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MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T-cells in healthy adults

Corinna La Rosa, Jeff Longmate, Joy Martinez, Qiao Zhou, Teodora I. Kaltcheva, Weimin Tsai, Jennifer Drake, Mary Carroll, Felix Wussow, Flavia Chiuppesi, Nicola Hardwick, Sanjeet Dadwal, Ibrahim Aldoss, Ryotaro Nakamura, John A. Zaia and Don J. Diamond

Key points

  • First in human trial of Triplex vaccine shows safety and expansion of durable CMV-specific T-cells with potential for viremia control.

  • Triplex is immunogenic in both CMV seronegative and seropositive healthy adults with or without previous smallpox vaccination.

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 three immunodominant CMV antigens which stimulates a host anti-viral 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 intramuscularly in 8 subjects/DL, with an identical booster injection 28 days later and one 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 were 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 IFN-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, while off-target vaccine responses activating memory T-cells from the related herpesvirus EBV remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant recipients (HCT) and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This study is registered as NCT01941056 @ www.clinicaltrials.gov.

  • Submitted July 25, 2016.
  • Accepted October 18, 2016.