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Viral mutations to attenuate cytomegalovirus-based vaccine vectors

November 28, 2019

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Rhesus cytomegalovirus (RhCMV)–based vaccines have been found to maintain effector memory T cell responses (TEM) that protect 50% of rhesus monkeys (RMs) challenged with simian immunodeficiency virus (SIV). However, human CMV (HCMV) causes disease in immunosuppressed patients and therefore the clinical translation of the vaccines will depend upon developing attenuation strategies. The authors found that “intrinsic” immunity can be used to attenuate strain 68-1 RhCMV vectors without impairing their immunogenicity. The tegument proteins, pp71 and UL35, encoded by UL82 and UL35 of HCMV were found to counteract cell-intrinsic restriction via degradation of host transcriptional repressors. When the corresponding RhCMV genes, Rh110 and Rh59, were deleted from 68-1 RhCMV, the authors found that there was only a modest decrease in growth in vitro, but in vivo the modified vectors had little to no amplification at the injection site and dissemination to distant sites. ΔRh110 was not shed at any time following infection and was not transmitted to naïve hosts, either through close contact (mother to infant) or via leukocyte transfusion. In contrast, ΔRh59 was both shed and transmitted by leukocyte transfusion, suggesting that there was less effective attenuation. The T cell immunogenicity of ΔRh110 was identical to that of 68-1 RhCMV with respect to magnitude, TEM phenotype, epitope targeting and durability. Therefore the pp71 deletion preserves the CMV vector’s immunogenicity while limiting vector spread, suggesting that this could be used as an attenuation strategy for HCMV vectors.

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Marshall EE, Malouli D, Hansen SG, Gilbride RM, Hughes CM, et al. ISSN: Sci Transl Med; 11(501): pii: eaaw2603

2019

Added: November 28, 2019