Inter-epitope spacer variation within polytopic L2-based human papillomavirus antigens affects immunogenicity.
Journal
NPJ vaccines
ISSN: 2059-0105
Titre abrégé: NPJ Vaccines
Pays: England
ID NLM: 101699863
Informations de publication
Date de publication:
24 Feb 2024
24 Feb 2024
Historique:
received:
25
07
2023
accepted:
05
02
2024
medline:
25
2
2024
pubmed:
25
2
2024
entrez:
24
2
2024
Statut:
epublish
Résumé
The human papillomavirus minor capsid protein L2 is being extensively explored in pre-clinical studies as an attractive vaccine antigen capable of inducing broad-spectrum prophylactic antibody responses. Recently, we have developed two HPV vaccine antigens - PANHPVAX and CUT-PANHPVAX- both based on heptameric nanoparticle antigens displaying polytopes of the L2 major cross-neutralizing epitopes of eight mucosal and twelve cutaneous HPV types, respectively. Prompted by the variable neutralizing antibody responses against some of the HPV types targeted by the antigens observed in previous studies, here we investigated the influence on immunogenicity of six distinct glycine-proline spacers inserted upstream to a specific L2 epitope. We show that spacer variants differentially influence antigen immunogenicity in a mouse model, with the antigen constructs M8merV6 and C12merV6 displaying a superior ability in the induction of neutralizing antibodies as determined by pseudovirus-based neutralization assays (PBNAs). L2-peptide enzyme-linked immunosorbent assay (ELISA) assessments determined the total anti-L2 antibody level for each antigen variant, showing for the majority of sera a correlation with their repective neutralizing antibody level. Surface Plasmon Resonance revealed that L2 epitope-specific, neutralizing monoclonal antibodies (mAbs) display distinct avidities to different antigen spacer variants. Furthermore, mAb affinity toward individual spacer variants was well correlated with their neutralizing antibody induction capacity, indicating that the mAb affinity assay predicts L2-based antigen immunogenicity. These observations provide insights on the development and optimization of L2-based HPV vaccines.
Identifiants
pubmed: 38402256
doi: 10.1038/s41541-024-00832-0
pii: 10.1038/s41541-024-00832-0
doi:
Types de publication
Journal Article
Langues
eng
Pagination
44Subventions
Organisme : CSC | Chinese Government Scholarship
ID : 202008080014
Informations de copyright
© 2024. The Author(s).
Références
Hebner, C. M. & Laimins, L. A. Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity. Rev. Med. Virol. 16, 83–97 (2006).
doi: 10.1002/rmv.488
pubmed: 16287204
Dürst, M., Gissmann, L., Ikenberg, H. & zur Hausen, H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc. Natl Acad. Sci. USA 80, 3812–3815 (1983).
doi: 10.1073/pnas.80.12.3812
pubmed: 6304740
pmcid: 394142
Boshart, M. et al. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. Embo j. 3, 1151–1157 (1984).
doi: 10.1002/j.1460-2075.1984.tb01944.x
pubmed: 6329740
pmcid: 557488
Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol Rev. 16, 1–17 (2003).
doi: 10.1128/CMR.16.1.1-17.2003
pubmed: 12525422
pmcid: 145302
zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer 2, 342–350 (2002).
doi: 10.1038/nrc798
pubmed: 12044010
de Sanjose, S. et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 11, 1048–1056 (2010).
doi: 10.1016/S1470-2045(10)70230-8
pubmed: 20952254
Shimizu, A., Yamaguchi, R. & Kuriyama, Y. Recent advances in cutaneous HPV infection. J. Dermatol. https://doi.org/10.1111/1346-8138.16697 (2023).
Lehtinen, M. et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 13, 89–99 (2012).
doi: 10.1016/S1470-2045(11)70286-8
pubmed: 22075171
Haghshenas, M. R., Mousavi, T., Kheradmand, M., Afshari, M. & Moosazadeh, M. Efficacy of human papillomavirus L1 protein vaccines (cervarix and gardasil) in reducing the risk of cervical intraepithelial neoplasia: a meta-analysis. Int. J. Preventive Med. 8, 44 (2017).
doi: 10.4103/ijpvm.IJPVM_413_16
Mariz, F. C. et al. Sustainability of neutralising antibodies induced by bivalent or quadrivalent HPV vaccines and correlation with efficacy: a combined follow-up analysis of data from two randomised, double-blind, multicentre, phase 3 trials. Lancet Infect. Dis. 21, 1458–1468 (2021).
doi: 10.1016/S1473-3099(20)30873-2
pubmed: 34081923
Pouyanfard, S. et al. Minor capsid protein L2 polytope induces broad protection against oncogenic and mucosal human papillomaviruses. J. Virol. 92, https://doi.org/10.1128/JVI.01930-17 (2018).
