.pone.0201060.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fang, T., Tao, Z., Liu, Y., Yu, C., Zhi, R., and Yu, R. (2018) Expression, purification and characterization of diphtheria toxin mutant CRM197 in Eschrichia coli, Chinese J. Biotechnol., 34, 561-568, https://doi.org/10.13345/j.cjb.170333.

    Article  CAS  Google Scholar 

  44. Chai, P., Pu, X., Ge, J., Ren, S., Xia, X., Luo, A., Wang, S., Wang, X., and Li, J. (2021) The recombinant protein combined vaccine based on the fragment C of tetanus toxin and the cross-reacting material 197, Appl. Microbiol. Biotechnol., 105, 1683-1692, https://doi.org/10.1007/s00253-021-11139-8.

    Article  CAS  PubMed  Google Scholar 

  45. Khodak, Y. A., Ryazanova, A. Y., Vorobiev, I. I., Kovalchuk, A. L., Ovechko, N. N., and Aparin, P. G. (2023) High-level production of soluble cross-reacting material 197 in Escherichia coli cytoplasm due to fine tuning of the target gene’s mRNA structure, Biotech, 12, 9, https://doi.org/10.3390/biotech12010009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Retallack, D. M., Chew, L., and Jin, H. (2010) High Level Expression of Recombinant CRM197. Patent No. WO 2011/123139 A1.

  47. Dukhovlinov, I. V., Bogomolova, E. G., Dobrovolskaya, O. V., Ishuk, C. A., Fedorova, E. A., Klimov, N. A., and Simbirtsev, A. S. (2018) Investigation of production of a non-toxic diphteria toxin variant CRM197 in Escherichia coli cells [in Russian], Med. Acad.J., 18, 64-70.

    Article  Google Scholar 

  48. Dukhovlinov, I. V., Fedorova, E. A., Bogomolova, E. G., Dobrovolskaya, O. V., Chernyaeva, E. N., Al-Shekhadat, R. I., and Simbirtsev, A. S. (2015) Production of recombinant protein CRM197 in Escherichia coli [in Russian], Russ. J. Infect. Immun., 5, 37-44, https://doi.org/10.15789/2220-7619-2015-1-37-44.

    Article  Google Scholar 

  49. Baglioni, P., Hochkoeppler, A., and Stefan, A. (2010) Bacterial Expression of an Artificial Gene for the Production of CRM197 and Its Derivatives. Patent No. WO 2010/150230 A1.

  50. Lee, H. C., Koo, B. S., Seo, H. J., Kim, J. S., Park, A. R., and Jang, S. W. (2019) Method for Efficiently Recovering and Purifying Active CRM197 from Insoluble CRM197 Protein Expressed in Inclusion Body. Patent No. WO 2019/151601 A1.

  51. Akshay, G., Ravi, P. N. M., Narender, D. M., and Mahima, D. (2016) Codon Optimized Polynucleotide for High Level Expression of CRM197. Patent No. WO 2016/079755 A1.

  52. Moxiao, L., Xue, Z., Donghai, W., Yingxia, S., Junxian, G., Jingyi, W., and Qingmin, W. (2010) Diphtheria Toxin Muton CRM197 and Its Preparation Process. Patent No. CN 100999548 A.

  53. Jingyi, W., Lixia, S., Tongwen, X., Ting, D., Xue, Z., and Kebo, W. (2012) Method for Purifying CRM197 Mutant. Patent No. CN 101265288 B.

  54. Lin, F., Xiao, J., and Wei, W. (2013) Preparation Method of Diphtheria Toxin Mutant CRM197. Patent No. CN 103266125 A.

  55. Mao, H. (2018) The Preparation Method of Diphtheria Toxin Muton CRM 197 Patent No. CN 104140972 B.

  56. Akshay, G., Tushar, J., Khrishnanad, T., Yogesh, M., Narender, D. M., and Mahima, D. (2017) Industrially Scalableprocess for Recovering Biologically Active Recombinant Carrier Proteins. Patent No. WO 2017/081700 A1.

  57. Blattner, C. R., Frisch, D. A., Novy, R. E., Henker, T. M., Steffen, E. A., Blattner, F. R., Choi, H., Posfai, G., and Landry, C. F. (2015) Enhanced Production of Recombinant CRM197 in E. coli. Patent No. WO 2015/134402 A1.

  58. Blais, N., Dehottay, P. M. H., Dewerchin, M., Goffin, P., and Martin, D. (2011) Expression System. Patent No. WO 2011/042516 A2.

  59. Ihssen, J., Kowarik, M., and Thony-Meyer, L.C. (2014) Methods and Compositions Relating to CRM197. Patent No. WO 2014/102265 A1.

