Abstract
Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (TEM) providing continuous, life-long anti-pathogen immune activity. To allow for the clinical testing of human CMV (HCMV)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone TR3 representing a wildtype genome. We demonstrate that TR3 can be stably propagated in vitro and that, despite species incompatibility, recombinant TR3 vectors elicit high frequencies of TEM to inserted antigens in rhesus macaques (RM). Live-attenuated versions of TR3 were generated by deleting viral genes required to counteract intrinsic and innate immune responses. In addition, we eliminated subunits of a viral pentameric glycoprotein complex thus limiting cell tropism. We show in a humanized mouse model that such modified vectors were able to establish persistent infection but lost their ability to reactivate from latency. Nevertheless, attenuated TR3 vectors preserved the ability to elicit and maintain TEM to inserted antigens in RM. We further demonstrate that attenuated TR3 can be grown in approved cell lines upon elimination of an anti-viral host factor using small interfering RNA, thus obviating the need for a complementing cell line. In sum, we have established a versatile platform for the clinical development of live attenuated HCMV-vectored vaccines and immunotherapies.
Highlights
Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer
We demonstrated that rhesus CMV (RhCMV)-based vaccines eliciting T cells against antigens of the malaria parasite Plasmodium knowlesi strongly reduced the release of liver stage parasites into the blood[7]
We previously demonstrated that human CMV (HCMV) TR and other clinical isolates can establish persistent infection in a humanized mouse model in which human CD34+ hematopoietic precursor cells (HPC) are engrafted into NOD-scidIL2Rγc null (NSG) mice[37,38,39,40]
Summary
Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. One of the most unique aspects of RhCMV-based vectors is their ability to elicit and indefinitely maintain high frequencies of circulating and tissue-resident effector memory CD4+ and CD8+ T cells (TEM) to the inserted antigens[4,5]. Since T cell effector differentiation is antigen-driven, it is likely that CMV-induced TEM are maintained by continuous or recurring antigen exposure due to viral persistence and reactivation in antigen presenting cells (APC)[9] This immune stimulation does not seem to require viral dissemination within the host as long as latency is established. Spread-deficient animal CMV species that maintain all unique T cell immunity features provide a blueprint for the design of highly attenuated HCMV-vectors for human use. We developed a robust and versatile live attenuated vaccine vector platform that is suitable for clinical testing
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