Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity

Abstract

Live-attenuated, spread-deficient rhesus CMV vectors retain T cell immunogenicity. Building a safer CMV vector Vaccine vectors based on cytomegalovirus (CMV) show strong T cell induction and protection against a multitude of pathogens. However, CMV can be harmful to people who are immunodeficient or immunosuppressed. Marshall et al. genetically modified rhesus CMV to allow engagement of host intrinsic immunity. The modified ΔRh110 vector did not spread once administered to nonhuman primates but still induced robust T cell immunity. Hansen et al. showed in a simian immunodeficiency virus (SIV) challenge model that the ΔRh110 vector provided equivalent protection to the parental vector, enabling control and progressive clearance of virus from more than half of the vaccinated primates. Most protected animals that were rechallenged 3 years later were able to control the second challenge, demonstrating the durability of this vaccine. Mutations in the human CMV vector should lead to a potent but restrained CMV that could be used widely in people. Rhesus cytomegalovirus (RhCMV)–based vaccines maintain effector memory T cell responses (TEM) that protect ~50% of rhesus monkeys (RMs) challenged with simian immunodeficiency virus (SIV). Because human CMV (HCMV) causes disease in immunodeficient subjects, clinical translation will depend upon attenuation strategies that reduce pathogenic potential without sacrificing CMV’s unique immunological properties. We demonstrate that “intrinsic” immunity can be used to attenuate strain 68-1 RhCMV vectors without impairment of immunogenicity. The tegument proteins pp71 and UL35 encoded by UL82 and UL35 of HCMV counteract cell-intrinsic restriction via degradation of host transcriptional repressors. When the corresponding RhCMV genes, Rh110 and Rh59, were deleted from 68-1 RhCMV (ΔRh110 and ΔRh59), we observed only a modest growth defect in vitro, but in vivo, these modified vectors manifested little to no amplification at the injection site and dissemination to distant sites, in contrast to parental 68-1 RhCMV. ΔRh110 was not shed at any time after infection and was not transmitted to naïve hosts either by close contact (mother to infant) or by leukocyte transfusion. In contrast, ΔRh59 was both shed and transmitted by leukocyte transfusion, indicating less effective attenuation than pp71 deletion. The T cell immunogenicity of ΔRh110 was essentially identical to 68-1 RhCMV with respect to magnitude, TEM phenotype, epitope targeting, and durability. Thus, pp71 deletion preserves CMV vector immunogenicity while stringently limiting vector spread, making pp71 deletion an attractive attenuation strategy for HCMV vectors.