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Divergent memory responses driven by adenoviral vectors are impacted by epitope competition

Julia M Colston, Claire Hutchings, Senthil Chinnakannan, Andrew Highton, Christian Perez Shibayama, Burkhard Ludewig & Paul Klenerman

abstract Adenoviral vectors induce robust epitope-specific CD8 T cell responses. Within the repertoire of responses generated both conventional memory evolution and the phenomenon of memory inflation are seen. The rules governing which epitopes inflate are not fully known, but may include a role for both antigen processing and competition. To investigate this, we looked at memory generated from vectors targeting the Gp33-41 (KAVYNFATC/K9C) epitope from the gp of lymphocytic choriomeningitis virus (LCMV) in mice. This well-described epitope has both the Gp33-41 and Gp34-41 epitopes embedded within it. Vaccination with a full-length gp or a minigene Ad-Gp33/K9C vector-induced conventional memory responses against the immunodominant Gp33/K9C epitope but a strong inflationary response against the Gp34/A8C epitope. These responses showed sustained in vivo function, with complete protection against LCMV infectious challenge. Given the unexpected competition between epitopes seen in the minigene model, we further tested epitope competition using the full-length Ad-LacZ (β-galactosidase) model. Generation of an Ad-LacZ vector with a single amino acid disruption of the inflationary β-gal /D8V epitope transformed the β-gal /I8V epitope from conventional to inflationary memory. This work collectively demonstrates the importance of epitope competition within adenoviral vector inserts and is of relevance to future studies using adenoviral vectored immunogens.
   
citation Colston J M, Hutchings C, Chinnakannan S, Highton A, Perez Shibayama C, Ludewig B, Klenerman P. Divergent memory responses driven by adenoviral vectors are impacted by epitope competition. Eur J Immunol 2019;.
   
type journal paper/review (English)
date of publishing 20-5-2019
journal title Eur J Immunol
ISSN electronic 1521-4141
PubMed 31106398
DOI 10.1002/eji.201948143
contact Burkhard Ludewig