The objective of this project is to determine whether humans vaccinated with a fibroblast-adapted CMV vaccine develop the extraordinary unconventional CD8+ T cell responses that were recently reported by Louis Picker's group in monkeys vaccinated with a fibroblast-adapted rhesus-CMV. These responses covered an extremely broad range of peptides, were promiscuous with respect to MHC isoforms, and many of the CD8+ T cells recognized peptides in the context of MHC class II molecules. Unconventional T cells are not elicited by natural CMV infection in either monkeys or humans, and Hansen et al showed that they were only elicited by fibroblast-adapted CMV, i.e. CMV that lacks the ability to form a pentameric complex of glycoproteins needed for entry into macrophages, endothelial and epithelial cells. Monkey and human immune systems differ in several ways, most dramatically in their MHC genes, which in rhesus macaques are extremely polygenic and polymorphic. It is unknown whether a human fibroblast-adapted CMV vaccine would elicit similarly unconventional responses in humans. To address this question, we will exploit an ongoing clinical study of fibroblast-adapted CMV vaccines based on the Towne and Toledo strains in humans. PBMC will be collected before and at regular intervals after vaccination. Leukopheresis will be performed on subjects who seroconvert to establish a repository of PBMC and enable intensive dissection of the response. T cell responses will be analyzed to determine the specificity of the CD8+ T cell response, the breadth of peptide recognition, and the nature of MHC restriction.
Vaccines based on cytomegalovirus (CMV) are being developed in order to protect against CMV, which is a major cause of birth defects, and for use as vectors to develop vaccines against other diseases, including AIDS. Recent studies in monkeys showed that these vaccines can stimulate an extremely unusual immune response that could be very beneficial, but it is not known whether the same response would occur in humans. The goal of this project is to use an ongoing human CMV vaccine trial to determine whether the same unusual immune responses occur in humans.
| Murray, Susan E; Nesterenko, Pavlo A; Vanarsdall, Adam L et al. (2017) Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans. J Exp Med 214:1889-1899 |
| Adler, Stuart P; Manganello, Anne-Marie; Lee, Ronzo et al. (2016) A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimera Vaccines in Cytomegalovirus-Seronegative Men. J Infect Dis 214:1341-1348 |
