Phs 398 (rev. 9/04), continuation page

Teaching affiliate of f
Harvard Medical School lll


TECHNOLOGY

Herpes simplex virus (HSV) infections can cause significant clinical problems and even death in
individuals who are immunodeficient or suffering from disorders of skin integrity. Approximately 80% of
adults in the United States are infected with HSV, of whom 50 to 60 million are infected with HSV-2.
HSV-2 is now the leading cause of genital ulcer disease, and genital HSV-2 infection triples the risk for
sexually acquiring HIV infection. Currently, no medication can prevent primary HSV infections or
decrease the incidence of recurrences. Thus, there is a huge demand for a safe and effective HSV
vaccine.
During the past decade, many studies have focused on the development of various HSV replication-
defective viruses and neuroattenuated mutants as potential vaccines against HSV infection. However, the
ability of these recombinants to establish lifelong latent infection and to co-replicate with wild-type HSV
raises a critical concern for the use of these recombinants in humans, especially as a therapeutic vaccine in
individuals who have been latently infected with HSV. Aiming to significantly increase the safety of HSV
recombinant viral vaccines while retaining the capability of expressing a broad array of viral gene
products, using the T-RExTM (Invitrogen, CA) gene switch technology developed by Dr. Yao and the
dominant-negative mutant polypeptide of HSV-1 origin binding protein UL9, Dr. Yao constructed a novel
class of HSV-1 recombinants (U.S. patent, 6,251,640 B1) with key features of being replication defective,
and capable of inhibiting wild-type HSV-1 and HSV-2 infections (dominant-negative). CJ9-gD is a
prototype of the dominant-negative and replication-defective HSV-1 recombinant viral vaccine that
expresses high-levels of HSV-1 major antigen glycoprotein D (gD) independent of HSV viral DNA
replication. CJ9-gD cannot establish latent infection in vivo and elicits strong and long-lasting HSV-
specific neutralizing Ab as well as CD4+ and CD8+ T-cell responses at levels comparable to those induced
in wild-type HSV-1-immunized mice. Immunization with CJ9-gD elicits strong and effective protective
immune response against HSV-1 infection in both mouse and guinea pig models of HSV-1 infections.
Given these favorable safety and immunological profiles of CJ9-gD and aiming to maximize levels of
gD2 expression, Dr. Yao has recently constructed a dominant-negative and replication-defective HSV-2
recombinant (CJ2-gD2), which expresses gD2 as efficient as wild-type HSV-2 infection, and can exert a
powerful trans-inhibitory effect on the replication of wild type HSV-2 in co-infected cells. CJ2-gD2 is a
more effective vaccine than CJ9-gD in protection against wild-type HSV-2 genital infection and disease
as well as reduction of latent infection by the challenge wild-type HSV-2 in sensory ganglia.
Furthermore, intracerebral injection of high dose of CJ2-gD2 causes no mortality and morbidity in mice.
Collectively, given these demonstrated preclinical immunogenicity and its unique safety profiles, CJ2-
gD2 possess unique advantages over any previously described vaccine candidate in prevention against
HSV-2 genital infection and disease.
Key features of CJ2-gD: Replication-defective and trans-dominant-negative; Avirulent and incapable of
establishment of latent infection; Immediate early overexpression of primary immunogen gD2; Able to
achieve high production titer through use of novel tetracycline repressor gene switch technology; and
ICP0 knock-out reduces cytotoxicity and major cytokine evasion mechanism.

Source: http://www.biotransfer.ca/LOD/lod_2010_08.pdf