Fusion of a viral antigen to invariant chain leads to augmented T-cell immunity and improved protection in gene-gun DNA-vaccinated mice

Abstract

It has recently been demonstrated that a recombinant replication-deficient human adenovirus 5 (Ad5) vector expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) fused to the p31 invariant (Ii) chain confers broad, long-lasting T-cell immunity that completely protects C57BL/6 mice against lethal peripheral challenge. The current study questioned whether the same strategy, i.e. linkage of GP to an Ii chain, could be applied to a naked DNA vaccine. Following gene-gun immunization with the linked construct (DNA-IiGP), GP-specific CD4 + T cells could not be detected by flow cytometry. However, inclusion of the Ii chain augmented the priming of GP-specific CD8 + T cells directed towards both immunodominant ) and subdominant (GP 276-286 and GP 92-101 ) epitopes, and vaccination with DNA-IiGP conferred significantly improved protection against systemic LCMV infection compared with the unlinked construct. In contrast, substantial protection against peripheral challenge was not observed. Additional experiments with T-cell subset-depleted or perforin-deficient mice revealed that virus control in vaccinated mice depends critically on cytotoxic CD8 + T cells. Finally, priming with the naked DNA vaccine was shown to augment the immune response raised by subsequent immunization with the Ad5 vector. In conclusion, this study showed that the immunoenhancing effect of Ii chain linkage is not limited to the Ad5 vector, but is also relevant with a DNA platform. Furthermore, given the fact that the Ii chain enhances the presentation of more than one epitope, this suggests that Ii-chain-based DNA vaccines may be promising candidates for various heterologous prime-boost regimes.

Enhanced and Sustained CD8+ T Cell Responses with an Adenoviral Vector-Based Hepatitis C Virus Vaccine Encoding NS3 Linked to the MHC Class II Chaperone Protein Invariant Chain

“…We found that linkage of Ii to HCV NS3 enhanced, accelerated, and broadened the CD8 + T cell response in a similar manner as seen in the LCMV model (28,40). The Ad-IiNS3-induced CD8 + T cell frequencies shown in this study are, to our knowledge, considerably higher than any of the previously published frequencies obtained after vaccination with HCV NS proteins (17)(18)(19)(20).…”

“…In conclusion, our laboratory has shown previously that Iilinkage of the vaccine Ag could enhance, broaden, accelerate, and prolong CD4 + and CD8 + T cell responses toward the model virus LCMV independent of vaccination platform (28,40). The current study further explored the benefits of the Ii linkage technology by applying it to an Ag of human disease relevance, HCV NS3, which moreover is well known for its low immunogenicity (17)(18)(19)(20).…”

Harnessing the Potential of Adenovirus Vectored Vaccines

“…The MHC class II associated invariant chain linked antigen concept was also tested as a DNA vaccine, and found to increase CD8+ T cell responses working both alone and as a primer for an adenoviral boost. Moreover, the MHC class II associated Invariant chain linked antigen concept was also beneficial when applied in the booster supporting the conclusion that increased direct presentation benefits adenovirus induced CD8+ T cell responses after the initial priming (Grujic et al, 2009). …”

“…The use of DNA priming is logical and results in a broadening of the CD4+ T cell response, an increase in the IL-2 competence of the primed CD8+ T cells and improved protection after SIV challenge (Casimiro et al, 2005;Cox et al, 2008;Wu et al, 2005). Please note that although some animal studies point to an improved immunogenicity of DNA primed adenovirus immunizations (Grujic et al, 2009), this has not been verified in humans (Bett et al, 2010). Although DNA primed adenovirus immunization have shown some promise, it pales in comparison to the recent pre-clinical results obtained using adenoviruses of different serotypes (Liu et al, 2009) or adenovirus as primers for MVA vectors (ReyesSandoval et al, 2010).…”

Vaccine Strategies against Human Papillomavirus: A Discussion Focused on Developing Countries

“…For this reason, there have been a large number of studies aimed at enhancing the DNA vaccine through the improving of the DNA delivery systems and DNA sequence (codon optimization and/or fusion with other genes for the improvement of vaccinal antigens) [70][71][72][73][74][75][76][77][78].…”