A Paradigm Shift: Vaccine-Induced Antibodies as an Immune Correlate of Protection Against Herpes Simplex Virus Type 1 Genital Herpes

Abstract

More than a half-billion people worldwide are infected with genital herpes [1]. During primary infection, herpes simplex virus (HSV) establishes latency in lumbosacral dorsal root ganglia. The natural history of genital herpes is characterized by frequent episodes of recurrences that may be symptomatic or asymptomatic and that transmit virus to sexual partners or from mother to infant during labor and delivery [2–4]. Genital herpes increases the risk of human immunodeficiency virus (HIV) acquisition and transmission by 3to 4-fold, which underscores the importance of a vaccine to prevent genital herpes [5]. The Herpevac Trial for Women was a large, multicenter, randomized controlled trial of HSV-2 glycoprotein D (gD2) subunit antigen vaccine administered with monophosphoryl lipid A and alum to HSV-1 and HSV-2 doubly seronegative women [6].The primary end point was prevention of genital herpes disease caused by HSV-1 and HSV-2 between months 2 (1 month after the second of 3 doses) and 20. Disease was defined as clinically compatible signs and symptoms confirmed by viral culture, seroconversion, or both. That end point was not achieved. Prevention of HSV-1 or HSV-2 infection, with or without disease, was a secondary end point. Infection was defined by seroconversion after the second vaccine dose (months 2–20) or after the third vaccine dose (months 7–20). Significant reduction in infection and disease was noted for HSV-1, but not HSV-2, after the second and third immunizations. The highest vaccine efficacy against HSV-1 occurred after the third immunization and was 82% among confirmed cases of genital disease. Overall, HSV-1 comprised 60% of the genital herpes infections in the placebo group, which is consistent with the changing epidemiology of infection in North America that is shifting toward HSV-1 as the most common cause of primary genital herpes [7]. It is not surprising that a gD2 vaccine protected against HSV-1 as HSV gD1 and gD2 share >80% amino acid sequence homology; however, it is surprising that the vaccine protected only against HSV-1. Ongoing studies are attempting to explain this perplexing result. In this issue of The Journal of Infectious Diseases, Belshe et al evaluated the immune correlates of protection against HSV-1 genital disease in women vaccinated with the GSK gD2 vaccine. The authors present a more detailed analysis of the immune correlates of protection than reported initially in the Herpevac Trial for Women [6]. Enzyme-linked immunosorbent assay (ELISA) antibody titers, rather than CD4 or CD8 T-cell responses, correlated with protection against HSV-1. Among subjects who received the gD2 vaccine, HSV-1 infection rates were 2.5% in individuals with the lowest ELISA titers compared with <1% in subjects with the highest antibody responses. Higher antibody titers were associated with lower rates of both HSV-1 infection and disease. Antibody responses correlated with CD4 T-cell responses; however, the CD4 T-cell responses did not correlate with vaccine efficacy, suggesting that the association between antibody and CD4 T-cell responses was relatively weak. Many clinicians and researchers will be surprised to learn that antibodies, rather than T cells, correlated with protection against HSV-1 genital infection and disease. Severe HSV recurrent disease is common when CD4 and CD8 T cells decline in HIV-1–infected individuals or when subjects are treated Received and accepted 19 November 2013; electronically published 27 November 2013. Correspondence: Harvey M. Friedman, MD, Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, 522E Johnson Pavilion, Philadelphia, PA 19104 (hfriedma@mail.med.upenn.edu). The Journal of Infectious Diseases 2014;209:813–5 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jit658