MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults
| Autor: | John A. Zaia, Jennifer Drake, Felix Wussow, Mary Carroll, Flavia Chiuppesi, Ryotaro Nakamura, Don J. Diamond, Ibrahim Aldoss, Sanjeet Dadwal, Nicola Hardwick, Weimin Tsai, Corinna La Rosa, Teodora Kaltcheva, Joy Martinez, Qiao Zhou, Jeff Longmate |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Modified vaccinia Ankara T-Lymphocytes viruses Immunology Cytomegalovirus Booster dose Lymphocyte Activation complex mixtures Biochemistry Immediate-Early Proteins Viral Matrix Proteins Dryvax Cytomegalovirus Vaccines Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Antigen Vaccines DNA Humans Medicine 030212 general & internal medicine Antigens Viral Transplantation business.industry Viral Vaccine virus diseases Viral Vaccines Cell Biology Hematology Middle Aged Phosphoproteins Virology Vaccination 030104 developmental biology chemistry Trans-Activators Female Vaccinia business |
| Zdroj: | Blood. 129:114-125 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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