Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo

Suárez, N. M., Lau, B. , Kemble, G. M., Lee, R., Mocarski, E. S., Wilkinson, G. W.G., Adler, S. P., McVoy, M. A. and Davison, A. J. (2017) Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo. Virus Genes, 53(4), pp. 650-655. (doi:10.1007/s11262-017-1452-0) (PMID:28391502) (PMCID:PMC5527331)

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Abstract

Human cytomegalovirus (HCMV) is an important opportunistic pathogen in immunocompromised patients and a major cause of congenital birth defects when acquired in utero. In the 1990s, four chimeric viruses were constructed by replacing genome segments of the high passage Towne strain with segments of the low passage Toledo strain, with the goal of obtaining live attenuated vaccine candidates that remained safe but were more immunogenic than the overly attenuated Towne vaccine. The chimeras were found to be safe when administered to HCMV-seronegative human volunteers, but to differ significantly in their ability to induce seroconversion. This suggests that chimera-specific genetic differences impacted the ability to replicate or persist in vivo and the consequent ability to induce an antibody response. To identify specific genomic breakpoints between Towne and Toledo sequences and establish whether spontaneous mutations or rearrangements had occurred during construction of the chimeras, complete genome sequences were determined. No major deletions or rearrangements were observed, although a number of unanticipated mutations were identified. However, no clear association emerged between the genetic content of the chimeras and the reported levels of vaccine-induced HCMV-specific humoral or cellular immune responses, suggesting that multiple genetic determinants are likely to impact immunogenicity. In addition to revealing the genome organization of the four vaccine candidates, this study provided an opportunity to probe the genetics of HCMV attenuation in humans. The results may be valuable in the future design of safe live or replication-defective vaccines that optimize immunogenicity and efficacy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davison, Professor Andrew and Lau, Dr Betty and Suarez, Dr Nicolas
Authors: Suárez, N. M., Lau, B., Kemble, G. M., Lee, R., Mocarski, E. S., Wilkinson, G. W.G., Adler, S. P., McVoy, M. A., and Davison, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Virus Genes
Publisher:Springer
ISSN:0920-8569
ISSN (Online):1572-994X
Published Online:08 April 2017
Copyright Holders:Copyright © 2017 Springer Science+Business Media
First Published:First published in Virus Genes 53(4): 650-655
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH