Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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.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. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

Influenza- and MCMV-induced memory CD8 T cells control respiratory vaccinia virus infection despite residence in distinct anatomical niches

“…These T cells provided protection from the relevant tumors or pathogens expressing these epitopes. [21][22][23][24][25][26][27][28][29] The protective capacity correlated with the size of the inflationary T cell pool in the peripheral organ and blood. 2,3,29 Here, we compared the local protective capacity of antigenicspecific CD8 T RM cells (induced by influenza virus infection) and inflationary T cells (induced by MCMV infection) in lung tissue towards a secondary respiratory infection with vaccinia virus (VV) encoding the same antigen.…”

Epidemiology and biology of a herpesvirus in rabies endemic vampire bat populations

“…), and possess a remarkable capability for super-infection 18,[20][21][22] . Finally, BHV vectors induce potent immunological responses that are often equally or more powerful and longer lasting than those induced by natural infections with target viruses 23 . The immune response is also potentially selfboosting given the propensity for latency and reactivation of herpesviruses.…”

MCMV based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

“…CMV has aroused great interest as a vaccine vector in recent years due to its strong immunogenicity and ability to establish life-long inflationary CD8 + T cell-response (59). Many studies have demonstrated that exogenous antigens fused to the CMV genome provide protection against corresponding pathogens, but almost all of the previous publications handled T cell-based immune protection (17,18,20,21,28,37) and barely covered B cell-based humoral responses, which prevent viral spread via extracellular fluids (60).…”