Modeling pre-existing immunity to adenovirus in rodents: Immunological requirements for successful development of a recombinant adenovirus serotype 5-based ebola vaccine

Jin Huk Choi, Stephen C. Schafer, Lihong Zhang, Terry Juelich, Alexander N. Freiberg, Maria A. Croyle

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Pre-existing immunity (PEI) to human adenovirus serotype 5 (Ad5) worldwide is the primary limitation to routine clinical use of Ad5-based vectors in immunization platforms. Using systemic and mucosal PEI induction models in rodents (mice and guinea pigs), we assessed the influence of PEI on the type of adaptive immune response elicited by an Ad5-based vaccine for Ebola with respect to immunization route. Splenocytes isolated from vaccinated animals revealed that immunization by the same route in which PEI was induced significantly compromised Ebola Zaire glycoprotein (ZGP)-specific IFN-γ+ CD8+ T cells and ZGP-specific multifunctional CD8+ T cell populations. ZGP-specific IgG1 antibody levels were also significantly reduced and a sharp increase in serum anti-Ad5 neutralizing antibody (NAB) titers were noted following immunization. These immune parameters correlated with poor survival after lethal challenge with rodent-adapted Ebola Zaire virus (ZEBOV). Although the number of IFN-γ+ CD8+ T cells was reduced in animals given the vaccine by a different route from that used for PEI induction, the multifunctional CD8+ T cell response was not compromised. Survival rates in these groups were higher than when PEI was induced by the same route as immunization. These results suggest that antigen-specific multifunctional CD8+ T cell and Th2 type antibody responses compromised by PEI to Ad5 are required for protection from Ebola. They also illustrate that methods for induction of PEI used in preclinical studies must be carefully evaluated for successful development of novel Ad5-based vaccines.

Original languageEnglish (US)
Pages (from-to)3342-3355
Number of pages14
JournalMolecular Pharmaceutics
Volume10
Issue number9
DOIs
StatePublished - Sep 3 2013

Keywords

  • Pre-existing immunity
  • Zaire Ebola virus
  • adenovirus serotype 5
  • guinea pig
  • mouse
  • multifunctional CD8+ T cell response
  • vaccine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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