Construction and properties of a herpes simplex virus 2 dl5-29 vaccine candidate strain encoding an HSV-1 virion host shutoff protein

Abstract

The replication-defective herpes simplex virus 2 (HSV-2) dl5-29 mutant virus strain with deletions in the UL5 and UL29 genes has been shown to protect mice and guinea pigs against challenge with wild type (wt) HSV-2 and to protect against ocular disease caused by HSV-1 infection. The dl5-29 strain is currently being prepared for clinical trials as a herpes vaccine candidate. As a possible approach to improve the efficacy of dl5-29 as a genital herpes vaccine, we replaced the UL41 gene encoding the virion host shutoff function (vhs) with the UL41 gene from HSV-1. While the HSV-2 UL41 and HSV-1 UL41 gene products have analogous functions, vhs-1 is 40-fold less active than vhs-2. Previously, it was shown that disruption of the UL41 gene can increase the efficacy of dl5-29 as a vaccine against HSV-2. These properties led us to hypothesize that replacement of vhs-2 by vhs-1 would decrease cytopathic effects in infected host cells, allowing longer survival of antigen-presenting cells and induction of stronger immune responses. The new recombinant dl5-29-41.1 virus shows nearly the same immunogenicity and protection against HSV-2 challenge as the parental dl5-29 virus or a triply deleted mutant virus, dl5-29-41, in the murine model of infection, and grows to higher titers than the parental strain in complementing cells, which is important for GMP production. The results have implications for the design of future HSV-2 vaccine candidates and mechanisms of induction of protective immunity against genital herpes.

T-cell immunity to human alphaherpesviruses

“…Provision of multiple effector T-cell populations with diverse specificity seems attractive given recent data that the CD8 and CD4 T-cell response to natural infection with HSV-1 targets 17 and 22 proteins, respectively [19,21]. Replication-incompetent whole virus formats are advancing to clinical trials [104], while replication-competent candidates – which are highly active in challenge-escalation animal models – remain interesting if safety concerns can be overcome [105]. An inherently lower immunogenicity observed with replication-incompetent viruses relative to wild-type viruses can be overcome with additional vaccine doses, at least in the case of orthopoxviruses such as VV [106].…”

Replication-Defective Herpes Simplex Virus Mutant Strains as Genital Herpes Vaccines and Vaccine Vectors

“…Inactivation of the vhs gene in dl5-29 virus generated the dl5-29-41L virus, which was more immunogenic and induced greater protection than dl5-29 virus in some but not all situations [26,30]. Replacement of the HSV-2 vhs gene with the HSV-1 vhs gene, which encodes a less active form of vhs, to give the dl5-29-41.1 virus, gave a virus that replicated better than dl5-29, expressed slightly lower levels of viral proteins, and induced immune responses and protective immunity that approximated those induced by dl5-29 [50]. These results argue that the HSV-1 vhs protein enhances growth of HSV-2 but that the RNase activity may have to be inactivated to give optimal immunogenicity.…”

Prospects and perspectives for development of a vaccine against herpes simplex virus infections

“…This virus, dl5-29, fails to form plaques or to give any detectable single cycle yields in normal monkey or human cells, but expresses nearly the same pattern of gene products as wild-type virus, and induces antibody titers in mice that are equivalent to those induced by single deletion mutant viruses [111]. Further improvements of immunogenicity for this virus have been reported in mice after deletion of the UL41 gene [112], although the triple deletion virus did not appear to provide better protection against HSV-2 challenge in mouse or guinea pig studies [113,114]. In addition, a comparison of this vaccine to adjuvanted gD2 demonstrated its superiority in the guinea pig model of genital HSV-2 infection [115].…”