Developing A Tissue-Targeted Ocular HSV Therapeutic Vaccine

SUMMARY/ABSTRACT
Herpes simplex type virus-1 (HSV-1) infects over 3.72 billion people worldwide, including 200 million individuals
in the United States. Following primary infection of the cornea, HSV-1 establishes latency in sensory neurons of
the trigeminal ganglia (TG). Reactivation of HSV-1 from latently infected TG leads to shedding of the virus in
tears causing recurrent ocular herpetic disease, a major cause of infectious blindness in the Western world.
Currenly, an FDA-approved herpes simplex vaccine is unavailable. Our long-term goal is to develop an
immunotherapeutic ocular herpes vaccine. While a role for CD8+ T cells (but not CD4+ T cells) in reducing HSV-
1 reactivations from latently infected TG is gaining wider acceptance, the small numbers of functional tissue-
resident memory CD8+ TRM cells that are present in latently infected TG are not enough to prevent virus
reactivation. We have made several significant findings, during the last funding period: (1) HSV-specific CD8+ T
cells from “naturally protected” HLA-A*0201-positive asymptomatic individuals (who never develop recurrent
ocular herpetic disease despite being infected) mainly targeted five HSV-1 epitopes; (2) Phenotypic and
transcriptomicprofiling indicates that frequent HSV-specific CD8+ TRM cells, which expressed high levels of
tissue-homing and tissue-residency receptors (i.e. CXCR3, IL-2R/IL-15R, CD69, and CD103), found in the TG
of HSV-1 infected HLA-A*0201 transgenic rabbits (HLA Tg rabbits) are associated with decreased virus
shedding; (3) Topical ocular delivery to latently infected HLA Tg rabbits of prototype neurotropic adeno-
associated virus (AAV8) constructs, which express either the T cell attracting CXCL11 chemokine (CXCR3
ligand) or IL-2/IL-15 cytokines (IL-2Rb/IL-15Rb ligands), increased the frequency of TG-resident CD8+ TRM cells
specific to the five immunodominant epitopes; (4) Increased numbers of exhausted TG-resident CD8+ TRM cells
were associated with increased virus shedding in HLA Tg rabbits; and (5) Ex vivo blockade of T cells exhaustion
pathways PD-1, LAG-3 and TIGIT, ex vivo, in rabbit TG explants significantly reduced virus reactivation. Building
on the above published and preliminary results, the central hypothesis of this revised competitive renewal
proposal is that a TG-targeted vaccine that boosts the number, function and longevity of anti-viral TG-resident
CD8+TRM cells will reduce virus reactivation and shedding. Specific Aims: Aim 1: Test the hypothesis that a
tissue-targeted Prime/Pull/Keep therapeutic vaccine (designated as PPK vaccine) that incorporates the five
immunodominant HSV-1 CD8+ TRM cell epitopes (prime), CXCL11 (pull) and IL-2/IL-15 (keep) will boost the
number and longevity of TG-resident CD8+ TRM cells and significantly decrease HSV-1 reactivation in latently
infected HLA Tg rabbits. Aim 2: Test the hypothesis that tissue-targeted PPK vaccine combined with blockade
of PD-1, LAG-3 and/or TIGIT immune checkpoints will increase the number of functional CD8+ TRM cells in the
TG and produce even more robust protection in latently infected HLA Tg rabbits. This translational research is
expected to pave the way towards developing a PPK vaccine to protect against recurrent ocular herpes in man.

Grant Number: 5R01EY019896-13
NIH Institute/Center: NIH
Principal Investigator: Lbachir BenMohamed