  60. Hsu, Y., Sheu, S., Lei, B., and Wu, T. (2015) Development of the Soluble Recombinant CRM197 Production by E. coli. Patent No. US 2015/0184215 A1.

  61. Masson, L., Arbour, M., and Gauriat, M. (2019) Systems and Methods for the Production of Diphtheria Toxin Polypeptides. Patent No. WO 2019/035058 A1.

  62. Boock, J. T., Waraho-Zhmayev, D., Mizrachi, D., and DeLisa, M. P. (2015) Beyond the cytoplasm of Escherichia coli: localizing recombinant proteins where you want them, Methods Mol. Biol., 1258, 79-97, https://doi.org/10.1007/978-1-4939-2205-5_5.

    Article  CAS  PubMed  Google Scholar 

  63. Graham, L. L., Beveridge, T. J., and Nanninga, N. (1991) Periplasmic space and the concept of the periplasm, Trends Biochem. Sci., 16, 328-329, https://doi.org/10.1016/0968-0004(91)90135-i.

    Article  CAS  PubMed  Google Scholar 

  64. Oganesyan, N., and Lees, A. (2015) Expression and Purification of CRM197 and Related Proteins. Patent No. WO 2015/117093 A1.

  65. Goretzki, K., and Habermann, E. (1985) Enzymatic hydrolysis of tetanus toxin by intrinsic and extrinsic proteases. Characterization of the fragments by monoclonal antibodies, Med. Microbiol. Immunol., 174, 139-150, https://doi.org/10.1007/bf02298124.

    Article  CAS  PubMed  Google Scholar 

  66. Bagetta, G., and Nisticò, G. (1994) Tetanus toxin as a neurobiological tool to study mechanisms of neuronal cell death in the mammalian brain, Pharmacol. Ther., 62, 29-39, https://doi.org/10.1016/0163-7258(94)90003-5.

    Article  CAS  PubMed  Google Scholar 

  67. Cohen, J. E., Wang, R., Shen, R. F., Wu, W. W., and Keller, J. E. (2017) Comparative pathogenomics of Clostridium tetani, PLoS One, 12, e0182909, https://doi.org/10.1371/journal.pone.0182909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Roper, M. H., Wassilak, S. G. F., Tiwari, T. S. P., and Orenstein, W. A. (2017) Tetanus Toxoid, 7th Edn., Elsevier, Philadelphia, PA, USA.

  69. Bayart, C., Peronin, S., Jean, E., Paladino, J., Talaga, P., and Borgne, M. L. (2017) The combined use of analytical tools for exploring tetanus toxin and tetanus toxoid structures, J. Chromatogr., 1054, 80-92, https://doi.org/10.1016/j.jchromb.2017.04.009.

    Article  CAS  Google Scholar 

  70. Kaumaya, P. T., Kobs-Conrad, S., Seo, Y. H., Lee, H., Vanbuskirk, A. M., Feng, N., Sheridan, J. F., and Stevens, V. (1993) Peptide vaccines incorporating a “promiscuous” T-cell epitope bypass certain haplotype restricted immune responses and provide broad spectrum immunogenicity, J. Mol. Recognit., 6, 81-94, https://doi.org/10.1002/jmr.300060206.

    Article  CAS  PubMed  Google Scholar 

  71. Franke, E. D., Corradin, G., and Hoffman, S. L. (1997) Induction of protective CTL responses against the Plasmodium yoelii circumsporozoite protein by immunization with peptides, J. Immunol., 159, 3424-3433, https://doi.org/10.4049/jimmunol.159.7.3424.

    Article  CAS  PubMed  Google Scholar 

  72. Wen, X., Wen, K., Cao, D., Li, G., Jones, R. W., Li, J., Szu, S., Hoshino, Y., and Yuan, L. (2014) Inclusion of a universal tetanus toxoid CD4+ T cell epitope P2 significantly enhanced the immunogenicity of recombinant rotavirus ΔVP8* subunit parenteral vaccines, Vaccine, 32, 4420-4427, https://doi.org/10.1016/j.vaccine.2014.06.060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Su, Q. D., Zou, Y. N., Yi, Y., Shen, L. P., Ye, X. Z., Zhang, Y., Wang, H., Ke, H., Song, J. D., Hu, K. P., Cheng, B. L., Qiu, F., Yu, P. C., Zhou, W. T., Zhao, R., Cao, L., Dong, G. F., Bi, S. L., Wu, G. Z., Gao, G. F., et al. (2021) Recombinant SARS-CoV-2 RBD with a built in T helper epitope induces strong neutralization antibody response, Vaccine, 39, 1241-1247, https://doi.org/10.1016/j.vaccine.2021.01.044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ashton, A. C., Li, Y., Doussau, F., Weller, U., Dougan, G., Poulain, B., and Dolly, J. O. (1995) Tetanus toxin inhibits neuroexocytosis even when its Zn2+-dependent protease activity is removed, J. Biol. Chem., 270, 31386-31390, https://doi.org/10.1074/jbc.270.52.31386.

