Abstract
CMV infection is an important complication of patient recovery from transplantation, and affects a wide variety of individuals including newborns and HIV patients with advanced disease. An effective CMV vaccine for patients who have already acquired an infection has yet to successfully incorporate an antigenic repertoire capable of eliciting a cellular immune response. To address this problem, we have developed a vaccine candidate derived from modified vaccinia Ankara (MVA) that expresses three immunodominant antigens (pp65, IE1, IE2) from CMV, we have termed CMV-MVA. While other antigens are also immunologically recognized to varying degrees, the evidence for these three antigens to be involved in protective immune responses in a majority of CMV-infected patients is compelling and justifies their inclusion into a vaccine to prevent viremia and control infection. MVA has an extensive history of successful delivery into rodents, Rhesus macaques, and other non-human primates, and more recently as a clinical vaccine in cancer patients and HIV patients in a state of immunosuppression. CMV-MVA is engineered with a bacterial marker to track its purification, which can be removed by recombination, a requirement for clinical development. The novelty of this vaccine is the fusion of the two largest and adjacent protein-coding exons from the immediate-early (IE) region of CMV, their successful expression as a fusion protein in MVA, and robust immunogenicity in both primary and memory response models. The advantages of this approach include placement of all vaccine antigens in one vector, and diminishing the dose of virus needed to attain sufficient immunity simultaneously against all of the included antigens. Evaluation of the immunogenicity of the viral vaccine in transgenic HLA mouse models (A2, B7, A11) shows that it can stimulate primary immunity against all three antigens in both the CD4+ and CD8+ T cell subsets. Evaluation using human PBMC from CMV-positive donors shows robust stimulation of existing CMV-specific T cells in both the CD4+ and CD8+ T cell subset. These results extend to both healthy volunteers and patients within 6 months of receiving hematopoietic cell transplant (HCT). Evaluating PBMC from transplant recipients in all three risk categories (D+/R+,D+/R−, D−R+), we found an equivalently strong recognition of both antigens, in some cases more vigorous than in the PBMC of healthy adults. This candidate vaccine is being developed in partnership with the NCI as a therapeutic for HCT recipients. Strategies of vaccine delivery include vaccinating the transplant donor, and/or the recipient at day 90 or later, if warranted clinically and with sufficient evidence of safety. The ongoing evaluation of a DNA vaccine against CMV suggests a worthwhile strategy of combining MVA with a plasmid DNA vaccine. Our preliminary studies using DNA prime and MVA boost in Rhesus macaques show it to be a more powerful CMV vaccine regimen than either component given separately. Evidence for the capacity of CMV-MVA to modify viremia through immunologic mechanisms from both clinical and monkey studies will be presented.
Vaccination of rhesus macaques with a vif-deleted simian immunodeficiency virus proviral DNA vaccine