Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8⁺ T cell immunity

Flatz L, et al. Nat Med. 2010;16: 339-45.

Speaker: Te-Hsin Yen (顏德欣)                                                     Time: 15:10~16:00, Oct 27, 2010

Commentator: Dr. Shainn-Wei Wang (王憲威 老師)          Place: Room 601

Abstract:

Vaccines had controlled many infectious diseases in the world, but the induction of protective and long-lived cytotoxic T lymphocytes (CTLs) is an unmet yet important goal of vaccination. Viral vectors, such as vaccinia virus and adenovirus 5, have been modified to express a vaccine antigen of interest. However, a significant proportion of the global population carries adenovirus 5-neutralizing antibodies obtained from natural infection¹. Therefore, it is important to develop viral vectors that elicit effective T cell immunity without concomitant induction of antibodies that blocks vector re-administration. Recently, the lymphocytic choriomeningitis virus (LCMV) genome has been manipulated². LCMV glycoprotein (LCMV-GP) mediates receptor binding, cell entry and represents the only target for LCMV neutralizing antibodies³. Here, the authors hypothesized the viral GP could be replace by a gene encoding a vaccine antigen. They generated replication deficient LCMV (rLCMV) vectors and confirmed the rLCMV particles formed in cultured cells were GP deficient, replication incompetent and lack of pathogenicity in vivo. After injection of increasing dosage of rLCMV-OVA or rAd-OVA into C57BL/6 mice, they found that rLCMV vectors elicited high frequency of specific CD8⁺ T cells, and could be efficiently amplified in homologous prime-boost immunizations. Further, rLCMV vectors induce T helper type 1 CD4⁺ T cells and neutralizing antibody responses to vaccine antigen. They also attested the efficacy and protective capacity of rLCMV-induced CTL response from vaccinated C57BL/6 mice. These experimental findings indicated rLCMV could be a safer vector that can elicit higher immunogenicity used in humans and the lack of rLCMV replication suggests that these vectors may show utility as a vaccine platform against infectious disease and cancer.

References:

1.      Roberts, D.M. et al., 2006. Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity. Nature 441: 239–243.

2.      Flatz, L. et al., 2006. Recovery of an arenavirus entirely from RNA polymerase I/II-driven cDNA. Proc. Natl. Acad. Sci.USA 103 : 4663–4668.

3.      Buchmeier, M.J., Bowen, M.D. & Peters, C.J. 2001. Arenaviridae: The viruses and their replication. in Fields Virology (eds. Knipe, D.M. and Howley, P.M.) 1635–1668. (Lippincott Williams & Wilkins, Philadelphia, Pennsylvania,).