    Article  CAS  PubMed  Google Scholar 

  75. Li, Y., Aoki, R., and Dolly, J. O. (1999) Expression and characterisation of the heavy chain of tetanus toxin: reconstitution of the fully-recombinant dichain protein in active form, J. Biochem., 125, 1200-1208, https://doi.org/10.1093/oxfordjournals.jbchem.a022404.

    Article  CAS  PubMed  Google Scholar 

  76. Li, Y., Foran, P., Lawrence, G., Mohammed, N., Chan-Kwo-Chion, C. K., Lisk, G., Aoki, R., and Dolly, O. (2001) Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways, J. Biol. Chem., 276, 31394-31401, https://doi.org/10.1074/jbc.M103517200.

    Article  CAS  PubMed  Google Scholar 

  77. Blum, F. C., Przedpelski, A., Tepp, W. H., Johnson, E. A., and Barbieri, J. T. (2014) Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells, Infect. Immun., 82, 873-881, https://doi.org/10.1128/iai.01539-13.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Przedpelski, A., Tepp, W. H., Pellett, S., Johnson, E. A., and Barbieri, J. T. (2020) A novel high-potency tetanus vaccine, mBio, 11, https://doi.org/10.1128/mBio.01668-20.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Chang, M. J., Ollivault-Shiflett, M., Schuman, R., Ngoc Nguyen, S., Kaltashov, I. A., Bobst, C., Rajagopal, S. P., Przedpelski, A., Barbieri, J. T., and Lees, A. (2022) Genetically detoxified tetanus toxin as a vaccine and conjugate carrier protein, Vaccine, 40, 5103-5113, https://doi.org/10.1016/j.vaccine.2022.07.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chang, M., Oganesyan, N., and Lees, A. (2021) Production of Soluble Recombinant Protein. Patent No. WO 2021/188379 A2.

  81. Janson, H., Hedén, L. O., Grubb, A., Ruan, M. R., and Forsgren, A. (1991) Protein D, an immunoglobulin D-binding protein of Haemophilus influenzae: cloning, nucleotide sequence, and expression in Escherichia coli, Infect. Immun., 59, 119-125, https://doi.org/10.1128/iai.59.1.119-125.1991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Munson, R. S., Jr., and Sasaki, K. (1993) Protein D, a putative immunoglobulin D-binding protein produced by Haemophilus influenzae, is glycerophosphodiester phosphodiesterase, J. Bacteriol., 175, 4569-4571, https://doi.org/10.1128/jb.175.14.4569-4571.1993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Janson, H., Hedén, L. O., and Forsgren, A. (1992) Protein D, the immunoglobulin D-binding protein of Haemophilus influenzae, is a lipoprotein, Infect. Immun., 60, 1336-1342, https://doi.org/10.1128/iai.60.4.1336-1342.1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Akkoyunlu, M., Janson, H., Ruan, M., and Forsgren, A. (1996) Biological activity of serum antibodies to a nonacylated form of lipoprotein D of Haemophilus influenzae, Infect. Immun., 64, 4586-4592, https://doi.org/10.1128/iai.64.11.4586-4592.1996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Behrouzi, A., Bouzari, S., Siadat, S. D., Jafari, A., and Irani, S. (2015) Molecular cloning, expression and purification of truncated hpd fragment of Haemophilus influenzae in Escherichia coli, Jundishapur J. Microbiol., 8, e23218, https://doi.org/10.5812/jjm.23218.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Akkoyunlu, M., Melhus, A., Capiau, C., van Opstal, O., and Forsgren, A. (1997) The acylated form of protein D of Haemophilus influenzae is more immunogenic than the nonacylated form and elicits an adjuvant effect when it is used as a carrier conjugated to polyribosyl ribitol phosphate, Infect. Immun., 65, 5010-5016, https://doi.org/10.1128/iai.65.12.5010-5016.1997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Croxtall, J. D., and Keating, G. M. (2009) Pneumococcal polysaccharide protein D-conjugate vaccine (Synflorix; PHiD-CV), Paediatric Drugs, 11, 349-357, https://doi.org/10.2165/11202760-000000000-00000.

    Article  PubMed  Google Scholar 

  88. Novotny, L. A., Jurcisek, J. A., Godfroid, F., Poolman, J. T., Denoël, P. A., and Bakaletz, L. O. (2006) Passive immunization with human anti-protein D antibodies induced by polysaccharide protein D conjugates protects chinchillas against otitis media after intranasal challenge with Haemophilus influenzae, Vaccine, 24, 4804-4811, https://doi.org/10.1016/j.vaccine.2006.03.021.

