Varicella–Zoster Virus Vaccine — Grown-ups Need It, Too
http://www.100md.com
《新英格兰医药杂志》
A few years ago, I had zoster (shingles) — no surprise, since I was over 60 years of age, and zoster is usually a disease of later life. Fortunately, both the rash and the pain disappeared within a few days. I was grateful not to have to endure the dreaded chronic pain of postherpetic neuralgia, which can last for months or years, and there was no complicating zoster paresis, myelopathy, or vasculopathy. I recalled my first encounter with varicella–zoster virus (VZV) as a child with varicella (chickenpox); I had to stay home from school for nearly a week (not so terrible) and could not join my friends to play ball outside (that was terrible). Now, the acute pain of zoster confirmed what I had learned during years of caring for patients with zoster and its complications — that for older adults, all these problems can be far more serious than childhood varicella usually is.
In the United States, zoster affects hundreds of thousands of people annually, most of whom are older than 50 years of age. Because VZV becomes latent in cranial-nerve ganglia, dorsal-root ganglia, and autonomic ganglia along the entire neuraxis, zoster can crop up anywhere on the body. The pain often is long-lasting. In 36.6 percent of patients with zoster who are older than 60 years of age and in 47.5 percent of those older than 70, pain persists for more than one year.1 The pain is not easily controlled. The large number of topical medications (e.g., capsaicin, ketamine, and lidocaine patches) and oral medications (e.g., gabapentin, carbamazepine, amitriptyline, and even narcotic agents) used to treat postherpetic neuralgia attest to the lack of a single effective medication. Furthermore, in immunocompromised persons, zoster can recur, is more protracted, and is associated with a greater incidence of VZV myelitis (weakness and incontinence) and of vasculopathy (changes in mental status, speech disturbances, seizure, and severe motor deficit), which kills nearly one third of patients.2
The status of immunity to VZV among elderly persons reflects the waning cell-mediated immunity to the virus.3 Thus, zoster may be seen as a continuum, from its occurrence among elderly persons to its greater incidence among patients with more seriously immunocompromised status — those undergoing treatment for cancer, those with AIDS, and recipients of organ transplants. Nevertheless, a waning VZV-specific cell-mediated immunity is stimulated by naturally occurring zoster or immunization against VZV. For example, the frequency of VZV-specific T lymphocytes is higher among older patients who have had zoster than among age-matched controls, and it persists for at least two years.4 Furthermore, among people 55 to 87 years of age with immunity to VZV who were given the live attenuated Oka-strain VZV vaccine, the frequency of T-cell response to VZV was similar to that among those 35 to 40 years of age. The boost in cell-mediated immunity to VZV was maintained over 24 months, and the dose of the virus and the age of those vaccinated did not significantly influence the response.5
These findings set the stage for the large-scale Shingles Prevention Study reported by Oxman and colleagues in this issue of the Journal,6 the goal of which was to determine the effect of vaccination against VZV in preventing zoster. Healthy adults 60 years of age or older (median age, 69 years) were vaccinated with an investigational attenuated Oka/Merck "zoster" vaccine containing 18,700 to 60,000 plaque-forming units of virus — considerably more than the approximately 1350 plaque-forming units in the Oka/Merck VZV vaccine that has been administered to American children since approval by the Food and Drug Administration (FDA) in 1995. More than 38,000 recipients of the zoster vaccine were followed closely for three years.
The results are impressive. The double-blind, placebo-controlled study showed a 61 percent reduction in pain and discomfort (the burden of illness) in herpes zoster, and the incidence of postherpetic neuralgia in the vaccine group was reduced by 66 percent. The incidence of zoster in the placebo group was 11.12 per 1000 person-years. This percentage approximates the results of an epidemiologic survey performed a decade ago, which showed an incidence of zoster exceeding 10 cases per 1000 person-years among people older than 75 years.7 The elderly population has been rapidly increasing — the U.S. Census Bureau conservatively estimated that the population 85 years of age or older increased by 1 million from 1995 to 2005,8 and the population 60 to 85 years of age increased even more. In fact, the high incidence of zoster found in the placebo group in the Shingles Prevention Study points to an urgent need for effective therapy. Although oral antiviral therapy shortens the duration of zoster and analgesic medications provide some relief of pain, "an ounce of prevention. . . ."
Like the live varicella vaccine administered to children, live zoster vaccine appears to be safe and effective clinically. Serious adverse effects or deaths occurred in 1.4 percent of recipients in both the vaccine and placebo groups. In a subgroup of more than 6000 subjects who kept daily diaries of minor adverse events for a period of 42 days after vaccination, erythema, pain or tenderness, swelling, pruritus, or other adverse events at the injection site were reported in 48 percent of vaccine recipients as compared with 17 percent of placebo recipients. In the same subgroup, serious adverse events were reported in 1.9 percent of vaccine recipients, as compared with 1.3 percent of placebo recipients, and the difference was statistically significant (P=0.03). Furthermore, although the Oka/Merck VZV vaccine can, on rare occasions, unmask a childhood immunodeficiency disorder, no cases of dissemination of the virus were reported that might have been attributed to the zoster vaccine in a person with an undiagnosed disorder such as lymphoma or leukemia.
