Towards a rational design of an asymptomatic clinical herpes vaccine: the old, the new, and the unknown

Abstract

The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally "protected" exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4(+) and CD8(+) T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation "asymptomatic" clinical herpes vaccines, and discuss future mucosal "asymptomatic" prime-boost vaccines that could optimize local protective immunity.

Figure 1

The majority of ocular herpes vaccines are injected parenterally, and although they induced strong systemic immune responses, they failed to generate significant local immune responses either in the eye or in trigeminal ganglia (TG). Local immune responses at these sites are likely needed to prevent virus transmission and to reduce virus replication, which should eventually reduce viral latency/reactivation and limit the severity of ocular herpes. Several results from our lab strongly suggest that there is linear association between presence of “asymptomatic” CD8⁺ T cells (bleu circles) in the TG and ocular mucosal immune system with the lack of eye disease. In contrast, the absence of asymptomatic CD8⁺ T cells and presence of symptomatic CD8⁺ T cells (red circles) may increase the rate of HSV reactivation and pathology. The upper panel shows scenario of an asymptomatic HSV-1 infection and the lower panel shows symptomatic HSV-1 infection and eye disease.

Figure 2

Illustration of steps in developing an asymptomatic lipopeptides-base herpes vaccine. The lipopeptide vaccine formulation is developed following multistep strategy. This starts from the identification of a symptomatic and asymptomatic herpes population and highly immunogenic HSV proteins. Next, asymptomatic CD4⁺ and CD8⁺ T-cell epitopes are discovered and covalently linked to a TLR2 agonist (Palmitic acid) leading to self-adjuvanting lipopeptides [12].

Figure 3

A representative diagram showing the advantages of lipopeptide-based vaccines strategy, as elaborated in the text (see Section 6).