    Article  CAS  PubMed  Google Scholar 

  89. Nurkka, A., Joensuu, J., Henckaerts, I., Peeters, P., Poolman, J., Kilpi, T., and Käyhty, H. (2004) Immunogenicity and safety of the eleven valent pneumococcal polysaccharide-protein D conjugate vaccine in infants, Pediatric Infect. Dis. J., 23, 1008-1014, https://doi.org/10.1097/01.inf.0000143640.03214.18.

    Article  Google Scholar 

  90. Prymula, R., Peeters, P., Chrobok, V., Kriz, P., Novakova, E., Kaliskova, E., Kohl, I., Lommel, P., Poolman, J., Prieels, J. P., and Schuerman, L. (2006) Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study, Lancet, 367, 740-748, https://doi.org/10.1016/s0140-6736(06)68304-9.

    Article  CAS  PubMed  Google Scholar 

  91. Einhorn, M. S., Weinberg, G. A., Anderson, E. L., Granoff, P. D., and Granoff, D. M. (1986) Immunogenicity in infants of Haemophilus influenzae type B polysaccharide in a conjugate vaccine with Neisseria meningitidis outer-membrane protein, Lancet, 2, 299-302, https://doi.org/10.1016/s0140-6736(86)90001-2.

    Article  CAS  PubMed  Google Scholar 

  92. Granoff, D. M., Anderson, E. L., Osterholm, M. T., Holmes, S. J., McHugh, J. E., Belshe, R. B., Medley, F., and Murphy, T. V. (1992) Differences in the immunogenicity of three Haemophilus influenzae type B conjugate vaccines in infants, J. Pediatrics, 121, 187-194, https://doi.org/10.1016/s0022-3476(05)81186-2.

    Article  CAS  Google Scholar 

  93. Liu, M. A., Friedman, A., Oliff, A. I., Tai, J., Martinez, D., Deck, R. R., Shieh, J. T., Jenkins, T. D., Donnelly, J. J., and Hawe, L. A. (1992) A vaccine carrier derived from Neisseria meningitidis with mitogenic activity for lymphocytes, Proc. Natl. Acad. Sci. USA, 89, 4633-4637, https://doi.org/10.1073/pnas.89.10.4633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Qi, H. L., Tai, J. Y., and Blake, M. S. (1994) Expression of large amounts of neisserial porin proteins in Escherichia coli and refolding of the proteins into native trimers, Infect. Immun., 62, 2432-2439, https://doi.org/10.1128/iai.62.6.2432-2439.1994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fusco, P. C., Michon, F., Laude-Sharp, M., Minetti, C. A., Huang, C. H., Heron, I., and Blake, M. S. (1998) Preclinical studies on a recombinant group B meningococcal porin as a carrier for a novel Haemophilus influenzae type b conjugate vaccine, Vaccine, 16, 1842-1849, https://doi.org/10.1016/s0264-410x(98)00174-1.

    Article  CAS  PubMed  Google Scholar 

  96. Fusco, P. C., Michon, F., Tai, J. Y., and Blake, M. S. (1997) Preclinical evaluation of a novel group B meningococcal conjugate vaccine that elicits bactericidal activity in both mice and nonhuman primates, J. Infect. Dis., 175, 364-372, https://doi.org/10.1093/infdis/175.2.364.

    Article  CAS  PubMed  Google Scholar 

  97. Xia, M., Wei, C., Wang, L., Cao, D., Meng, X. J., Jiang, X., and Tan, M. (2016) Development and evaluation of two subunit vaccine candidates containing antigens of hepatitis E virus, rotavirus, and astrovirus, Sci. Rep., 6, 25735, https://doi.org/10.1038/srep25735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ferrari, G., Garaguso, I., Adu-Bobie, J., Doro, F., Taddei, A. R., Biolchi, A., Brunelli, B., Giuliani, M. M., Pizza, M., Norais, N., and Grandi, G. (2006) Outer membrane vesicles from group B Neisseria meningitidis delta gna33 mutant: proteomic and immunological comparison with detergent-derived outer membrane vesicles, Proteomics, 6, 1856-1866, https://doi.org/10.1002/pmic.200500164.

