Aging, Immunity, and the Varicella–Zoster Virus
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《新英格兰医药杂志》
Older people and their physicians are all too well acquainted with herpes zoster — commonly called shingles, from the Latin cingulum, or "girdle." Most recognize that aging creates a special vulnerability to this often severely painful skin rash caused by varicella–zoster virus (VZV). VZV is so named because varicella (chickenpox) represents the first encounter between the virus and the host, and herpes zoster represents the second. VZV persists in the sensory ganglia of the cranial nerves and the spinal dorsal-root ganglia after varicella resolves, and it may become reactivated after many decades of latency; molecular analyses of VZV DNA demonstrate that herpes zoster is a reappearance of one's childhood virus. The debilitating pain syndromes that accompany this reactivation have motivated the search for effective medical interventions. In this issue of the Journal, Oxman et al. (pages 2271–2284) report a new strategy that uses immunization with a live attenuated VZV vaccine, derived from the Oka strain, to reduce the morbidity associated with herpes zoster in healthy men and women older than 60 years of age. Pediatric Oka vaccines prevent varicella-related illness and death. A higher-potency Oka vaccine now promises to ameliorate recurrent VZV at the other end of the age spectrum.
VZV, like other herpesviruses, has evolved a genetic program that controls virus–host interactions so that its survival in the human population is ensured. The vesicular skin lesions of varicella and herpes zoster contain the high concentrations of infectious VZV that are needed for transmission to susceptible persons. During varicella outbreaks, VZV infects most children in a community, but those born later will escape infection unless the virus is reintroduced.
What perturbs the latent VZV genome is not understood, but reactivations that cause herpes zoster in adults provide a reliable source of transmissible virus. This resurfacing of VZV requires the movement of virions from the neurons, along axons, to the skin, where the virus must evade innate and adaptive host immune responses, spread from cell to cell, and form lesions that eventually penetrate the epidermis. The clinical experience indicates that these mechanisms of VZV immune evasion are most successful in the elderly.
The localized skin rash is not a serious problem, but the prodromal pain associated with herpes zoster is a sign of the active infection of sensory ganglia. The syndrome of zoster sine herpete also suggests direct involvement of the ganglia, and autopsy studies have confirmed the destruction of neurons and satellite cells during VZV reactivation.1 As a consequence of this pathogenic process, the benefit of antiviral therapy with acyclovir and related agents is limited in patients with herpes zoster. Neurologic damage begins before the characteristic dermatomal rash appears, and postherpetic neuralgia can be prolonged and intractable despite early antiviral therapy and aggressive pain management.
The concept that VZV takes advantage of waning immunity to ensure its persistence in the population by causing herpes zoster is supported by correlations between age and a diminished capacity of peripheral-blood T cells from persons who are immune, and therefore latently infected, to proliferate and produce interferon- when stimulated with VZV antigens in vitro. VZV-specific T-cell immunity is elicited by primary VZV infection and is required for the resolution of varicella. Memory CD4 and CD8 T cells that recognize VZV proteins remain readily detectable in younger adults, in whom herpes zoster is relatively rare (see graph). Robust memory-T-cell immunity to VZV may reflect either the extent of the initial expansion of VZV-specific T cells elicited during primary infection or periodic boosting on exposure to varicella or on abortive, subclinical reactivation (or some combination of these mechanisms). Loss of VZV-specific T-cell responses also defines periods of susceptibility to herpes zoster in immunocompromised patients. In contrast, anti-VZV IgG antibodies persist, and persons who are at risk for herpes zoster because of declining T-cell responses continue to be protected from varicella. Functionally, VZV-specific memory T cells probably control the later stages of reactivation that produce the typical signs of herpes zoster, rather than preventing latent VZV genomes in the ganglia from beginning to replicate. Over time, waning VZV-specific T-cell immunity may place a person in a "danger zone" for symptomatic VZV reactivation (see graph).
Host Factors in VZV Latency and Reactivation.
Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (blue line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (dashed green line) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV-specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for zoster occurrence (dashed blue line).
Giving inactivated varicella vaccine to recipients of hematopoietic-cell transplants results in an earlier reconstitution of VZV-specific T-cell immunity and a lower incidence of herpes zoster2 — demonstrating that VZV-specific T cells play a definitive role in maintaining the virus–host equilibrium in favor of the host. Similarly, the effectiveness of the high-potency Oka vaccine probably results from the restoration of VZV-specific T cells to a level above the threshold for herpes zoster — either by reversing a gradual decline from the original expansion of VZV-specific memory T cells or by substituting immunization for exogenous or endogenous reexposures that boost immunity (see graph). The effect of immunization against VZV demonstrates that naturally acquired immunity can be enhanced in a manner that controls the medical consequences of a persistent viral pathogen. It also suggests that it would be worthwhile to investigate the use of therapeutic vaccines against other herpesviruses in healthy and high-risk patients.
Translating the observations of Oxman et al. into clinical practice will require the licensing of higher-potency VZV vaccines, because the pediatric vaccines derived from the attenuated Oka strain are not adequate for boosting T-cell responses in older adults. Clinical experience is also required to determine the duration of protection, as well as whether repeated doses should be given and, if so, at what intervals. The burden-of-illness end point used by Oxman et al. is a composite of the effects on incidence and morbidity. Although the effect of vaccination on incidence was more limited in persons 70 years of age or older than in those who were 60 to 69 years old, the effect on the burden of illness was substantial in the former group because the severity and duration of pain were worse. More information is needed to determine whether these benefits are sustained in the very old.