Mariz, F. C. et al. A broadly protective vaccine against cutaneous human papillomaviruses. NPJ Vaccines 7, 116 (2022).
doi: 10.1038/s41541-022-00539-0
pubmed: 36216845
pmcid: 9550855
Seitz, H. et al. Robust in vitro and in vivo neutralization against multiple high-risk HPV types induced by a thermostable thioredoxin-L2 vaccine. Cancer Prev. Res (Philos.) 8, 932–941 (2015).
doi: 10.1158/1940-6207.CAPR-15-0164
Ogun, S. A., Dumon-Seignovert, L., Marchand, J. B., Holder, A. A. & Hill, F. The oligomerization domain of C4-binding protein (C4bp) acts as an adjuvant, and the fusion protein comprised of the 19-kilodalton merozoite surface protein 1 fused with the murine C4bp domain protects mice against malaria. Infect. Immun. 76, 3817–3823 (2008).
doi: 10.1128/IAI.01369-07
pubmed: 18474650
pmcid: 2493234
Spagnoli, G. et al. Broadly neutralizing antiviral responses induced by a single-molecule HPV vaccine based on thermostable thioredoxin-L2 multiepitope nanoparticles. Sci. Rep. 7, 18000 (2017).
doi: 10.1038/s41598-017-18177-1
pubmed: 29269879
pmcid: 5740060
Ahmels, M. et al. Next generation L2-based HPV vaccines cross-protect against cutaneous papillomavirus infection and tumor development. Front. Immunol. 13, 1010790 (2022).
doi: 10.3389/fimmu.2022.1010790
pubmed: 36263027
pmcid: 9574214
Chen, X., Zaro, J. L. & Shen, W. C. Fusion protein linkers: property, design and functionality. Adv. Drug Deliv. Rev. 65, 1357–1369 (2013).
doi: 10.1016/j.addr.2012.09.039
pubmed: 23026637
George, R. A. & Heringa, J. An analysis of protein domain linkers: their classification and role in protein folding. Protein Eng. 15, 871–879 (2002).
doi: 10.1093/protein/15.11.871
pubmed: 12538906
Argos, P. An investigation of oligopeptides linking domains in protein tertiary structures and possible candidates for general gene fusion. J. Mol. Biol. 211, 943–958 (1990).
doi: 10.1016/0022-2836(90)90085-Z
pubmed: 2313701
Aurora, R., Creamer, T. P., Srinivasan, R. & Rose, G. D. Local interactions in protein folding: lessons from the α-Helix. J. Biol. Chem. 272, 1413–1416 (1997).
doi: 10.1074/jbc.272.3.1413
pubmed: 9019474
Zhao, H. L. et al. Increasing the homogeneity, stability and activity of human serum albumin and interferon-alpha2b fusion protein by linker engineering. Protein Expr. Purif. 61, 73–77 (2008).
doi: 10.1016/j.pep.2008.04.013
pubmed: 18541441
Klein, J. S., Jiang, S., Galimidi, R. P., Keeffe, J. R. & Bjorkman, P. J. Design and characterization of structured protein linkers with differing flexibilities. Protein Eng. Des. Select.: PEDS 27, 325–330 (2014).
doi: 10.1093/protein/gzu043
Choi, H., Park, H., Son, K., Kim, H. M. & Jung, Y. Fabrication of rigidity and space variable protein oligomers with two peptide linkers. Chem. Sci. 10, 10428–10435 (2019).
doi: 10.1039/C9SC04158C
pubmed: 32110335
pmcid: 6988741
Reddy Chichili, V. P., Kumar, V. & Sivaraman, J. Linkers in the structural biology of protein–protein interactions. Protein Sci. 22, 153–167 (2013).
doi: 10.1002/pro.2206
pubmed: 23225024
Chen, H. et al. Effect of linker length and flexibility on the clostridium thermocellum esterase displayed on bacillus subtilis spores. Appl. Biochem. Biotechnol. 182, 168–180 (2017).
