Abstract
Most commercialized virus-like particle (VLP) vaccines use aluminum salt as adjuvant, even though VLPs provoke adequate antibody responses without adjuvant. We do not have detailed knowledge of how adjuvant affects the profile of anti-VLP antibodies. Meanwhile, there is evidence that differences between vaccination protocols influence the glycosylation of antibodies, which may alter their effector functions. In the present study a murine model was used to investigate the effects of dosing schedule and adjuvant on the antibody profiles and glycosylation levels of antigen-specific antibody responses to human papillomavirus type 16 L1 (HPV16 L1) VLPs. Mice received subcutaneously 2,000 ng of antigen divided into 4 or 7 doses. The HPV16 L1 VLPs elicited > 4 log10 anti-HPV16 L1 IgG titers without adjuvant, and aluminum hydroxide as adjuvant increased IgG titers 1.3- to 4-fold and reduced the anti-HPV16 L1 IgG2a / anti-HPV16 L1 IgG1 ratio value (use of aluminum hydroxide reduced the ratio of the IgG2a). Immunization with HPV16 L1 VLPs in combination with Freund’s adjuvant enhanced IgG titers 5- to 12-fold. Seven-dose immunization markedly increased anti-HPV16 L1 IgM titers compared to four-dose immunization, as well as increasing the proportion of glycosylated antibodies. Our results suggest that antibody glycosylation can be controlled immunologically, and IgG and IgM profiles and glycosylation profiles of the vaccine-induced antibodies can be used as indicators reflecting the vaccine characteristics. These results indicate that the HPV16 L1 VLP dosing schedule can affect the quality of antigen-specific antibody responses. We suggest that dosing schedules should be noted in vaccination protocols for VLP-based vaccines.
Article PDF
Similar content being viewed by others
References
Chackerian, B., Rangel, M., Hunter, Z., and Peabody, D.S. 2006. Virus and virus-like particle-based immunogens for Alzheimer’s disease induce antibody responses against amyloid-beta without concomitant T cell responses. Vaccine 24, 6321–6331.
Cimica, V. and Galarza, J.M. 2017. Adjuvant formulations for viruslike particle (VLP) based vaccines. Clin. Immunol. 183, 99–108.
Clapp, T., Siebert, P., Chen, D.X., and Braun, L.J. 2011. Vaccines with aluminum-containing adjuvants: Optimizing vaccine efficacy and thermal stability. J. Pharm. Sci. 100, 388–401.
Firacative, C., Gressler, A.E., Schubert, K., Schulze, B., Muller, U., Brombacher, F., von Bergen, M., and Alber, G. 2018. Identification of T helper (Th)1- and Th2-associated antigens of Cryptococcus neoformans in a murine model of pulmonary infection. Sci. Rep. 8, 2681.
Fuenmayor, J., Godia, F., and Cervera, L. 2017. Production of virus-like particles for vaccines. N Biotechnol. 39, 174–180.
Gao, Y., Wijewardhana, C., and Mann, J.F.S. 2018. Virus-like particle, liposome, and polymeric particle-based vaccines against HIV-1. Front. Immunol. 9, 345.
Guo, N., Liu, Y., Masuda, Y., Kawagoe, M., Ueno, Y., Kameda, T., and Sugiyama, T. 2005. Repeated immunization induces the increase in fucose content on antigen-specific IgG N-linked oligosaccharides. Clin. Biochem. 38, 149–153.
Higel, F., Seidl, A., Sorgel, F., and Friess, W. 2016. N-glycosylation heterogeneity and the influence on structure, function and pharmacokinetics of monoclonal antibodies and Fc fusion proteins. Eur. J. Pharm. Biopharm. 100, 94–100.
HogenEsch, H., O’Hagan, D.T., and Fox, C.B. 2018. Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. NPJ Vaccines 3, 51.
Huang, X., Wang, X., Zhang, J., Xia, N., and Zhao, Q. 2017. Escherichia coli-derived virus-like particles in vaccine development. NPJ Vaccines 2, 3.
Isa, M.B., Martinez, L., Giordano, M., Passeggi, C., de Wolff, M.C., and Nates, S. 2002. Comparison of immunoglobulin G subclass profiles induced by measles virus in vaccinated and naturally infected individuals. Clin. Diagn. Lab. Immunol. 9, 693–697.
Jennewein, M.F. and Alter, G. 2017. The immunoregulatory roles of antibody glycosylation. Trends Immunol. 38, 358–372.
Jin, Y., Kim, S.C., Kim, H.J., Ju, W., Kim, Y.H., and Kim, H.J. 2016. A lectin-based diagnostic system using circulating antibodies to detect cervical intraepithelial neoplasia and cervical cancer. Glycobiology 26, 100–107.
Kim, H.J., Cho, S.Y., Park, M.H., and Kim, H.J. 2018. Comparison of the size distributions and immunogenicity of human papillomavirus type 16 L1 virus-like particles produced in insect and yeast cells. Arch. Pharm. Res. 41, 544–553.
Kim, H.J. and Kim, H.J. 2017. Yeast as an expression system for producing virus-like particles: what factors do we need to consider? Lett. Appl. Microbiol. 64, 111–123.