What is certain is that although reactivation of VZV is rarely life-threatening, the effect of herpes zoster and postherpetic neuralgia on the quality of life is serious for many older people. According to the 2000 Census, 35.0 million people in the United States were older than 65 — a 12.0 percent increase from 1990 — and this trend will be even more dramatic as the baby boomers begin to turn 60. The possibility that a feared consequence of aging may be minimized or avoided is an important advance.
Dr. Arvin reports having received consultation fees from Merck.
Source Information
Dr. Arvin is a professor of pediatrics and microbiology and immunology at the Stanford University School of Medicine, Stanford, Calif.
References
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingham R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635-645.
Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hemapoietic-cell transplants. N Engl J Med 2002;347:26-34.(Ann Arvin, M.D.)
VZV, like other herpesviruses, has evolved a genetic program that controls virus–host interactions so that its survival in the human population is ensured. The vesicular skin lesions of varicella and herpes zoster contain the high concentrations of infectious VZV that are needed for transmission to susceptible persons. During varicella outbreaks, VZV infects most children in a community, but those born later will escape infection unless the virus is reintroduced.
What perturbs the latent VZV genome is not understood, but reactivations that cause herpes zoster in adults provide a reliable source of transmissible virus. This resurfacing of VZV requires the movement of virions from the neurons, along axons, to the skin, where the virus must evade innate and adaptive host immune responses, spread from cell to cell, and form lesions that eventually penetrate the epidermis. The clinical experience indicates that these mechanisms of VZV immune evasion are most successful in the elderly.
The localized skin rash is not a serious problem, but the prodromal pain associated with herpes zoster is a sign of the active infection of sensory ganglia. The syndrome of zoster sine herpete also suggests direct involvement of the ganglia, and autopsy studies have confirmed the destruction of neurons and satellite cells during VZV reactivation.1 As a consequence of this pathogenic process, the benefit of antiviral therapy with acyclovir and related agents is limited in patients with herpes zoster. Neurologic damage begins before the characteristic dermatomal rash appears, and postherpetic neuralgia can be prolonged and intractable despite early antiviral therapy and aggressive pain management.
The concept that VZV takes advantage of waning immunity to ensure its persistence in the population by causing herpes zoster is supported by correlations between age and a diminished capacity of peripheral-blood T cells from persons who are immune, and therefore latently infected, to proliferate and produce interferon- when stimulated with VZV antigens in vitro. VZV-specific T-cell immunity is elicited by primary VZV infection and is required for the resolution of varicella. Memory CD4 and CD8 T cells that recognize VZV proteins remain readily detectable in younger adults, in whom herpes zoster is relatively rare (see graph). Robust memory-T-cell immunity to VZV may reflect either the extent of the initial expansion of VZV-specific T cells elicited during primary infection or periodic boosting on exposure to varicella or on abortive, subclinical reactivation (or some combination of these mechanisms). Loss of VZV-specific T-cell responses also defines periods of susceptibility to herpes zoster in immunocompromised patients. In contrast, anti-VZV IgG antibodies persist, and persons who are at risk for herpes zoster because of declining T-cell responses continue to be protected from varicella. Functionally, VZV-specific memory T cells probably control the later stages of reactivation that produce the typical signs of herpes zoster, rather than preventing latent VZV genomes in the ganglia from beginning to replicate. Over time, waning VZV-specific T-cell immunity may place a person in a "danger zone" for symptomatic VZV reactivation (see graph).
Host Factors in VZV Latency and Reactivation.
Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (blue line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (dashed green line) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV-specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for zoster occurrence (dashed blue line).
Giving inactivated varicella vaccine to recipients of hematopoietic-cell transplants results in an earlier reconstitution of VZV-specific T-cell immunity and a lower incidence of herpes zoster2 — demonstrating that VZV-specific T cells play a definitive role in maintaining the virus–host equilibrium in favor of the host. Similarly, the effectiveness of the high-potency Oka vaccine probably results from the restoration of VZV-specific T cells to a level above the threshold for herpes zoster — either by reversing a gradual decline from the original expansion of VZV-specific memory T cells or by substituting immunization for exogenous or endogenous reexposures that boost immunity (see graph). The effect of immunization against VZV demonstrates that naturally acquired immunity can be enhanced in a manner that controls the medical consequences of a persistent viral pathogen. It also suggests that it would be worthwhile to investigate the use of therapeutic vaccines against other herpesviruses in healthy and high-risk patients.
Translating the observations of Oxman et al. into clinical practice will require the licensing of higher-potency VZV vaccines, because the pediatric vaccines derived from the attenuated Oka strain are not adequate for boosting T-cell responses in older adults. Clinical experience is also required to determine the duration of protection, as well as whether repeated doses should be given and, if so, at what intervals. The burden-of-illness end point used by Oxman et al. is a composite of the effects on incidence and morbidity. Although the effect of vaccination on incidence was more limited in persons 70 years of age or older than in those who were 60 to 69 years old, the effect on the burden of illness was substantial in the former group because the severity and duration of pain were worse. More information is needed to determine whether these benefits are sustained in the very old.
What is certain is that although reactivation of VZV is rarely life-threatening, the effect of herpes zoster and postherpetic neuralgia on the quality of life is serious for many older people. According to the 2000 Census, 35.0 million people in the United States were older than 65 — a 12.0 percent increase from 1990 — and this trend will be even more dramatic as the baby boomers begin to turn 60. The possibility that a feared consequence of aging may be minimized or avoided is an important advance.
Dr. Arvin reports having received consultation fees from Merck.
Source Information
Dr. Arvin is a professor of pediatrics and microbiology and immunology at the Stanford University School of Medicine, Stanford, Calif.
References
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingham R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635-645.
Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hemapoietic-cell transplants. N Engl J Med 2002;347:26-34.(Ann Arvin, M.D.)