Saturday, March 12, 2011

Novel Recombinant HSV-2 Vaccine?

Harvard Herpes investigators Natalie Akhrameyeva  and colleagues are suggesting a novel strategy to combat Herpes Simplex Virus-2 (HSV-2) through the use of a dominant-negative recombinant subunit vaccine that expresses HSV's glycoprotein D. 

Currently, HSV1 and HSV2 therapies have a number of drawbacks: treatments that reduce asymptomatic and symptomatic recurrences must be taken daily, they are unable to block latent infection, and they have generally failed as antivirals to block  further spread and infection. Provided this and the fact that 50-60 million Americans are currently plagued with HSV-2, the will  to create an efficacious  and safe vaccine is vast. The ideal vaccine for HSV would then elicit  broad and robust humoral and CD4/8+ T-cell responses, provide life long immunity (likely then a live, attenuated virus), and not trigger outbreaks for latently infected persons.

In this paper, Akhrameyeva et al. use tetracycline gene-switch technology (T-REx) and a dominant-negative mutant of HSV-1 replication binding protein UL9 (UL9-C535C) to construct a replication-defective HSV-1 recombinant (CJ83193) whose ICP0 gene (infected cell polypeptide 0) was replaced with mutant UL9-C535C controlled by a tetracycline operator (tetO) with an hCMV major immediate-early promoter. They took this recombinant HSV-1 went on to replace its essential UL9 with a HSV-1 glycoprotein D (gD) gene. And given  its chimeric background, this secondary recombinant vaccine, dubbed CJ9-gD, when tested in mice, was able to elicit a robust and lasting specific humoral and T-cell response. They then revised this chimera to produce an HSV-2 recombinant (CJ9-gD2) to specifically address HSV-2. This vaccine, when tested in cultured cells was able to inhibit wild-type HSV-2 replication while remaining avirulent in mice when inoculated intracerebrally. It was able to induce a specific  HSV-2 gD (gD2) neutralizing antibody response and T-cell response in immunized mice--additionally(!) having the capacity to protect mice after a  post-immunization challenge and the establishment of latent viral DNA (decreased by ten-fold) compared to sham-vaccinated mice. If this data is indeed real and can pass the numerous testing trials, this vaccine is a candidate to become the next recombinant viral vaccine.

The sheer number of nondescript alpha-numeric terms in this paper is a bit daunting and non-reader-friendly but this is certainly an interesting look at vaccine design and the logic behind it.

- Vy Tran

Akhrameyeva N, Pengqei Z, Sugiyama N, Behar S, Yao F.  Development of a Glycoprotein D-expressing Dominant-negative and Replication-defective HSV-2 Recombinant Viral Vaccine against HSV-2 Infection in Mice. J. Virology: JVI Accepts, published online ahead of print on 9 March 2011

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