    Article  CAS  PubMed  Google Scholar 

  99. Gerke, C., Colucci, A. M., Giannelli, C., Sanzone, S., Vitali, C. G., Sollai, L., Rossi, O., Martin, L. B., Auerbach, J., Di Cioccio, V., and Saul, A. (2015) Production of a Shigella sonnei vaccine based on generalized modules for membrane antigens (GMMA), 1790GAHB, PLoS One, 10, e0134478, https://doi.org/10.1371/journal.pone.0134478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rossi, O., Pesce, I., Giannelli, C., Aprea, S., Caboni, M., Citiulo, F., Valentini, S., Ferlenghi, I., MacLennan, C. A., D’Oro, U., Saul, A., and Gerke, C. (2014) Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants, J. Biol. Chem., 289, 24922-24935, https://doi.org/10.1074/jbc.M114.566570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Berlanda Scorza, F., Doro, F., Rodríguez-Ortega, M. J., Stella, M., Liberatori, S., Taddei, A. R., Serino, L., Gomes Moriel, D., Nesta, B., Fontana, M. R., Spagnuolo, A., Pizza, M., Norais, N., and Grandi, G. (2008) Proteomics characterization of outer membrane vesicles from the extraintestinal pathogenic Escherichia coli DeltatolR IHE3034 mutant, Mol. Cell. Proteomics, 7, 473-485, https://doi.org/10.1074/mcp.M700295-MCP200.

    Article  CAS  PubMed  Google Scholar 

  102. Van de Waterbeemd, B., Streefland, M., van der Ley, P., Zomer, B., van Dijken, H., Martens, D., Wijffels, R., and van der Pol, L. (2010) Improved OMV vaccine against Neisseria meningitidis using genetically engineered strains and a detergent-free purification process, Vaccine, 28, 4810-4816, https://doi.org/10.1016/j.vaccine.2010.04.082.

    Article  CAS  PubMed  Google Scholar 

  103. Keiser, P. B., Biggs-Cicatelli, S., Moran, E. E., Schmiel, D. H., Pinto, V. B., Burden, R. E., Miller, L. B., Moon, J. E., Bowden, R. A., Cummings, J. F., and Zollinger, W. D. (2011) A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression, Vaccine, 29, 1413-1420, https://doi.org/10.1016/j.vaccine.2010.12.039.

    Article  CAS  PubMed  Google Scholar 

  104. Berlanda Scorza, F., Colucci, A. M., Maggiore, L., Sanzone, S., Rossi, O., Ferlenghi, I., Pesce, I., Caboni, M., Norais, N., Di Cioccio, V., Saul, A., and Gerke, C. (2012) High yield production process for Shigella outer membrane particles, PLoS One, 7, e35616, https://doi.org/10.1371/journal.pone.0035616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Koeberling, O., Ispasanie, E., Hauser, J., Rossi, O., Pluschke, G., Caugant, D. A., Saul, A., and MacLennan, C. A. (2014) A broadly-protective vaccine against meningococcal disease in sub-Saharan Africa based on generalized modules for membrane antigens (GMMA), Vaccine, 32, 2688-2695, https://doi.org/10.1016/j.vaccine.2014.03.068.

    Article  CAS  PubMed  Google Scholar 

  106. Rossi, O., Caboni, M., Negrea, A., Necchi, F., Alfini, R., Micoli, F., Saul, A., MacLennan, C. A., Rondini, S., and Gerke, C. (2016) Toll-like receptor activation by generalized modules for membrane antigens from lipid a mutants of Salmonella enterica serovars Typhimurium and Enteritidis, Clin. Vaccine Immunol., 23, 304-314, https://doi.org/10.1128/cvi.00023-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Rosenthal, J. A., Huang, C. J., Doody, A. M., Leung, T., Mineta, K., Feng, D. D., Wayne, E. C., Nishimura, N., Leifer, C., DeLisa, M. P., Mendez, S., and Putnam, D. (2014) Mechanistic insight into the TH1-biased immune response to recombinant subunit vaccines delivered by probiotic bacteria-derived outer membrane vesicles, PLoS One, 9, e112802, https://doi.org/10.1371/journal.pone.0112802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rappazzo, C. G., Watkins, H. C., Guarino, C. M., Chau, A., Lopez, J. L., DeLisa, M. P., Leifer, C. A., Whittaker, G. R., and Putnam, D. (2016) Recombinant M2e outer membrane vesicle vaccines protect against lethal influenza A challenge in BALB/c mice, Vaccine, 34, 1252-1258, https://doi.org/10.1016/j.vaccine.2016.01.028.

    Article  CAS  PubMed  Google Scholar 

  109. Gujrati, V., Kim, S., Kim, S. H., Min, J. J., Choy, H. E., Kim, S. C., and Jon, S. (2014) Bioengineered bacterial outer membrane vesicles as cell-specific drug-delivery vehicles for cancer therapy, ACS Nano, 8, 1525-1537, https://doi.org/10.1021/nn405724x.

