A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimera Vaccines in Cytomegalovirus-Seronegative Men

Abstract

Background: Human cytomegalovirus (HCMV) infection causes disease in newborns and transplant recipients. A HCMV vaccine (Towne) protects transplant recipients.

Methods: The genomes of Towne and the nonattenuated Toledo strain were recombined, yielding 4 Towne/Toledo chimera vaccines. Each of 36 HCMV-seronegative men received 1 subcutaneous dose of 10, 100, or 1000 plaque-forming units (PFU) in cohorts of 3. Safety and immunogenicity were evaluated over 12 weeks after immunization and for 52 weeks for those who seroconverted.

Results: There were no serious local or systemic reactions. No subject had HCMV in urine or saliva. For chimera 3, none of 9 subjects seroconverted. For chimera 1, 1 of 9 seroconverted (the seroconverter received 100 PFU). For chimera 2, 3 subjects seroconverted (1 received 100 PFU, and 2 received 1000 PFU). For chimera 4, 7 subjects seroconverted (1 received 10 PFU, 3 received 100 PFU, and 3 received 1000 PFU). All 11 seroconverters developed low but detectable levels of neutralizing activity. CD4⁺ T-cell responses were detectable in 1 subject (who received 100 PFU of chimera 4). Seven subjects receiving chimera 2 or 4 had detectable CD8⁺ T-cell responses to IE1; 3 responded to 1-2 additional antigens.

Conclusions: The Towne/Toledo chimera vaccine candidates were well tolerated and were not excreted. Additional human trials of chimeras 2 and 4 are appropriate.

Clinical trials registration: NCT01195571.

Keywords: cytomegalovirus; pregnancy; transplantation; vaccines.

Figure 1.

Neutralizing responses measured using ARPE-19 epithelial cells (A) or MRC-5 fibroblasts (B) for subjects 34, 35, and 36, who received 1000 plaque-forming units of chimera 4 vaccine.

Figure 2.

Geometric mean titers (GMTs) indicating neutralizing responses 12 weeks after immunization (horizontal line), with minima and maxima (solid vertical lines), among subjects who received 100 or 1000 plaque-forming units of chimera 2 or 4 vaccine. The GMTs in naturally seropositive subjects, determined using a fibroblast-based assay, is 25. The epithelial cell–based GMT for seropositive subjects is 3000.

Figure 3.

T-cell responses to vaccination. A, Gating hierarchy for assessment of T-cell responses. Shown are IE-1 responses in 2 representative subjects. B, Proportion of seroconverters (n = 11) who mounted CD4⁺ or CD8⁺ T-cell responses to overlapping peptide pools covering the indicated proteins. C, Kinetics of CD8⁺ T-cell responses to IE-1 overlapping peptide pools in the indicated subjects. All subjects displayed are seroconverters, except subject 21. D, Proportion of total memory (CD95^+/low) and effector memory (CD95^+/lowCD28⁻) cells among CD8⁺ T cells over time for subject 23, who may have been exposed to wild-type human cytomegalovirus between week 52 and 101 after vaccination. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α.