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Review
. 2019 Oct 17;7(4):152.
doi: 10.3390/vaccines7040152.

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

Affiliations
Review

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

Mario Alberto Ynga-Durand et al. Vaccines (Basel). .

Abstract

Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.

Keywords: cytomegalovirus; immunization; immunotherapy; memory inflation; vaccine development; vaccine vector.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
High and low avidity epitopes expressed by strong promoters revealed inflationary response kinetics. Those expressed under weak promoters induced less robust responses, demonstrating that quality of T-cell responses depends on the context of antigenic expression. While the response was always weaker against low avidity antigens, memory inflation was maintained even against them. Weak expression and low avidity resulted in weak responses and no memory inflation.
Figure 2
Figure 2
Antigen accessibility and memory inflation. Locating an epitope sequence to the C-terminus of a protein optimizes peptide processing by the constitutive proteasome and allows the development of inflationary CD8 T-cell responses. This acts as a primary filter that acts independently of the promoter expressing the antigen and selects the epitopes that can be presented by major histocompatibility complex I in non-professional antigen presenting cells.
Figure 3
Figure 3
Antigenic competition. Strong and early expression of epitopes engaging T cell receptors with high avidity selects for cognate T-cell clones. These T cells repress subsequent Cytomegalovirus gene expression and thus restrict the MHC presentation of antigenic epitopes that would be expressed later in a reactivating virus. Therefore, such epitopes are progressively outcompeted and the immune response increasingly focuses on the selected few winners of inflation.
Figure 4
Figure 4
The infection route determines the sites of virus infection and thus the type of T-cell responses. Upon intranasal infection, MCMV reaches cells in lungs on both sides of the basal lamina and induces tissue resident memory T cell (TRM) responses in the surface of the lung epithelium but also reaches stromal cells that may induce effector memory T cell (TEM) responses. Parenteral infection cannot induce TRM, likely due to poor access to the epithelial cells.

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