Varicella Vaccine and Infection with Varicella–Zoster Virus
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《新英格兰医药杂志》
Varicella–zoster virus is the cause of both varicella (chickenpox) and herpes zoster (shingles). A live attenuated varicella vaccine was developed in Japan in 1974, and in 1995 it was approved for use in the United States. The policy of universal vaccination of susceptible children and adults has had a profound effect on the epidemiology of varicella. Its effect on the epidemiology of zoster remains to be seen, in part because of the long delay between primary infection with varicella–zoster virus and the subsequent occurrence of zoster.
Before varicella vaccine was introduced, chickenpox developed in approximately 4 million persons, most of them children, in the United States annually (see Figure 1); about 12,000 of these patients were hospitalized with complications, and about 145 — most of whom had previously been healthy — died. Data from sentinel surveillance areas show that since 1995 the incidence of varicella has declined dramatically, by as much as 90 percent; moreover, as Nguyen et al. report in this issue of the Journal (pages 450–458), mortality from varicella has decreased by about 66 percent. The largest decreases in incidence and mortality have occurred in the primary target group for varicella vaccination — children one to four years of age.
Figure 1. Child with Typical Varicella Lesions at Various Stages of Development.
This unvaccinated adolescent had fever and a classic, extensive varicella rash characterized by pruritic vesicular lesions with erythematous bases.
A major question about the vaccine program is whether vaccine-induced immunity in children will wane over time, leaving cohorts of susceptible adults, in whom the illness is often more severe. As the incidence of varicella decreases, natural boosts to immunity from asymptomatic infection after exposure to varicella, which used to occur commonly, will become rare. Postlicensure studies indicate that the vaccine's effectiveness does decrease over time, from 97 percent in the first year to about 84 percent through eight years after vaccination. Consequently, chickenpox in a previously immunized person — called "breakthrough varicella" — is now relatively common.
Indeed, a number of outbreaks of chickenpox have been reported in both day-care centers and schools in which more than 75 percent of the children had been vaccinated. Breakthrough varicella is usually a very mild disease, and the rash often does not look like typical chickenpox: there are fewer lesions, and most of them are papular or papulovesicular, rather than vesicular (see Figure 2). The atypical presentation makes it difficult to diagnose isolated cases clinically. Children with breakthrough varicella can still transmit the virus, although transmission is less frequent than from unimmunized children with varicella. Consequently, the routine administration of a second dose of the vaccine to all children may be necessary for more effective control of varicella.
Figure 2. Breakthrough Varicella in a Vaccinated Child.
This child had breakthrough varicella two years after having received varicella vaccine. He was afebrile and had a small number of nonpruritic papulovesicular lesions, which were positive for varicella–zoster virus on polymerase-chain-reaction analysis.
Zoster, which used to affect about 15 percent of the population, occurs when latent virus in dorsal-root ganglia becomes reactivated and causes a vesicular and often painful rash with a dermatomal distribution; the rash may be followed by severe neuralgia that lasts for weeks or even months. Zoster usually occurs in persons with relative immunologic compromise, such as elderly persons or patients receiving immunosuppressive therapy. Before zoster can develop, a primary infection with either wild-type or vaccine-type varicella–zoster virus must occur. Although seeding during viremia may play a role, the primary way that the virus reaches the ganglia is through sensory nerves in skin lesions during primary infection. Since skin lesions from vaccination occur in only 5 to 7 percent of vaccinees, and then usually in relatively small numbers, it is not surprising that the frequency of zoster seems to be lower among vaccinees than among persons who have had chickenpox.
Some believe that periodic exposure to persons with varicella, which may provide a boost to cell-mediated immunity against the virus, is important in maintaining immunity to zoster. As the incidence of varicella decreases further, such stimulation of immunity from exogenous exposure will become rare. The result may be an increase in the incidence of zoster among persons who have had chickenpox, as well as a decrease in the average age at which zoster occurs. Others believe that such exogenous exposure to varicella–zoster virus is not so important in preventing zoster. Instead, they argue, reactivation of latent varicella–zoster virus is common, but in most instances the person's own immune system responds and prevents the development of zoster. Advocates of this model, in which endogenous stimulation helps to maintain immunity, foresee a reduction in the incidence of zoster. They posit that the growing number of vaccinees should have a lower incidence of zoster, whereas the frequency of zoster among the diminishing number of persons who have had chickenpox should not be affected by changes in the incidence of varicella.
Our ability to assess changes in both the incidence and the severity of zoster is hampered by two facts: surveillance has been relatively poor, and only the more severe cases are diagnosed. Better systems for the surveillance of zoster are being established. It is also possible that the varicella vaccine may be useful in helping to prevent zoster if it is administered to elderly persons who have had chickenpox. The results of a randomized trial assessing the vaccine's effectiveness in preventing zoster in the elderly are expected to become available in the near future.
It is clear that in the short time that it has been in use, varicella vaccine has greatly reduced both morbidity and mortality from varicella. The vaccine may also have a key role to play in preventing zoster. It is important to continue to monitor closely the epidemiology of both varicella and zoster so that the long-term effects of universal vaccination on both these illnesses can be assessed and so that vaccine policy can be modified, if necessary.
