Eliciting unnatural immune responses by activating cryptic epitopes in viral antigens

Young Jae Lee, Ji Eun Yu, Paul Kim, Jeong Yoon Lee, Yu Cheol Cheong, Yoon Jae Lee, Jun Chang, Baik Lin Seong

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Antigenic variation in viral surface antigens is a strategy for escaping the host’s adaptive immunity, whereas regions with pivotal functions for infection are less subject to antigenic variability. We hypothesized that genetically invariable and immunologically dormant regions of a viral surface antigen could be exposed to the host immune system and activated by rendering them susceptible to antigen-processing machinery in professional antigen-presenting cells (APCs). Considering the frequent antigen drift and shift in influenza viruses, we identified and used structural modeling to evaluate the conserved regions on the influenza hemagglutinin (HA) surface as potential epitopes. Mutant viruses containing the cleavage motifs of cathepsin S within HA were generated. Immunization of mice showed that the mutant, but not the wild-type virus, elicited specific antibodies against the cryptic epitope. Those antibodies were purified, and specific binding to HA was confirmed. These results suggest that an unnatural immune response can be elicited through the processing of target antigens in APCs, followed by presentation via the major histocompatibility complex, if not subjected to regulatory pathways. By harnessing the antigen-processing machinery, our study shows a proof-of-principle for designer vaccines with increased efficacy and safety by either activating cryptic, or inactivating naturally occurring, epitopes of viral antigens.

Original languageEnglish
Pages (from-to)4658-4669
Number of pages12
JournalFASEB Journal
Issue number9
StatePublished - Sep 2018

Bibliographical note

Funding Information:
This study was supported by the Korean Health Technology Research and Development Project, Ministry of Health and Welfare (Grants HI13C0826, HI15C2875, and HI15C2934) and the National Research Foundation of Korea funded by the Ministry of Education (Grant 2014M3A9E4064743). The authors declare no conflicts of interest.

Publisher Copyright:
© The Author(s).


  • Antigen processing
  • Hemagglutinin
  • Influenza virus
  • Invariable site


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