Immune Protection by a Cytomegalovirus Vaccine Vector Expressing a Single Low-Avidity Epitope

Abstract

Experimental CMV-based vaccine vectors expressing a single MHC class I-restricted high-avidity epitope provided strong, T cell-dependent protection against viruses or tumors. In this study we tested the low-avidity epitope KCSRNRQYL, and show that a mouse CMV (MCMV) vector provides complete immune control of recombinant vaccinia virus expressing the same epitope if KCSRNRQYL is expressed within the immediate-early MCMV gene The same epitope expressed within the early gene provided no protection, although MCMV vectors expressing the high-avidity epitope SSIEFARL induced protective immunity irrespective of gene expression context. Immune protection was matched by Ag-induced, long-term expansion of effector memory CD8 T cells, regardless of epitope avidity. We explained this pattern by observing regularities in Ag competition, where responses to high-avidity epitopes outcompeted weaker ones expressed later in the replicative cycle of the virus. Conversely, robust and early expression of a low-avidity epitope compensated its weak intrinsic antigenicity, resulting in strong and sustained immunity and immune protection.

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

“…The antigen-specific CD8 + T cells during latent infection bear predominantly a CD8T EM phenotype and localize in secondary lymphoid or non-lymphoid organs [14]. They may provide immune protection against diverse viral targets [13, 15–18], but also against bacterial [19] or tumor antigens [20, 21].…”

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

“…In contrast, insertion of the HSV-1 epitope in the context of the M45 gene, an early gene, was associated with an early expansion followed by contraction. Interestingly, both vectors induced TEM responses [14] and protective immunity, which was confirmed in an HSV-1 challenge experiment [33] or upon challenge with a recombinant VV expressing the HSV-1 epitope [15]. Another set of recombinant MCMVs expressing the low-avidity H-Y derived epitope [146] in either ie2 or M45 gene locations showed a similar pattern of inflationary responses that were restricted to the ie2 gene expression context [15], although at lower levels (Figure 1).…”

“…Interestingly, both vectors induced TEM responses [14] and protective immunity, which was confirmed in an HSV-1 challenge experiment [33] or upon challenge with a recombinant VV expressing the HSV-1 epitope [15]. Another set of recombinant MCMVs expressing the low-avidity H-Y derived epitope [146] in either ie2 or M45 gene locations showed a similar pattern of inflationary responses that were restricted to the ie2 gene expression context [15], although at lower levels (Figure 1). However, in this case, only the ie2 expression context resulted in protective TEM against a recombinant VV expressing the same epitope [15].…”

“…Another set of recombinant MCMVs expressing the low-avidity H-Y derived epitope [146] in either ie2 or M45 gene locations showed a similar pattern of inflationary responses that were restricted to the ie2 gene expression context [15], although at lower levels (Figure 1). However, in this case, only the ie2 expression context resulted in protective TEM against a recombinant VV expressing the same epitope [15]. Therefore, the TEM phenotype of responding cells was associated with immune protection in these studies.…”

“…This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates.…”