    Article  CAS  PubMed  Google Scholar 

  110. Daleke-Schermerhorn, M. H., Felix, T., Soprova, Z., Ten Hagen-Jongman, C. M., Vikström, D., Majlessi, L., Beskers, J., Follmann, F., de Punder, K., van der Wel, N. N., Baumgarten, T., Pham, T. V., Piersma, S. R., Jiménez, C. R., van Ulsen, P., de Gier, J. W., Leclerc, C., Jong, W. S., and Luirink, J. (2014) Decoration of outer membrane vesicles with multiple antigens by using an autotransporter approach, Appl. Environ. Microbiol., 80, 5854-5865, https://doi.org/10.1128/aem.01941-14.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Gnopo, Y. M. D., Watkins, H. C., Stevenson, T. C., DeLisa, M. P., and Putnam, D. (2017) Designer outer membrane vesicles as immunomodulatory systems – reprogramming bacteria for vaccine delivery, Adv. Drug Deliv. Rev., 114, 132-142, https://doi.org/10.1016/j.addr.2017.05.003.

    Article  CAS  PubMed  Google Scholar 

  112. Micoli, F., Alfini, R., Di Benedetto, R., Necchi, F., Schiavo, F., Mancini, F., Carducci, M., Palmieri, E., Balocchi, C., Gasperini, G., Brunelli, B., Costantino, P., Adamo, R., Piccioli, D., and Saul, A. (2020) GMMA is a versatile platform to design effective multivalent combination vaccines, Vaccines, 8, 540, https://doi.org/10.3390/vaccines8030540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jiang, L., Driedonks, T. A. P., Jong, W. S. P., Dhakal, S., Bart van den Berg van Saparoea, H., Sitaras, I., Zhou, R., Caputo, C., Littlefield, K., Lowman, M., Chen, M., Lima, G., Gololobova, O., Smith, B., Mahairaki, V., Riley Richardson, M., Mulka, K. R., Lane, A. P., Klein, S. L., Pekosz, A., et al. (2022) A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants, J. Extracell. Vesicles, 11, e12192, https://doi.org/10.1002/jev2.12192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Scaria, P. V., Rowe, C. G., Chen, B. B., Muratova, O. V., Fischer, E. R., Barnafo, E. K., Anderson, C. F., Zaidi, I. U., Lambert, L. E., Lucas, B. J., Nahas, D. D., Narum, D. L., and Duffy, P. E. (2019) Outer membrane protein complex as a carrier for malaria transmission blocking antigen Pfs230, NPJ Vaccines, 4, 24, https://doi.org/10.1038/s41541-019-0121-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Palmieri, E., Kis, Z., Ozanne, J., Di Benedetto, R., Ricchetti, B., Massai, L., Carducci, M., Oldrini, D., Gasperini, G., Aruta, M. G., Rossi, O., Kontoravdi, C., Shah, N., Mawas, F., and Micoli, F. (2022) GMMA as an alternative carrier for a glycoconjugate vaccine against group A streptococcus, Vaccines, 10, 1034, https://doi.org/10.3390/vaccines10071034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Micoli, F., Alfini, R., Di Benedetto, R., Necchi, F., Schiavo, F., Mancini, F., Carducci, M., Oldrini, D., Pitirollo, O., Gasperini, G., Balocchi, C., Bechi, N., Brunelli, B., Piccioli, D., and Adamo, R. (2021) Generalized modules for membrane antigens as carrier for polysaccharides: impact of sugar length, density, and attachment site on the immune response elicited in animal models, Front. Immunol., 12, 719315, https://doi.org/10.3389/fimmu.2021.719315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pavliakova, D., Moncrief, J. S., Lyerly, D. M., Schiffman, G., Bryla, D. A., Robbins, J. B., and Schneerson, R. (2000) Clostridium difficile recombinant toxin A repeating units as a carrier protein for conjugate vaccines: studies of pneumococcal type 14, Escherichia coli K1, and Shigella flexneri type 2a polysaccharides in mice, Infect. Immun., 68, 2161-2166, https://doi.org/10.1128/iai.68.4.2161-2166.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lukac, M., Pier, G. B., and Collier, R. J. (1988) Toxoid of Pseudomonas aeruginosa exotoxin A generated by deletion of an active-site residue, Infect. Immun., 56, 3095-3098, https://doi.org/10.1128/iai.56.12.3095-3098.1988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lukac, M., and Collier, R. J. (1988) Restoration of enzymic activity and cytotoxicity of mutant, E553C, Pseudomonas aeruginosa exotoxin A by reaction with iodoacetic acid, J. Biol. Chem., 263, 6146-6149, https://doi.org/10.1016/S0021-9258(18)68762-9.

