Development of Recombinant HSV-Based Vaccine Vectors

Abstract

Herpes simplex virus (HSV) causes significant morbidity on the human population through such clinical syndromes as cold sores, genital herpes, herpes stromal keratitis, and encephalitis. Attempts to generate efficacious vaccines to date have failed. We have recently described the use of a conditionally replication-competent HSV-1 vector to immunize mice against a lethal challenge of HSV-1. The unique feature of this vaccine vector is that its replication is tightly controlled and can only occur in the presence of local heat and the presence of a small molecule inducer (an antiprogestin). This gives it the safety advantage of a replication-defective vaccine vector as well as the advantage of a replication-competent vector in that it is able to stimulate innate and adaptive aspects of the immune response in a natural context that a replication-defective vector cannot. In this chapter we provide a brief overview of HSV vaccines followed by the methodology used to propagate and utilize replication-conditional HSV vectors as vaccines.

Immunization by Replication-Competent Controlled Herpesvirus Vectors

“…HSV-GS3 ( Fig. 1B ) was constructed as previously described ( 3 , 35 ). HSV-GS7 was derived from the intermediate vector HSV-17GS43 ( 35 ), which contains an insertion between the UL43 and UL44 genes of a transactivator cassette containing a GLP65 gene under the control of a promoter cassette that combined a human HSP70B promoter and a GAL4-responsive promoter ( 31 ).…”

“…Currently, there is no vaccine for treating or preventing HSV-1 or HSV-2 infections. Several new candidate vaccines have been developed in recent years, some of which have entered clinical evaluation ( 3 – 7 ). Another example is influenza virus infections.…”

Immunization by replication-competent controlled herpesvirus vectors

“…HSV-GS3 (Fig. 1B) was constructed as previously described (3,34). HSV-GS7 was derived from intermediate vector HSV-17GS43 (34) that contains an insertion between the UL43 and UL44 genes of a transactivator cassette containing a GLP65 gene under the control of a promoter cassette that combined a human HSP70B promoter and a GAL4-responsive promoter (31).…”

“…Subsequently, on days 2 and 3, the cells were again incubated at 43.5°C for 30 min and then returned to 37°C. Picking and amplification of plaques, screening and plaque purification was performed essentially as described for HSV-GS3 (3,34). The resulting plaque-purified HSV-GS11 was verified by Southern blot as well as by PCR and DNA sequence analysis of the recombination junctions.…”

“…Currently, there is no vaccine for treating or preventing HSV-1 or HSV-2 infections. There are many ongoing research projects directed toward developing effective vaccines, of which some are being/have been tested in the clinic (3,4), with GEN-003 (Genocea) (5), HSV529 (Sanofi) (6) and HSV-2 0ΔNLS (Rational Vaccines) (7) receiving the most attention. Another example are influenza infections.…”