Should zoster vaccine be recommended for every VZV-seropositive, middle-aged adult who is healthy (i.e., without immunocompromise due to cancer, drug therapy, or AIDS) and who has not had zoster? Two main factors affect the answer to this question. First is the future risk of zoster among middle-aged adults who were vaccinated in childhood as compared with the current risk. By 2047, most, although not all, middle-aged Americans will have received VZV vaccine in childhood. Like the wild-type VZV, the Oka/Merck vaccine virus becomes latent in ganglia.9 If the viral burden is less in the ganglia of adults who were vaccinated in infancy, then the incidence of zoster may be reduced in those adults as compared with those who as children had naturally occurring chickenpox. Alternatively, the cell-mediated immunity to VZV in vaccine recipients may be reduced by their exposure to fewer cases of varicella, which would normally boost immune responsiveness, supporting the need to vaccinate middle-aged adults.
Second, the cost-effectiveness of vaccination must be considered before such a recommendation can be made. The Shingles Prevention Study used a disease-specific measure, the burden of illness due to herpes zoster,10 to assess severity of illness among the study participants. Herpes-zoster burden-of-illness scores correlated with the number of quality-adjusted life-years gained,10 the standard denominator of cost-effectiveness.11 As with any new therapy, the cost-effectiveness of the vaccine will depend on its price. To nonindigent recipients of the currently used childhood VZV vaccine (Varivax), the price of vaccination is between $50 and $100 (the sum of the cost of vaccine plus the visit or facility fee). An adult vaccine might cost more, given its greater potency. Nevertheless, the zoster vaccine appears to have been highly cost-effective in the Shingles Prevention Study (i.e., in the range of $2,000 per quality-adjusted life-year gained, even assuming a vaccine cost of $500). This admittedly rough estimate does not include the cost of complications related to vaccination or the provider's time required to administer it. However, $2,000 per quality-adjusted life-year gained is probably an underestimation of the vaccine's cost-effectiveness, since gains in the quality of life among vaccine recipients are likely to persist beyond the three years of the study period. Thus, the vaccine should fall well within the traditional cutoff point of $50,000 per quality-adjusted life-year used to evaluate new therapies, and it would appear to be at least as cost-effective as other currently used vaccines.12 Zoster vaccine may even be cost-saving.
If the FDA were to require another large multi-institutional study before zoster vaccine is licensed, it will be another decade until the findings of Oxman et al. can be confirmed or repudiated. Since zoster and its attendant neurologic complication of postherpetic neuralgia are common and serious, it seems prudent to market the zoster vaccine, but only if a large number of those vaccinated are followed closely, particularly those over 85 years of age, among whom the cell-mediated immune response to VZV is likely to be less robust than among those 20 to 25 years younger. This follow-up would allow not only a further determination of possible risk to vaccine recipients but also an estimation of the vaccine's effectiveness in the population of the oldest old. The Census Bureau projects that by the year 2040, there will be 8 million to 13 million Americans 85 years of age or older.8 It is hoped that the use of a zoster vaccine will reduce or eradicate zoster and its related complications, just as measles vaccine has wiped out not only measles but also measles-associated postinfectious encephalomyelitis and subacute sclerosing panencephalitis in regions where the vaccine is used.
Even though my episode of zoster was brief, I would gladly have paid to receive the zoster vaccine, knowing that the risk of the development of zoster might have been 50 percent less. Grown-ups should welcome the zoster vaccine. We may need it more than children do.
Source Information
From the Departments of Neurology and Microbiology, University of Colorado Health Sciences Center, Denver.
References
de Moragas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm 1957;75:193-6.
Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. Ann Neurol 1983;14:543-553.
Miller AE. Selective decline in cellular immune response to varicella-zoster virus in the elderly. Neurology 1980;30:582-587.
Hayward A, Levin M, Wolf W, Angelova G, Gilden D. Varicella-zoster virus-specific immunity after herpes zoster. J Infect Dis 1991;163:873-875.
Levin MJ, Murray M, Rotbart HA, Zerbe GO, White CJ, Hayward AR. Immune response of elderly individuals to a live attenuated varicella vaccine. J Infect Dis 1992;166:253-259.
Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605-1609.
Campion EW. The oldest old. N Engl J Med 1994;330:1819-1820.
Gelb LD, Dohner DE, Gershon AA, et al. Molecular epidemiology of live, attenuated varicella virus vaccine in children with leukemia and in normal adults. J Infect Dis 1987;155:633-640.
