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Abstract
No vaccines are approved for prevention or treatment of genital herpes. The focus of genital herpes vaccine trials has been on prevention using herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) alone or combined with glycoprotein B. These prevention trials did not achieve their primary end points. However, subset analyses reported some positive outcomes in each study. The most recent trial was the Herpevac Trial for Women that used gD2 with monophosphoryl lipid A and alum as adjuvants in herpes simplex virus type 1 (HSV-1) and HSV-2 seronegative women. Unexpectedly, the vaccine prevented genital disease by HSV-1 but not HSV-2. Currently, HSV-1 causes more first episodes of genital herpes than HSV-2, highlighting the importance of protecting against HSV-1. The scientific community is conflicted between abandoning vaccine efforts that include gD2 and building upon the partial successes of previous trials. We favor building upon success and present approaches to improve outcomes of gD2-based subunit antigen vaccines.
Financial & competing interests disclosure
This work was supported by NIH NIAID grants. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Several large vaccine trials have evaluated the prevention of genital herpes. Relatively limited efforts have been directed toward treating genital herpes by immunization.
The large prevention trials have all used recombinant subunit antigens that target herpes simplex virus type 2 entry molecules, particularly glycoprotein D (gD2).
None of the large trials has met its primary end point; however, subset analyses have revealed some successes, most notably preventing genital herpes simplex virus type 1 disease.
Antibodies emerged as an immune correlate of protection against herpes simplex virus type 1 in the recent Herpevac Trial for Women.
Different opinions exist in the scientific community as to whether to abandon gD2-based subunit vaccines or to build upon the successes of prior trials.
We are proponents of building upon the successes of a gD2-based vaccine and present approaches to improve outcomes.
One approach is to prevent herpes simplex virus (HSV) from evading vaccine-induced immunity. Two HSV immune evasion molecules, glycoproteins C and E, are expressed on the virion envelope and at the infected cell surface; therefore, they are potential targets of antibodies produced by immunization that can bind to the glycoproteins and block their immune evasion activities.
Another approach involves a more rational design of vaccine antigens to better target domains on HSV entry molecules that are essential for virus entry.
A third approach involves improving T-cell response using antigens and chemokines in a prime and pull method or by selecting peptide antigens known to stimulate robust CD8+ T-cell responses in humans.
A fourth approach is to improve vaccine formulations by constructing virus-like particle immunogens and using novel adjuvants that stimulate potent B- and T-cell systemic and mucosal responses.
A fifth approach involves better use of animal models to align study end points with those used in human trials, to define whether seroconversion in immunized subjects is a valid marker of infection and to determine whether sterile immunity is an unnecessary goal for a prophylactic vaccine.
The multiple approaches that are available to improve the protection provided by subunit antigen vaccines support continued exploration of gD2-based vaccines for prevention of genital herpes.