Evaluation of a Live Attenuated Recombinant Virus RAV 9395 as a Herpes Simplex Virus Type 2 Vaccine in Guinea Pigs

Abstract

Recombinant virus RAV 9395 was constructed by deleting both copies of the gamma(1)34.5 gene, and the UL55 and UL56 open reading frames from herpes simplex virus type 2 (HSV-2) strain G. The potential use of RAV 9395 as an HSV-2 vaccine was investigated by evaluating the ability of RAV 9395 to protect guinea pigs from severe disease by HSV-2(G) challenge. RAV 9395 administered intramuscularly reduced both lesion development and severity in a dose-dependent manner in guinea pigs challenged with HSV-2(G). The frequency of reactivation of RAV 9395 from explanted dorsal root ganglia was low compared with that of HSV-2(G). Immunization with RAV 9395 at doses of 1 x 10(5) pfu and above generally precluded the establishment of latency by the challenge virus. The results presented in this report lend support for the development of genetically engineered live HSV vaccines.

Evaluation of AD472, a live attenuated recombinant herpes simplex virus type 2 vaccine in guinea pigs

“…No virus was detected in the ganglia of the 15 animals infected with AD472, whereas ganglia from two of the four animals infected with wt virus yielded infectious virus (data not shown). Thus, AD472 does not appear to replicate well enough in the vaginal tract to initiate an infection of the peripheral neurons with spread to the ganglia and has a greatly reduced capacity to replicate or establish latency in these ganglia, which is similar to results reported previously for RAV 9395 [20].…”

“…Cosmids 9394.54 and 9394.67 were derived from RAV 9394, the tk − predecessor of RAV 9395 and were used to reproduce the same γ 1 34.5 and UL55-56 deletions as described inRAV9395 [20]. Cosmid clone scpt43.5was used to delete UL43.5 via a 7.3 kb deletion and cosmid AD467 was used to delete the US10-12 region in the final virus.…”

“…A secondgeneration live attenuated vaccine, RAV 9395, was designed to delete a similar subset of viral genes without debilitating the replication of the virus to the degree observed with R7020, and also proved to be both safe and effective in the guinea pig model of genital herpes [20]. In this report, we describe a rationally designed live attenuated HSV-2 viral vaccine that is similar in concept to RAV 9395 that was described in a previous report and proved to be both safe and effective in preclinical studies [20].…”

Replication-competent herpes simplex vectors: design and applications

“…The concerns surrounding the development of a live viral vaccine for HSV are mainly safety issues revolving around the potential for reactivation from latency, recombination with wt virus, and the oncogenic potential of viral DNA. [8][9][10][11] The first attenuated HSV virus to be constructed and analyzed as a viral vaccine in humans was the NV1020 (formerly R7020) strain. 12,13 This virus, based on HSV-1 strain F, has a portion of the unique short region of the viral genome encoding glycoproteins G, D, I and E, replaced by the homologous region from HSV-2, and possesses one copy of ICP4.…”

“…8 When used as a live viral vaccine in a guinea pig model of HSV infection, it was shown to be protective, and also demonstrated that the immunologic answer depended on the route of administration of the virus. RAV 9395 is based on HSV-2 strain G, which Figure 1 Map of HSV-1 genome.…”