How is the mode of action of ∆gD-2 different than past failed attempts of other vaccine candidates?

We think that ∆gD-2 is more promising than other previous vaccine candidates because it provokes a different type of immune response against HSV-1 and HSV-2 that is more effective in preclinical models at clearing virus and preventing reactivation. Vaccination with ∆gD-2 elicits ADCC antibodies that facilitate the killing of infected cells and thereby block viral spread. Other vaccine candidates have induced a response that elicits primarily neutralizing antibodies that attach to free floating virus. However, the herpes virus can still move and spread cell to cell, thereby evading neutralizing antibodies and allowing persistence of the virus and viral reactivation.

Why did previous attempts to develop a herpes vaccine focus on neutralizing antibodies?

Decades of research in herpes vaccine development have focused primarily on subunit vaccines designed to elicit neutralizing antibodies against one or two viral proteins.⁶ When incubated with viral particles in vitro, neutralizing antibodies can prevent viral entry into cells. This strategy was effective as a vaccine for agents such as hepatitis B, however it had limited success with other pathogens such as herpes simplex viruses. The rationale for a subunit neutralizing antibody approach to HSV vaccine development emanated from observations that neutralizing antibodies that target viral glycoprotein D (gD) are elicited in response to natural human infection. While these antibodies do not prevent establishment of latency or prevent viral reactivation in pre-clinical models, they have been thought to limit the frequency and/or severity of clinical recurrences. Subunit vaccines comprised of recombinant gD alone or in combination with other viral proteins and with various adjuvants elicited high titer neutralizing antibodies and provided variable protection in pre-clinical models – but the clinical trial outcomes have been uniformly disappointing.

Why may ∆gD-2 work as both a preventative and a therapeutic vaccine?

Pending results from clinical trials, the same antibodies that activate cellular killing to prevent infection with herpes virus may also treat someone with recurrent disease. Following vaccination with ∆gD-2, the antibodies would rapidly clear the reactivated virus, thus preventing or ameliorating recurrent disease or transmission to others.

Why does the elimination of a surface protein lead to a different immune response?

Glycoprotein D (gD) competitively binds to a receptor called HVEM. The interactions between gD and HVEM represent an immune evasion mechanism as HVEM signaling plays a role in both generating and mediating ADCC responses. When gD binds to HVEM, it interferes with HVEM binding to an immune-stimulating protein called LIGHT. This results in a decrease in the generation of Fc-receptor antibodies as well as in the ability of Fc-receptor binding to mediate ADCC. Thus, the herpes virus blocks the host immune response through binding of gD to HVEM, avoiding the killing of infected cells. This is a key pathway the virus uses for immune evasion. As ΔgD-2 has no gD gene, it does not inhibit the HVEM-LIGHT system so the vaccine can stimulate a strong ADCC response.

If glycoprotein D (gD) is needed for viral cell entry, how does a gD-deleted vaccine replicate and stimulate an immune response?

HSV-2 contains a protein on its surface known as glycoprotein D (gD) which it needs to enter host cells. It is also essential for cell-to-cell spread of the virus. If the gD gene is deleted from HSV-2 and the virus is grown using a cell line that provides the HSV-1 gD protein to complement the missing surface protein, a hybrid virus is produced that is restricted to a single cycle of growth. When vaccinated, the gD-1 complemented HSV-2 virus replicates once, however the non-infectious progeny cannot spread from cell to cell as it lacks the gene that codes for glycoprotein D.

Mode of Action

Vaccination with a gD-deficient HSV induces immunity through ADCC antibodies, unlike gD-based candidate vaccines that induce predominantly neutralizing antibodies.

Adapted from Bolland & Pierce (2015).⁶