Dr. Shapiro reports having served as a consultant to Merck and on its Hepatitis A Vaccine Advisory Board.(Marietta Vázquez, M.D., a)
Before varicella vaccine was introduced, chickenpox developed in approximately 4 million persons, most of them children, in the United States annually (see Figure 1); about 12,000 of these patients were hospitalized with complications, and about 145 — most of whom had previously been healthy — died. Data from sentinel surveillance areas show that since 1995 the incidence of varicella has declined dramatically, by as much as 90 percent; moreover, as Nguyen et al. report in this issue of the Journal (pages 450–458), mortality from varicella has decreased by about 66 percent. The largest decreases in incidence and mortality have occurred in the primary target group for varicella vaccination — children one to four years of age.
Figure 1. Child with Typical Varicella Lesions at Various Stages of Development.
This unvaccinated adolescent had fever and a classic, extensive varicella rash characterized by pruritic vesicular lesions with erythematous bases.
A major question about the vaccine program is whether vaccine-induced immunity in children will wane over time, leaving cohorts of susceptible adults, in whom the illness is often more severe. As the incidence of varicella decreases, natural boosts to immunity from asymptomatic infection after exposure to varicella, which used to occur commonly, will become rare. Postlicensure studies indicate that the vaccine's effectiveness does decrease over time, from 97 percent in the first year to about 84 percent through eight years after vaccination. Consequently, chickenpox in a previously immunized person — called "breakthrough varicella" — is now relatively common.
Indeed, a number of outbreaks of chickenpox have been reported in both day-care centers and schools in which more than 75 percent of the children had been vaccinated. Breakthrough varicella is usually a very mild disease, and the rash often does not look like typical chickenpox: there are fewer lesions, and most of them are papular or papulovesicular, rather than vesicular (see Figure 2). The atypical presentation makes it difficult to diagnose isolated cases clinically. Children with breakthrough varicella can still transmit the virus, although transmission is less frequent than from unimmunized children with varicella. Consequently, the routine administration of a second dose of the vaccine to all children may be necessary for more effective control of varicella.
Figure 2. Breakthrough Varicella in a Vaccinated Child.
This child had breakthrough varicella two years after having received varicella vaccine. He was afebrile and had a small number of nonpruritic papulovesicular lesions, which were positive for varicella–zoster virus on polymerase-chain-reaction analysis.
Zoster, which used to affect about 15 percent of the population, occurs when latent virus in dorsal-root ganglia becomes reactivated and causes a vesicular and often painful rash with a dermatomal distribution; the rash may be followed by severe neuralgia that lasts for weeks or even months. Zoster usually occurs in persons with relative immunologic compromise, such as elderly persons or patients receiving immunosuppressive therapy. Before zoster can develop, a primary infection with either wild-type or vaccine-type varicella–zoster virus must occur. Although seeding during viremia may play a role, the primary way that the virus reaches the ganglia is through sensory nerves in skin lesions during primary infection. Since skin lesions from vaccination occur in only 5 to 7 percent of vaccinees, and then usually in relatively small numbers, it is not surprising that the frequency of zoster seems to be lower among vaccinees than among persons who have had chickenpox.
Some believe that periodic exposure to persons with varicella, which may provide a boost to cell-mediated immunity against the virus, is important in maintaining immunity to zoster. As the incidence of varicella decreases further, such stimulation of immunity from exogenous exposure will become rare. The result may be an increase in the incidence of zoster among persons who have had chickenpox, as well as a decrease in the average age at which zoster occurs. Others believe that such exogenous exposure to varicella–zoster virus is not so important in preventing zoster. Instead, they argue, reactivation of latent varicella–zoster virus is common, but in most instances the person's own immune system responds and prevents the development of zoster. Advocates of this model, in which endogenous stimulation helps to maintain immunity, foresee a reduction in the incidence of zoster. They posit that the growing number of vaccinees should have a lower incidence of zoster, whereas the frequency of zoster among the diminishing number of persons who have had chickenpox should not be affected by changes in the incidence of varicella.
Our ability to assess changes in both the incidence and the severity of zoster is hampered by two facts: surveillance has been relatively poor, and only the more severe cases are diagnosed. Better systems for the surveillance of zoster are being established. It is also possible that the varicella vaccine may be useful in helping to prevent zoster if it is administered to elderly persons who have had chickenpox. The results of a randomized trial assessing the vaccine's effectiveness in preventing zoster in the elderly are expected to become available in the near future.
It is clear that in the short time that it has been in use, varicella vaccine has greatly reduced both morbidity and mortality from varicella. The vaccine may also have a key role to play in preventing zoster. It is important to continue to monitor closely the epidemiology of both varicella and zoster so that the long-term effects of universal vaccination on both these illnesses can be assessed and so that vaccine policy can be modified, if necessary.
Dr. Shapiro reports having served as a consultant to Merck and on its Hepatitis A Vaccine Advisory Board.(Marietta Vázquez, M.D., a)