Coplan PM, Schmader K, Nikas A, et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J Pain 2004;5:344-56.
Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA 1996;276:1253-1258.
Prosser LA, Ray GT, O'Brien M, Kleinman K, Santoli J, Lieu TA. Preferences and willingness to pay for health states prevented by pneumococcal conjugate vaccine. Pediatrics 2004;113:283-290.(Donald H. Gilden, M.D.)
In the United States, zoster affects hundreds of thousands of people annually, most of whom are older than 50 years of age. Because VZV becomes latent in cranial-nerve ganglia, dorsal-root ganglia, and autonomic ganglia along the entire neuraxis, zoster can crop up anywhere on the body. The pain often is long-lasting. In 36.6 percent of patients with zoster who are older than 60 years of age and in 47.5 percent of those older than 70, pain persists for more than one year.1 The pain is not easily controlled. The large number of topical medications (e.g., capsaicin, ketamine, and lidocaine patches) and oral medications (e.g., gabapentin, carbamazepine, amitriptyline, and even narcotic agents) used to treat postherpetic neuralgia attest to the lack of a single effective medication. Furthermore, in immunocompromised persons, zoster can recur, is more protracted, and is associated with a greater incidence of VZV myelitis (weakness and incontinence) and of vasculopathy (changes in mental status, speech disturbances, seizure, and severe motor deficit), which kills nearly one third of patients.2
The status of immunity to VZV among elderly persons reflects the waning cell-mediated immunity to the virus.3 Thus, zoster may be seen as a continuum, from its occurrence among elderly persons to its greater incidence among patients with more seriously immunocompromised status — those undergoing treatment for cancer, those with AIDS, and recipients of organ transplants. Nevertheless, a waning VZV-specific cell-mediated immunity is stimulated by naturally occurring zoster or immunization against VZV. For example, the frequency of VZV-specific T lymphocytes is higher among older patients who have had zoster than among age-matched controls, and it persists for at least two years.4 Furthermore, among people 55 to 87 years of age with immunity to VZV who were given the live attenuated Oka-strain VZV vaccine, the frequency of T-cell response to VZV was similar to that among those 35 to 40 years of age. The boost in cell-mediated immunity to VZV was maintained over 24 months, and the dose of the virus and the age of those vaccinated did not significantly influence the response.5
These findings set the stage for the large-scale Shingles Prevention Study reported by Oxman and colleagues in this issue of the Journal,6 the goal of which was to determine the effect of vaccination against VZV in preventing zoster. Healthy adults 60 years of age or older (median age, 69 years) were vaccinated with an investigational attenuated Oka/Merck "zoster" vaccine containing 18,700 to 60,000 plaque-forming units of virus — considerably more than the approximately 1350 plaque-forming units in the Oka/Merck VZV vaccine that has been administered to American children since approval by the Food and Drug Administration (FDA) in 1995. More than 38,000 recipients of the zoster vaccine were followed closely for three years.
The results are impressive. The double-blind, placebo-controlled study showed a 61 percent reduction in pain and discomfort (the burden of illness) in herpes zoster, and the incidence of postherpetic neuralgia in the vaccine group was reduced by 66 percent. The incidence of zoster in the placebo group was 11.12 per 1000 person-years. This percentage approximates the results of an epidemiologic survey performed a decade ago, which showed an incidence of zoster exceeding 10 cases per 1000 person-years among people older than 75 years.7 The elderly population has been rapidly increasing — the U.S. Census Bureau conservatively estimated that the population 85 years of age or older increased by 1 million from 1995 to 2005,8 and the population 60 to 85 years of age increased even more. In fact, the high incidence of zoster found in the placebo group in the Shingles Prevention Study points to an urgent need for effective therapy. Although oral antiviral therapy shortens the duration of zoster and analgesic medications provide some relief of pain, "an ounce of prevention. . . ."
Like the live varicella vaccine administered to children, live zoster vaccine appears to be safe and effective clinically. Serious adverse effects or deaths occurred in 1.4 percent of recipients in both the vaccine and placebo groups. In a subgroup of more than 6000 subjects who kept daily diaries of minor adverse events for a period of 42 days after vaccination, erythema, pain or tenderness, swelling, pruritus, or other adverse events at the injection site were reported in 48 percent of vaccine recipients as compared with 17 percent of placebo recipients. In the same subgroup, serious adverse events were reported in 1.9 percent of vaccine recipients, as compared with 1.3 percent of placebo recipients, and the difference was statistically significant (P=0.03). Furthermore, although the Oka/Merck VZV vaccine can, on rare occasions, unmask a childhood immunodeficiency disorder, no cases of dissemination of the virus were reported that might have been attributed to the zoster vaccine in a person with an undiagnosed disorder such as lymphoma or leukemia.