    Article  CAS  PubMed  Google Scholar 

  120. Burkhardt, M., Reiter, K., Nguyen, V., Suzuki, M., Herrera, R., Duffy, P. E., Shimp, R., Jr., MacDonald, N. J., Olano, L. R., and Narum, D. L. (2019) Assessment of the impact of manufacturing changes on the physicochemical properties of the recombinant vaccine carrier ExoProtein A, Vaccine, 37, 5762-5769, https://doi.org/10.1016/j.vaccine.2018.09.037.

    Article  CAS  PubMed  Google Scholar 

  121. Margarit, I., Rinaudo, C. D., Galeotti, C. L., Maione, D., Ghezzo, C., Buttazzoni, E., Rosini, R., Runci, Y., Mora, M., Buccato, S., Pagani, M., Tresoldi, E., Berardi, A., Creti, R., Baker, C. J., Telford, J. L., and Grandi, G. (2009) Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm, J. Infect. Dis., 199, 108-115, https://doi.org/10.1086/595564.

    Article  PubMed  Google Scholar 

  122. Park, W. J., Yoon, Y. K., Park, J. S., Pansuriya, R., Seok, Y. J., and Ganapathy, R. (2021) Rotavirus spike protein ΔVP8* as a novel carrier protein for conjugate vaccine platform with demonstrated antigenic potential for use as bivalent vaccine, Sci. Rep., 11, 22037, https://doi.org/10.1038/s41598-021-01549-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Carvalho, R. J., Cabrera-Crespo, J., Tanizaki, M. M., and Gonçalves, V. M. (2012) Development of production and purification processes of recombinant fragment of pneumococcal surface protein A in Escherichia coli using different carbon sources and chromatography sequences, Appl. Microbiol. Biotechnol., 94, 683-694, https://doi.org/10.1007/s00253-011-3649-9.

    Article  CAS  PubMed  Google Scholar 

  124. Khan, M. N., and Pichichero, M. E. (2012) Vaccine candidates PhtD and PhtE of Streptococcus pneumoniae are adhesins that elicit functional antibodies in humans, Vaccine, 30, 2900-2907, https://doi.org/10.1016/j.vaccine.2012.02.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Feng, S., Xiong, C., Wang, G., Wang, S., Jin, G., and Gu, G. (2020) Exploration of recombinant fusion proteins YAPO and YAPL as carrier proteins for glycoconjugate vaccine design against Streptococcus pneumoniae infection, ACS Infect. Dis., 6, 2181-2191, https://doi.org/10.1021/acsinfecdis.0c00260.

    Article  CAS  PubMed  Google Scholar 

  126. Kapoor, N., Uchiyama, S., Pill, L., Bautista, L., Sedra, A., Yin, L., Regan, M., Chu, E., Rabara, T., Wong, M., Davey, P., Fairman, J., and Nizet, V. (2022) Non-native amino acid click chemistry-based technology for site-specific polysaccharide conjugation to a bacterial protein serving as both carrier and vaccine antigen, ACS Omega, 7, 24111-24120, https://doi.org/10.1021/acsomega.1c07360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Qian, W., Huang, Z., Chen, Y., Yang, J., Wang, L., Wu, K., Chen, M., Chen, N., Duan, Y., Shi, J., Zhang, Y., and Li, Q. (2020) Elicitation of integrated immunity in mice by a novel pneumococcal polysaccharide vaccine conjugated with HBV surface antigen, Sci. Rep., 10, 6470, https://doi.org/10.1038/s41598-020-62185-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Tsai, C. W., Duggan, P. F., Shimp, R. L., Jr., Miller, L. H., and Narum, D. L. (2006) Overproduction of Pichia pastoris or Plasmodium falciparum protein disulfide isomerase affects expression, folding and O-linked glycosylation of a malaria vaccine candidate expressed in P. pastoris, J. Biotechnol., 121, 458-470, https://doi.org/10.1016/j.jbiotec.2005.08.025.

    Article  CAS  PubMed  Google Scholar 

  129. Prasanna, M., Podsiadla-Bialoskorska, M., Mielecki, D., Ruffier, N., Fateh, A., Lambert, A., Fanuel, M., Camberlein, E., Szolajska, E., and Grandjean, C. (2021) On the use of adenovirus dodecahedron as a carrier for glycoconjugate vaccines, Glycoconjugate J., 38, 437-446, https://doi.org/10.1007/s10719-021-09999-3.

