Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial

Less than 200 years after the introduction of the smallpox vaccine, variola virus (VARV) was successfully eradicated by use of vaccines produced with vaccinia virus (VACV) [1]. However, along with the dramatic success of the vaccination program, frequent and sometimes severe adverse reactions to VACV vaccine were encountered, particularly in subjects with immunologic defects or dermatopathologic conditions. Since eradication, VACV vaccine has been reserved for highly selected individuals at risk for orthopoxvirus infections, but there are ongoing concerns over the potential use of VARV as a biological weapon. The development of safer, yet effective vaccines for future use against smallpox therefore remains of considerable interest. Modified vaccinia Ankara (MVA), an attenuated strain of VACV [2, 3], is much less reactogenic than widely used vaccinia strains, such as Dryvax or Elstree [4–8]. MVA was administered to approximately 120 000 persons [9] but was never used in a VARV-endemic area, and its effectiveness at preventing clinical smallpox is unknown. MVA is severely host restricted, and it is either unable to replicate in mammalian cell lines or replicates at a very low level [3, 10, 11]. Approximately 15% of the MVA genome was deleted during in vitro passage, compared with the parental strain [10, 12], but the block in replication in nonpermissive mammalian cells occurs late in the viral life cycle. Thus, because MVA-infected cells express very high levels of virally encoded proteins [13–15], including those encoded by foreign transgenes, there is considerable interest in using MVA as a vector in vaccines to prevent human immunodeficiency virus (HIV) infection, malaria, and infectious diseases due to other pathogens [16–18]. There is also substantial interest in the use of MVA as a vector to deliver tumor-specific antigens to induce immune responses that may help control malignancies, and several of these therapeutic vaccines have advanced to clinical trials [18–20]. Because preliminary studies suggested MVA was safe in immunocompromised hosts [21–24], we hypothesized that MVA would be safe, well-tolerated, and immunogenic in an important, well-characterized immunocompromised population—recipients of a hematopoietic stem cell transplant (HSCT). Vaccination with either traditional calf lymph–derived VACV (such as Dryvax or Elstree) or modern tissue culture-grown strains (the recently approved ACAM2000) are contraindicated for HSCT recipients [25]. Thus, establishing safety and immunogenicity of MVA in this group has implications for pre-event smallpox vaccine contingency planning, as well as for potential therapeutic vaccines against malignancies. We therefore conducted a randomized, placebo-controlled, double-blind study of MVA-BN (IMVAMUNE; Bavarian Nordic A/S, Kvistgaard, Denmark) in 24 individuals who received a HSCT >2 years previously.