Novel Strategy for Animal Model Testing of HCMV Vaccines

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DESCRIPTION (provided by applicant): A vaccine for prevention of congenital infection with human cytomegalovirus (HCMV) is an urgent public health priority. A subunit vaccine based on purified recombinant glycoprotein B (gB), expressed in Chinese hamster ovary (CHO) cells, is currently being tested in clinical trials. The rationale for this vaccine is based on observations that the majority of virus-neutralizing antibodies found in human convalescent sera are specific for this protein. The observation that purified, recombinant forms of guinea pig cytomegalovirus (GPCMV) gB are protective against infection and disease in the guinea pig model of congenital CMV infection lends credence to the hypothesis that HCMV gB vaccines might be efficacious against congenital infection. However, to date it has unfortunately been impossible to test the efficacy of the HCMV gB vaccine in an animal model, such as the GPCMV model. This is because the strict species-specificity of the respective CMVs makes it impossible to perform HCMV viral challenge experiments in guinea pigs, even though the human gB vaccine is immunogenic in these animals. Recently, however, the development of viral mutagenesis strategies based on the successful doing of CMV genomes as bacterial artificial chromosomes (BACs) in E. coli has represented a major advance in generating recombinant, chimeric viruses. It is now feasible to generate replication-competent GPCMVs with targeted insertions of heterologous HCMV genes into the viral genome. Against this backdrop, this proposal seeks to test the hypotheses that: 1) a novel, recombinant 'swap' mutant, expressing the HCMV gB protein in the context of the GPCMV genome, will retain replication competence and the ability to cause congenital infection and disease in vivo; and, 2) that purified, recombinant HCMV gB, administered with MF59 adjuvant, will protect against congenital infection and disease in pregnant animals challenged with the 'humanized' virus. These studies will represent the first efficacy test of a human CMV subunit vaccine in a small animal model of congenital CMV infection.