Vaccination against Herpes Zoster and Postherpetic Neuralgia

Herpes zoster (HZ), or shingles, is a disease of the sensory ganglion, nerves, and skin that results from reactivation of varicella-zoster virus (VZV) that has remained latent within sensory neurons after primary VZV infection (i.e., varicella, or chickenpox) [1–4]. HZ is characterized clinically by unilateral radicular pain and a vesicular rash that is generally limited to a single dermatome [1–6]. Neuropathic pain, likely due to neuronal damage and inflammation resulting from the multiplication and spread of the reactivated VZV, is a major manifestation of HZ, especially in older persons [1, 5–9]. The dermatomal HZ rash is frequently preceded by neuropathic pain; neuropathic pain usually accompanies the rash; and neuropathic pain and discomfort (e.g., allodynia and severe pruritus) may persist or develop after the dermatomal rash has healed—a debilitating complication of HZ known as “postherpetic neuralgia” (PHN) [5–7, 9–15]. The pain and discomfort associated with HZ can be prolonged and disabling, severely compromising the patient's quality of life and capacity to carry out activities of daily living [16]. The frequency and severity of HZ and PHN increase with increasing age; more than half of all recognized cases of HZ and most cases of clinically significant PHN occur in immunocompetent persons ⩾60 years of age [2–6, 9–15, 17]. Antiviral therapy reduces the duration and severity of HZ, but it does not prevent PHN [4, 9, 14, 15, 18–20]. PHN may persist for months or even years, and it is often refractory to treatment [19]. Thus, some means of preventing HZ and PHN is needed to reduce the burden of these painful conditions on older persons, who constitute a growing proportion of the populations of most developed countries [21–23]. In 1965, after 16 years of careful surveillance for varicella and HZ among the patients in his medical practice, Edgar Hope-Simpson published his seminal observations and a remarkably prescient hypothesis [3]. He observed that the incidence and severity of HZ increased with increasing age and hypothesized that this was due to an age-related decline in immunity to VZV. Hope-Simpson also observed that recurrences of HZ were relatively uncommon among immunocompetent persons (in contrast to the frequent recurrences of herpes simplex), and he hypothesized that this was because an episode of HZ induced an increase in immunity to VZV sufficient to “immunize” against a subsequent episode [3, 21]. Observations during the past 4 decades have supported the thesis that T cell-mediated immunity to VZV (VZV-CMI) is the major determinant of the risk and severity of HZ [2, 9, 21, 24–32]. The increased incidence and severity of HZ and PHN observed in older adults are closely correlated with a progressive age-related decline in VZV-CMI, whereas levels of antibody to VZV remain relatively constant with increasing age [2, 9, 21, 24, 27–32]. The development by Takahashi and his colleagues of the live attenuated Oka strain of VZV in the early 1970s made it possible to immunize VZV-naive children and adults against varicella [33–36] and to explore the possibility of boosting VZV-CMI in older adults [21, 31]. Subsequent studies have demonstrated that Oka-derived VZV vaccines can elicit a significant increase in VZV-CMI in immunocompetent older adults [32, 37–39] and can reduce the incidence and severity of HZ in recipients of bone marrow allografts [40, 41]. These observations led us to hypothesize that immunization of older adults with live attenuated Oka VZV vaccine would boost their waning VZVCMI and thereby provide protection against HZ and PHN [21, 31, 42, 43]. The Shingles Prevention Study (SPS), Department of Veterans Affairs Cooperative Study #403, was initiated to test this hypothesis by determining whether vaccination with an investigational live attenuated Oka/Merck VZV vaccine would decrease the incidence and/or severity of HZ and PHN in immunocompetent adults ⩾60 years of age. The results of the SPS presented here have been published elsewhere [18].