Kim, H.J., Kim, S.Y., Lim, S.J., Kim, J.Y., Lee, S.J., and Kim, H.J. 2010. One-step chromatographic purification of human papillomavirus type 16 L1 protein from Saccharomyces cerevisiae. Protein Expr. Purif. 70, 68–74.
Kim, H.J., Lee, S.J., and Kim, H.J. 2008. Antibody-based enzyme-linked lectin assay (ABELLA) for the sialylated recombinant human erythropoietin present in culture supernatant. J. Pharm. Biomed. Anal. 48, 716–721.
Kim, H.J., Lim, S.J., Kwag, H.L., and Kim, H.J. 2012. The choice of resin-bound ligand affects the structure and immunogenicity of column-purified human papillomavirus type 16 virus-like particles. PLoS One 7, e35893.
Kushnir, N., Streatfield, S.J., and 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, 58–83.
Lee, J.Y., Xu, M.L., Kim, H.J., Kang, H.A., and Kim, H.J. 2013. A comparative study of the adjuvanticity of Hansenula polymorpha, Saccharomyces cerevsiae and Yarrowia lipolytica in oral and nasal immunization with virus capsid antigens. Biotechnol. Lett. 35, 1881–1888.
Mahan, A.E., Jennewein, M.F., Suscovich, T., Dionne, K., Tedesco, J., Chung, A.W., Streeck, H., Pau, M., Schuitemaker, H., et al. 2016. Antigen-specific antibody glycosylation is regulated via vaccination. PLoS Pathog. 12, e1005456.
Marciani, D.J. 2016. A retrospective analysis of the Alzheimer’s disease vaccine progress - The critical need for new development strategies. J. Neurochem. 137, 687–700.
Marrack, P., McKee, A.S., and Munks, M.W. 2009. Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 9, 287–293.
Maupin, K.A., Liden, D., and Haab, B.B. 2012. The fine specificity of mannose-binding and galactose-binding lectins revealed using outlier motif analysis of glycan array data. Glycobiology 22, 160–169.
Riitho, V., Walters, A.A., Somavarapu, S., Lamp, B., Rumenapf, T., Krey, T., Rey, F.A., Oviedo-Orta, E., Stewart, G.R., Locker, N., et al. 2017. Design and evaluation of the immunogenicity and efficacy of a biomimetic particulate formulation of viral antigens. Sci. Rep. 7, 13743.
Rohovie, M.J., Nagasawa, M., and Swartz, J.R. 2017. Virus-like particles: Next-generation nanoparticles for targeted therapeutic delivery. Bioeng. Transl. Med. 2, 43–57.
Scherpenisse, M., Schepp, R.M., Mollers, M., Meijer, C.J., Berbers, G.A., and van der Klis, F.R. 2013. Characteristics of HPV-specific antibody responses induced by infection and vaccination: cross-reactivity, neutralizing activity, avidity and IgG subclasses. PLoS One 8, e74797.
Selman, M.H.J., de Jong, S.E., Soonawala, D., Kroon, F.P., Adegnika, A.A., Deelder, A.M., Hokke, C.H., Yazdanbakhsh, M., and Wuhrer, M. 2012. Changes in antigen-specific IgG1 Fc N-glycosylation upon influenza and tetanus vaccination. Mol. Cell Proteomics 11, M111.014563.
Stills, H.F. Jr. 2005. Adjuvants and antibody production: dispelling the myths associated with Freund’s complete and other adjuvants. ILAR J. 46, 280–293.
Thompson, R., Creavin, A., O’Connell, M., O’Connor, B., and Clarke, P. 2011. Optimization of the enzyme-linked lectin assay for enhanced glycoprotein and glycoconjugate analysis. Anal. Biochem. 413, 114–122.
Turner, G.S. 1978. Immunoglobulin (IgG) and (IgM) antibody responses to rabies vaccine. J. Gen. Virol. 40, 595–604.
Wang, J.W. and Roden, R.B. 2013. Virus-like particles for the prevention of human papillomavirus-associated malignancies. Expert. Rev. Vaccines 12, 129–141.
Xiang, S.D., Scholzen, A., Minigo, G., David, C., Apostolopoulos, V., Mottram, P.L., and Plebanski, M. 2006. Pathogen recognition and development of particulate vaccines: Does size matter? Methods 40, 1–9.
Zamora, E., Handisurya, A., Shafti-Keramat, S., Borchelt, D., Rudow, G., Conant, K., Cox, C., Troncoso, J.C., and Kirnbauer, R. 2006. Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice. J. Immunol. 177, 2662–2670.
Zheng, K., Bantog, C., and Bayer, R. 2011. The impact of glycosylation on monoclonal antibody conformation and stability. MAbs 3, 568–576.
Acknowledgements
This study is supported by the Graduate Research Scholarship 2018 of Chung-Ang University.
Author information
Authors and Affiliations
Corresponding author
Additional information
Conflicts of Interest
The authors declared no conflict of interest.
Rights and permissions
About this article
Cite this article
Park, MH., You, J.W., Kim, H.J. et al. IgG and IgM responses to human papillomavirus L1 virus-like particle as a function of dosing schedule and vaccine formulation. J Microbiol. 57, 821–827 (2019). https://doi.org/10.1007/s12275-019-9308-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12275-019-9308-z