Single and Combination Herpes Simplex Virus Type 2 Glycoprotein Vaccines Adjuvanted with CpG Oligodeoxynucleotides or Monophosphoryl Lipid A Exhibit Differential Immunity That Is Not Correlated to Protection in Animal Models

Abstract

Despite several attempts to develop an effective prophylactic vaccine for HSV-2, all have failed to show efficacy in the clinic. The most recent of these failures was the GlaxoSmithKline (GSK) subunit vaccine based on the glycoprotein gD with the adjuvant monophosphoryl lipid A (MPL). In a phase 3 clinical trial, this vaccine failed to protect from HSV-2 disease, even though good neutralizing antibody responses were elicited. We aimed to develop a superior, novel HSV-2 vaccine containing either gD or gB alone or in combination, together with the potent adjuvant CpG oligodeoxynucleotides (CPG). The immunogenic properties of these vaccines were compared in mice. We show that gB/CPG/alum elicited a neutralizing antibody response similar to that elicited by gD/CPG/alum vaccine but a significantly greater gamma interferon (IFN-␥) T cell response. Furthermore, the combined gB-gD/CPG/alum vaccine elicited significantly greater neutralizing antibody and T cell responses than gD/MPL/alum. The efficacies of these candidate vaccines were compared in the mouse and guinea pig disease models, including a novel male guinea pig genital disease model. These studies demonstrated that increased immune response did not correlate to improved protection. First, despite a lower IFN-␥ T cell response, the gD/CPG/alum vaccine was more effective than gB/CPG/alum in mice. Furthermore, the gB-gD/CPG/alum vaccine was no more effective than gD/MPL/alum in mice or male guinea pigs. We conclude that difficulties in correlating immune responses to efficacy in animal models will act as a deterrent to researchers attempting to develop effective HSV vaccines.

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs

“…The trivalent vaccine group outperformed gD2 alone despite inducing lower neutralizing antibody titers with and without complement, suggesting that neutralizing antibody titers are not sufficient to explain the vaccine protection [40]. It is possible that antibody-dependent cellular cytotoxicity contributed significantly to vaccine protection as reported for HSV-2 ΔgD2, a gD2 null live virus vaccine [41, 42].…”

The current state of vaccine development for ocular HSV-1 infection

“…Do these immune responses inhibit or exacerbate HSK? Data from experimental models suggest that these questions remain incompletely understood [82,86]. …”

Prospects and perspectives for development of a vaccine against herpes simplex virus infections

“…Likewise, natural killer cell recruitment and activation is in part dependent on interferon signaling. Augmentation of immune responses to HSV has been achieved in murine models with co-administration of the TLR9 agonist cPG [64]. Adjuvant development focused on maximizing stimulation of innate immunity may have a large impact on future candidate HSV vaccines [65,66].…”

“…Studies using lectin-purified gD and gB subunit vaccine demonstrated similar protection, not only against primary infection, but recurrent disease [79]. Adjuvant choice plays a crucial role in protection in adjuvanted glycoprotein studies in the guinea pig model, with adjuvants capable of eliciting robust cellular immune responses in additional to antibody responses appearing to enhance protection against disease [64,80-86]. Other novel routes of delivery of adjuvanted HSV glycoproteins have been evaluated, including intranasal administration [87,88].…”