Should zoster vaccine be recommended for every VZV-seropositive, middle-aged adult who is healthy (i.e., without immunocompromise due to cancer, drug therapy, or AIDS) and who has not had zoster? Two main factors affect the answer to this question. First is the future risk of zoster among middle-aged adults who were vaccinated in childhood as compared with the current risk. By 2047, most, although not all, middle-aged Americans will have received VZV vaccine in childhood. Like the wild-type VZV, the Oka/Merck vaccine virus becomes latent in ganglia.9 If the viral burden is less in the ganglia of adults who were vaccinated in infancy, then the incidence of zoster may be reduced in those adults as compared with those who as children had naturally occurring chickenpox. Alternatively, the cell-mediated immunity to VZV in vaccine recipients may be reduced by their exposure to fewer cases of varicella, which would normally boost immune responsiveness, supporting the need to vaccinate middle-aged adults.
Second, the cost-effectiveness of vaccination must be considered before such a recommendation can be made. The Shingles Prevention Study used a disease-specific measure, the burden of illness due to herpes zoster,10 to assess severity of illness among the study participants. Herpes-zoster burden-of-illness scores correlated with the number of quality-adjusted life-years gained,10 the standard denominator of cost-effectiveness.11 As with any new therapy, the cost-effectiveness of the vaccine will depend on its price. To nonindigent recipients of the currently used childhood VZV vaccine (Varivax), the price of vaccination is between $50 and $100 (the sum of the cost of vaccine plus the visit or facility fee). An adult vaccine might cost more, given its greater potency. Nevertheless, the zoster vaccine appears to have been highly cost-effective in the Shingles Prevention Study (i.e., in the range of $2,000 per quality-adjusted life-year gained, even assuming a vaccine cost of $500). This admittedly rough estimate does not include the cost of complications related to vaccination or the provider's time required to administer it. However, $2,000 per quality-adjusted life-year gained is probably an underestimation of the vaccine's cost-effectiveness, since gains in the quality of life among vaccine recipients are likely to persist beyond the three years of the study period. Thus, the vaccine should fall well within the traditional cutoff point of $50,000 per quality-adjusted life-year used to evaluate new therapies, and it would appear to be at least as cost-effective as other currently used vaccines.12 Zoster vaccine may even be cost-saving.
If the FDA were to require another large multi-institutional study before zoster vaccine is licensed, it will be another decade until the findings of Oxman et al. can be confirmed or repudiated. Since zoster and its attendant neurologic complication of postherpetic neuralgia are common and serious, it seems prudent to market the zoster vaccine, but only if a large number of those vaccinated are followed closely, particularly those over 85 years of age, among whom the cell-mediated immune response to VZV is likely to be less robust than among those 20 to 25 years younger. This follow-up would allow not only a further determination of possible risk to vaccine recipients but also an estimation of the vaccine's effectiveness in the population of the oldest old. The Census Bureau projects that by the year 2040, there will be 8 million to 13 million Americans 85 years of age or older.8 It is hoped that the use of a zoster vaccine will reduce or eradicate zoster and its related complications, just as measles vaccine has wiped out not only measles but also measles-associated postinfectious encephalomyelitis and subacute sclerosing panencephalitis in regions where the vaccine is used.
Even though my episode of zoster was brief, I would gladly have paid to receive the zoster vaccine, knowing that the risk of the development of zoster might have been 50 percent less. Grown-ups should welcome the zoster vaccine. We may need it more than children do.
Source Information
From the Departments of Neurology and Microbiology, University of Colorado Health Sciences Center, Denver.
References
de Moragas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm 1957;75:193-6.
Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. Ann Neurol 1983;14:543-553.
Miller AE. Selective decline in cellular immune response to varicella-zoster virus in the elderly. Neurology 1980;30:582-587.
Hayward A, Levin M, Wolf W, Angelova G, Gilden D. Varicella-zoster virus-specific immunity after herpes zoster. J Infect Dis 1991;163:873-875.
Levin MJ, Murray M, Rotbart HA, Zerbe GO, White CJ, Hayward AR. Immune response of elderly individuals to a live attenuated varicella vaccine. J Infect Dis 1992;166:253-259.
Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605-1609.
Campion EW. The oldest old. N Engl J Med 1994;330:1819-1820.
Gelb LD, Dohner DE, Gershon AA, et al. Molecular epidemiology of live, attenuated varicella virus vaccine in children with leukemia and in normal adults. J Infect Dis 1987;155:633-640.
Coplan PM, Schmader K, Nikas A, et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J Pain 2004;5:344-56.
Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA 1996;276:1253-1258.
Prosser LA, Ray GT, O'Brien M, Kleinman K, Santoli J, Lieu TA. Preferences and willingness to pay for health states prevented by pneumococcal conjugate vaccine. Pediatrics 2004;113:283-290.(Donald H. Gilden, M.D.)