doi: 10.1007/s12010-016-2318-y
pubmed: 27933482
Bai, Y. et al. The influence of hapten spacer arm length on antibody response and immunoassay development. Anal. Chim. Acta 1239, 340699 (2023).
doi: 10.1016/j.aca.2022.340699
pubmed: 36628767
Rubio, I. et al. The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies. Virology 409, 348–359 (2011).
doi: 10.1016/j.virol.2010.10.017
pubmed: 21074234
Nguyen, H. H., Park, J., Kang, S. & Kim, M. Surface plasmon resonance: a versatile technique for biosensor applications. Sensors 15, 10481–10510 (2015).
doi: 10.3390/s150510481
pubmed: 25951336
pmcid: 4481982
Spohn, G. & Bachmann, M. F. Exploiting viral properties for the rational design of modern vaccines. Expert Rev. Vaccines 7, 43–54 (2008).
doi: 10.1586/14760584.7.1.43
pubmed: 18251693
Jennings, G. T. & Bachmann, M. F. The coming of age of virus-like particle vaccines. 389, 521–536, https://doi.org/10.1515/BC.2008.064 (2008).
Schellenbacher, C., Roden, R. B. S. & Kirnbauer, R. Developments in L2-based human papillomavirus (HPV) vaccines. Virus Res. 231, 166–175 (2017).
doi: 10.1016/j.virusres.2016.11.020
pubmed: 27889616
Gambhira, R. et al. A protective and broadly cross-neutralizing epitope of human papillomavirus L2. J. Virol. 81, 13927–13931 (2007).
doi: 10.1128/JVI.00936-07
pubmed: 17928339
pmcid: 2168823
Tyler, M., Tumban, E. & Chackerian, B. Second-generation prophylactic HPV vaccines: successes and challenges. Expert Rev. Vaccines 13, 247–255 (2014).
doi: 10.1586/14760584.2014.865523
pubmed: 24350614
Kines, R. C., Thompson, C. D., Lowy, D. R., Schiller, J. T. & Day, P. M. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc. Natl Acad. Sci. USA 106, 20458–20463 (2009).
doi: 10.1073/pnas.0908502106
pubmed: 19920181
pmcid: 2787115
Day, P. M. & Schiller, J. T. The role of furin in papillomavirus infection. Future Microbiol 4, 1255–1262 (2009).
doi: 10.2217/fmb.09.86
pubmed: 19995186
Bronnimann, M. P. et al. Furin cleavage of L2 during papillomavirus infection: minimal dependence on cyclophilins. J. Virol. 90, 6224–6234 (2016).
doi: 10.1128/JVI.00038-16
pubmed: 27122588
pmcid: 4936150
Zhang, W., Kazakov, T., Popa, A. & DiMaio, D. Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires γ-secretase activity. mBio 5, e01777 (2014).
doi: 10.1128/mBio.01777-14
pubmed: 25227470
pmcid: 4172078
Arviv, O. & Levy, Y. Folding of multidomain proteins: biophysical consequences of tethering even in apparently independent folding. Proteins 80, 2780–2798 (2012).
doi: 10.1002/prot.24161
pubmed: 22890725
Ceballos-Alcantarilla, E. & Merkx, M. in Methods in Enzymology. 647 (ed Maarten M.) 1–22 (Academic Press, 2021).
Bachmann, M. F. et al. The role of antibody concentration and avidity in antiviral protection. 276, 2024–2027, https://doi.org/10.1126/science.276.5321.2024 (1997).
Liu, S. et al. Removal of endotoxin from recombinant protein preparations. Clin. Biochem. 30, 455–463 (1997).
doi: 10.1016/S0009-9120(97)00049-0
pubmed: 9316739
Kommareddy, S., Singh, M. & O’Hagan, D. T. in Immunopotentiators in Modern Vaccines (Second Edition) (eds Virgil E. J. C. Schijns & Derek T. O’Hagan) 249–263 (Academic Press, 2017).
Seitz, H., Dantheny, T., Burkart, F., Ottonello, S. & Müller, M. Influence of oxidation and multimerization on the immunogenicity of a thioredoxin-l2 prophylactic papillomavirus vaccine. Clin. Vaccin. Immunol. 20, 1061–1069 (2013).
doi: 10.1128/CVI.00195-13
Ribeiro-Müller, L. & Müller, M. Prophylactic papillomavirus vaccines. Clin. Dermatol. 32, 235–247 (2014).
doi: 10.1016/j.clindermatol.2013.08.008
pubmed: 24559559