Ocular Herpes Simplex: Changing Epidemiology, Emerging Disease Patterns, and the Potential of Vaccine Prevention and Therapy JAY S. PEPOSE, MD, PHD, TAMMIE L. KEADLE, DVM, PHD, AND LYNDA A. MORRISON, PHD ● PURPOSE: To review the changing epidemiology of herpes simplex virus infection, emerging patterns of herpetic ocular disease, and the challenges and promise of herpes simplex virus vaccine therapy. ● DESIGN: Perspective. ● METHODS: Literature review. ● RESULTS: An epidemic increase in genital herpes sim- plex type 2 infection is reflected in a 30% increase in HSV-2 antibodies in the United States since 1976. Approximately one in four people in the United States over age 30 is infected with HSV-2. Primary acquisition of herpes simplex type 1 is becoming progressively delayed in many industrialized countries, in contrast to developing nations where the virus is acquired early in life and is ubiquitous. Changes in sexual behavior among young adults have been associated with a recent increase in genital HSV-1 infection, resulting from oral-genital rather than genital-genital contact. Clinical trials of HSV vaccines using selected herpes simplex virus type 2 proteins mixed in adjuvant have shown limited efficacy in seronegative women, but not in men. ● CONCLUSIONS: The recent epidemic of genital herpes simplex type 2 infection is likely to result in an increase in neonatal ocular herpes and in delayed cases of acute retinal necrosis syndrome. The increase in genital HSV-1 may lead to industry production of vaccines that contain components of both HSV-1 and HSV-2 targeted toward limiting genital disease and transmission. As newer herpes simplex vaccines become available, oph- thalmologists must be vigilant that a boost in immunity against HSV does not have a paradoxical effect in exacerbating break-through cases that develop immune- mediated herpes simplex stromal keratitis. (Am J Oph- thalmol 2006;141:547–557. © 2006 by Elsevier Inc. All rights reserved.) T HE WORD “HERPES” DERIVES FROM THE GREEK VERB meaning “to creep or crawl” and was used to describe spreading cutaneous lesions in the writings of Hippocrates some 25 centuries ago. 1 Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) spread from sites of initial infection in skin or mucosal surfaces to neuronal cell bodies to establish latent infection, forming a unique long-term relationship with their host. Phylogenetic studies indicate that all eight members of the human herpesvirus family were likely derived from an ancestral viral genome. 2 Diversification of HSV-1 and HSV-2 dates back approximately 8 to 10 million years, 3 concomitant with evolution of specific anatomic tropisms for the epithelium of the oropharynx and the genital tract, respectively. For HSV-1 and HSV-2 to diverge and take on their distinct tropisms, oral and genital sites had to become microbiologically isolated from each other while oral-oral and genital-genital contact had to be maintained. It has been postulated that certain changes in the sexual behavior of ancient humans— continual sexual attractiveness of the ancestral human female throughout the entire menstrual cycle (with an attendant increase in the frequency of sexual intercourse) and the adoption of close face-to-face mating—provided the necessary conditions for the viral divergence of HSV-1 and HSV-2 2 as well as for their disparate pathobiology. Just as HSV biology and virulence are influenced by evolving viral and host genetics, recent changes in soci- Accepted for publication Oct 11, 2005. From the Pepose Vision Institute, St Louis, Missouri (J.S.P.); the Department of Ophthalmology and Visual Sciences, Washington Uni- versity School of Medicine, St Louis, Missouri (J.S.P., T.L.K.); and the Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri (L.A.M.). Supported in part by Public Health Service Grant RO1 EY11850 and the Midwest Cornea Research Foundation, St Louis, Missouri and PHS award AI57573 and GA2020 from the Fight for Sight Research Division of Prevent Blindness America. Inquiries to Jay S. Pepose, MD, PHD, Pepose Vision Institute, 16216 Baxter Road, Suite 205, Chesterfield, MO 63107; e-mail: jpepose@ peposevision.com © 2006 BY ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/06/$32.00 547 doi:10.1016/j.ajo.2005.10.008