Responses to fibroblast-adapted human cytomegalovirus (HCMV) vaccines conform to CD8 T cell recognition paradigms

Abstract Recently, a rhesus CMV-based SIV vaccine that clears SIV from half of vaccinated monkeys was shown to elicit unconventional CD8 T cell responses to both SIV and RhCMV (IE1) antigens in all immunized monkeys. These responses were characterized by i) recognition of an unusually large number of peptide epitopes within each antigen, and ii) MHCII restriction by ~2/3 of responding CD8 T cells (Hansen et al, Science, 2013). Unconventional responses were only elicited by fibroblast-adapted rhCMV strain 68-1 that lacks ability to infect cells other than fibroblasts due to loss of pentameric viral glycoprotein expression. To determine whether fibroblast-adapted human CMV (HCMV) vaccines also elicit unconventional CD8 T cell responses, we exploited an ongoing phase I clinical trial of live HCMV vaccines. These vaccines have similar fibroblast-restricted tropism to rhCMV68-1, although the precise genetic lesions differ. We analyzed CD8 T cell responses in 12 seroconverters by stimulating PBMC with overlapping peptide pools covering 20 HCMV antigens. Seven subjects in this low dose trial (100 or 1000 pfu) made consistent, measurable CD8 T cell responses. All 7 responded to IE1; 3 also responded to 1–2 additional antigens. We have mapped responses to individual 15mers in 3 subjects, and all revealed highly focused responses to 1–3 epitopes within IE1. In one HLA-B08 positive subject, the two responses mapped to known immunodominant B08-restricted IE1 epitopes. We have mapped 4 other epitopes to date; of these, 3 are 9mers and are likely conventional, but one may be a 13mer. Thus far, in contrast to RhCMV in monkeys, the CD8 T cell response to fibroblast-adapted HCMV vaccines in humans appears to be predominantly conventional. Supported by NIH R21 AI116107