title: MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults.
abstract: Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered IM in 8 subjects/DL, with an identical booster injection 28 days later and 1-year follow-up. Vaccinations at all DL were safe with no dose-limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity was transient and self-limiting. Robust, functional, and durable Triplex-driven expansions of CMV-specific T cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and interferon-γ production. Marked and durable CMV-specific T-cell responses were also detected in Triplex-vaccinated CMV-seronegatives, and in DryVax-vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection, was predominantly found on the membrane of CMV-specific and functional T cells, whereas off-target vaccine responses activating memory T cells from the related herpesvirus Epstein-Barr virus remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant (HCT) recipients and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This trial was registered at www.clinicaltrials.gov as #NCT02506933.
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Corinna
authors.initials: C
authors.lastname: La Rosa
authors.affiliation: Division of Biostatistics, Beckman Research Institute of City of Hope, Duarte, CA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Joy
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Teodora I
authors.initials: TI
authors.lastname: Kaltcheva
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Weimin
authors.initials: W
authors.lastname: Tsai
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drake
authors.affiliation: Clinical Trial Office.
authors.forename: Mary
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Felix
authors.initials: F
authors.lastname: Wussow
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Flavia
authors.initials: F
authors.lastname: Chiuppesi
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Nicola
authors.initials: N
authors.lastname: Hardwick
authors.affiliation: Department of Infectious Disease, and.
authors.forename: Sanjeet
authors.initials: S
authors.lastname: Dadwal
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Aldoss
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Center for Gene Therapy, City of Hope Comprehensive Cancer Center, Duarte, CA.
authors.forename: John A
authors.initials: JA
authors.lastname: Zaia
authors.affiliation: Department of Experimental Therapeutics and.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D003587:Cytomegalovirus; D022482:Cytomegalovirus Vaccines / Q000009:adverse effects / Q000276:immunology*; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology; D019444:Vaccines, DNA; D014763:Viral Matrix Proteins / Q000276:immunology; D014765:Viral Vaccines; D055815:Young Adult
chemical_list: D000956:Antigens, Viral; D022482:Cytomegalovirus Vaccines; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; C560489:MVA vaccine; D010750:Phosphoproteins; D015534:Trans-Activators; D019444:Vaccines, DNA; D014763:Viral Matrix Proteins; D014765:Viral Vaccines; C065418:cytomegalovirus matrix protein 65kDa