VSV Gene Therapy and Vaccines

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The generally low seroprevalence of VSV antibodies in the general population and genetic malleability indicated that VSV could be an attractive vector to develop new vaccines (26). VSV elicits strong humoral and cellular immune responses in vivo and naturally infects at mucosal surfaces (89-91). As mentioned, a major observation also included that VSV were found to accommodate large gene inserts and multiple genes in their genomes (88). Thus, it wasn't long before a variety of foreign viral glycoproteins were cloned into VSV vectors for the purpose of developing novel vaccines (89,92,93). Early studies involved placing the hemagglutinin (HA) or neuraminidase (NA) of influenza virus into VSV as extra genes. High-level expression of the heterologous products were obtained and animals inoculated with these VSV vectors were protected against lethal doses of influenza virus (88,89). Substitution of the VSV G protein with influenza virus HA was also found to function well and to exhibit similar protective efficacy (88). VSV vectors have subsequently been shown to be effective in vaccine studies designed to protect against respiratory syncytial virus (RSV), human papillomavirus (HPV), and viruses associated with acquired immunodeficiency syndrome (AIDS), amongst others (88-91,93-96). In addition, new generations of attenuated, nonpropagat-ing viruses are being developed where the VSV G protein has been deleted. These non-propagating viruses (AG) lacking G, which is essential for infectivity, are generated via helper-cells that supply the VSV G glycoprotein in trans (29,88,97). Budding viruses incorporate the G protein on their surface and are released. Such viruses can infect cells through the highly tropic G protein and commence replication. However, AG progeny viruses, when released from their primary targets, cannot infect other cells because they lack the G protein gene product. In vaccine studies, such viruses have been shown to retain their protective efficacy compared with their wild-type, replication competent counterparts, yet are considerably attenuated (88,97). Other studies have shown that the parts of the membrane-proximal stem region of VSV G can be fused to foreign genes with the result that the heterologous product substitutes for the G protein (97). Thus, these new recombinant viruses harbor new proteins on their surface, instead of G. Such strategies may be useful for developing recombinant VSVs that target specific cell types (93,98). For example, a recent study indicated that VSV expressing a chimeric Sindbis glycoprotein containing the Fc-binding domain of Staphylococcus aureus protein A, conjugated to an antibody to Her2/neu could target cancer cells overexpressing the Her2/neu receptor (99). Further, the ability to develop a variety of VSVs all with different sets of surface proteins is feasible and may prove useful in vaccines studies where sequential deliveries are required. Such viruses would avoid immune responses, such as neutralizing antibody, that would be generated by their predecessors and thus may exert significantly greater immunogenic/gene therapeutic activity (93). Similar strategies may be useful in oncolysis studies where delivery of the first viral treatment generates significant immune responses, effectively eliminating the effectiveness of a second similar dose. Indeed, the genetic malleability of VSV is one of the attractive incentives for further evaluating VSV as an anticancer agent.

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