Immunological Considerations for the Development of an Effective Herpes Vaccine

Abstract

Research is underway to develop a vaccine to prevent and cure infection from herpes simplex virus (HSV). It emphasizes the critical need for immunization to address public health issues and the shortcomings of existing treatment options. Furthermore, studies on the HSV vaccine advance the field of immunology and vaccine creation, which may help in the battle against other viral illnesses. The current lack of such a vaccine is, in part, due to herpes viral latency in sensory ganglions. Current vaccines rely on tissue-resident memory CD8⁺ T cells, which are known to provide protection against subsequent HSV reinfection and reactivation without correlating with other immune subsets. For that reason, there is no effective vaccine that can provide protection against latent or recurrent herpes infection. This review focuses on conventional methods for evaluating the efficacy of a herpes vaccine using differential CD8⁺ T cells and important unaccounted immune aspects for designing an effective vaccine against herpes.

Keywords: CD8 T cells; adaptive immunity; herpes simplex virus (HSV); innate immunity; memory T cells; vaccine design; virus latency.

Figure 1

The ocular route of HSV-1 infection from the mouth and/or eye to viral latency in trigeminal ganglion. (1) Primary viral infection and replication; (2) retrograde viral transmission to trigeminal ganglion (TG); (3) viral latency in sensory neurons/trigeminal ganglion; (4) reactivation of latent viruses; (5) reinfection to oral mucosa and virus shedding.

Figure 2

Kinetics of CD8 T cells in relation to functional versus non-functional epitopes. Functional epitopes (on the left) appear to induce long-lived effector memory and tissue-resident CD8⁺ T cells that reside within the mucosal tissues and related ganglions compared to non-functional epitopes of herpes antigens, which induce short-lived effector memory T cells (on the right). Upon reactivation of functional epitopes, naïve CD8 T cells are matured to central memory by the induction of pro-inflammatory cytokines. EM/RM CD8 T cells show unique phenotypic characteristics that support the function of viral clearance and long-term precursor of effector and memory CD8 T cells (on the left). On contrast, non-functional epitopes generated short-lived memory T cells with a major phenotype of central memory more than EM/RM CD8 T cells (on the right). Based on the high-affinity recognized antigen, long-lived effector memory T cells are generated from these functional epitopes of the antigen with high frequency compared to central memory or naïve T cells and characterized by higher expression of activity and tissue residency markers (CD103^high, CD69^high, CD11a^high, CD49a^high, CCR5^high, and IFN-γ^high).