    Article  CAS  Google Scholar 

  130. Astronomo, R. D., Kaltgrad, E., Udit, A. K., Wang, S. K., Doores, K. J., Huang, C. Y., Pantophlet, R., Paulson, J. C., Wong, C. H., Finn, M. G., and Burton, D. R. (2010) Defining criteria for oligomannose immunogens for HIV using icosahedral virus capsid scaffolds, Chem. Biol., 17, 357-370, https://doi.org/10.1016/j.chembiol.2010.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sungsuwan, S., Wu, X., and Huang, X. (2017) Evaluation of virus-like particle-based tumor-associated carbohydrate immunogen in a mouse tumor model, Methods Enzymol., 597, 359-376, https://doi.org/10.1016/bs.mie.2017.06.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yin, Z., and Huang, X. (2012) Recent development in carbohydrate based anti-cancer vaccines, J. Carbohydr. Chem., 31, 143-186, https://doi.org/10.1080/07328303.2012.659364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Li, M., Cripe, T. P., Estes, P. A., Lyon, M. K., Rose, R. C., and Garcea, R. L. (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, 2988-2995, https://doi.org/10.1128/jvi.71.4.2988-2995.1997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Edman, J. C., Hallewell, R. A., Valenzuela, P., Goodman, H. M., and Rutter, W. J. (1981) Synthesis of hepatitis B surface and core antigens in E. coli, Nature, 291, 503-506, https://doi.org/10.1038/291503a0.

    Article  CAS  PubMed  Google Scholar 

  135. Chen, X., Zhou, W., He, Q., Su, B., Zou, Y. (2021) Preparation, purification and identification of bacteriophage Qβ virus-like particles, China Biotechnol., 41, 42-49, https://doi.org/10.13523/j.cb.2103034.

    Article  CAS  Google Scholar 

  136. Kirnbauer, R., Booy, F., Cheng, N., Lowy, D. R., and Schiller, J. T. (1992) Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic, Proc. Natl. Acad. Sci. USA, 89, 12180-12184, https://doi.org/10.1073/pnas.89.24.12180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Harding, C. M., and Feldman, M. F. (2019) Glycoengineering bioconjugate vaccines, therapeutics, and diagnostics in E. coli, Glycobiology, 29, 519-529, https://doi.org/10.1093/glycob/cwz031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Riddle, M. S., Kaminski, R. W., Di Paolo, C., Porter, C. K., Gutierrez, R. L., Clarkson, K. A., Weerts, H. E., Duplessis, C., Castellano, A., Alaimo, C., Paolino, K., Gormley, R., and Gambillara Fonck, V. (2016) Safety and immunogenicity of a candidate bioconjugate vaccine against Shigella flexneri 2a administered to healthy adults: a single-blind, randomized phase I study, Clin. Vaccine Immunol., 23, 908-917, https://doi.org/10.1128/cvi.00224-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Huttner, A., Hatz, C., van den Dobbelsteen, G., Abbanat, D., Hornacek, A., Frölich, R., Dreyer, A. M., Martin, P., Davies, T., Fae, K., van den Nieuwenhof, I., Thoelen, S., de Vallière, S., Kuhn, A., Bernasconi, E., Viereck, V., Kavvadias, T., Kling, K., Ryu, G., Hülder, T., et al. (2017) Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial, Lancet, 17, 528-537, https://doi.org/10.1016/s1473-3099(17)30108-1.

    Article  CAS  Google Scholar 

  140. Kaaijk, P., van Straaten, I., van de Waterbeemd, B., Boot, E. P., Levels, L. M., van Dijken, H. H., and van den Dobbelsteen, G. P. (2013) Preclinical safety and immunogenicity evaluation of a nonavalent PorA native outer membrane vesicle vaccine against serogroup B meningococcal disease, Vaccine, 31, 1065-1071, https://doi.org/10.1016/j.vaccine.2012.12.031.

    Article  CAS  PubMed  Google Scholar 

  141. Koroleva, I. S., and Koroleva, M. A. (2021) World experience in the use serogroup B meningococcal vaccines [in Russian], Epidemiol. Vacc. Prevent., 20, 100-107, https://doi.org/10.31631/2073-3046-2021-20-6-100-107.

    Article  Google Scholar 

  142. Pizza, M., Bekkat-Berkani, R., and Rappuoli, R. (2020) Vaccines against meningococcal diseases, Microorganisms, 8, 1521, https://doi.org/10.3390/microorganisms8101521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The author expresses gratitude to I. I. Vorobiev and A. Y. Ryazanova.

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  1. Institute of Bioengineering, Federal Research Centre of Biotechnology, Russian Academy of Sciences, 117312, Moscow, Russia

    Yuliya A. Khodak

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  1. Yuliya A. Khodak
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Correspondence to Yuliya A. Khodak.

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The author declares no conflict of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by the author.

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Khodak, Y.A. Heterologous Expression of Recombinant Proteins and Their Derivatives Used as Carriers for Conjugate Vaccines. Biochemistry Moscow 88, 1248–1266 (2023). https://doi.org/10.1134/S0006297923090055

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  • DOI: https://doi.org/10.1134/S0006297923090055

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