Varicella vaccine:
What have we learned?

By Jay M. Lieberman, MD

Despite guidelines calling for universal immunization of children against chickenpox, many clinicians still are not vaccinating their patients. Here's the latest information on the issues that should guide the decision to immunize—vaccine safety and efficacy, transmission of the vaccine virus, duration of immunity, and more.

How long has it been since you saw a case of Haemophilus influenzae type b meningitis? Do you remember the last child you saw with measles? These infections, along with polio, tetanus, diphtheria, rubella, and mumps, are largely diseases of the past thanks to the widespread use of highly effective vaccines.

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

But what about chickenpox? Are you still seeing chickenpox? If so, why? A safe, effective vaccine has been available for almost six years, yet many of our children remain unprotected. Barriers to immunization include the misconception that chickenpox is just a benign childhood disease and a lack of knowledge about the vaccine itself. This article will review what we have learned about the varicella vaccine, and what we still do not know.

Why vaccinate against chickenpox?

For the vast majority of children, chickenpox is a relatively mild, somewhat annoying disease characterized by fever and an intensely pruritic rash. Just because chickenpox is benign for most children, however, does not mean it is benign for all children. Before licensure of the varicella vaccine, it was estimated that there were almost 4 million cases of chickenpox each year in the United States.¹ Even relatively rare complications, therefore, occurred with some frequency.

The Centers for Disease Control and Prevention (CDC) estimated that more than 11,000 hospitalizations due to chickenpox occurred annually in the US before the vaccine became available.¹ Moreover, about 100 people died every year from chickenpox and its complications. Almost half these deaths were in children, most of whom were previously healthy.²

The most common complication of chickenpox is bacterial superinfection of the skin and soft tissues, usually caused by Staphylococcus aureus or Streptococcus pyogenes (group A streptococcus [GAS]). The emergence of more serious complications of GAS infections over the past 15 years has changed the way many physicians look at chickenpox. Chickenpox is a major risk factor for streptococcal toxic shock syndrome and for invasive infections such as necrotizing fasciitis^3,4—a rare but life-threatening disease that can be averted in many children by preventing chickenpox.

Varicella is much more likely to be severe or complicated in adults than in children. Although adults make up only about 10% of cases of chickenpox, they account for more than half the deaths. In 1997, the CDC highlighted three fatal cases of chickenpox in young adult women.⁵ Two of the women were otherwise healthy, the third was on prednisone for Crohn's disease. All were unvaccinated and infected by unvaccinated preschool-aged children who had typical chickenpox. These deaths could have been avoided if the women or children (preferably both) had been immunized.

So tell me about the vaccine

One varicella vaccine (Varivax, Merck & Co., Inc.) is available in the US. It is a live, attenuated viral vaccine—meaning that it is a weakened strain of the virus—like the live, attenuated rubella, mumps, measles, and oral polio vaccines that have been used for years.

The virus strain used in the varicella vaccine was originally isolated in 1970 from an otherwise healthy 3-year-old boy in Japan.⁶ Since the boy's family name was Oka, the strain was named the Oka strain of varicella zoster virus (VZV). The virus was attenuated by serially passing it at reduced temperatures through various tissue cultures. The challenge in developing any safe, effective, live viral vaccine is to attenuate it enough so that it does not cause disease in vaccine recipients, but not so much that it does not induce an adequate immune response.

A number of other varicella vaccines are available around the world. All derive from the Oka strain of VZV. The attenuation and manufacturing processes of the vaccines differ, however, so it should not be assumed that the vaccines are necessarily equivalent.

Vaccine safety

Studies conducted before licensure of the chickenpox vaccine found that it was generally well tolerated.⁷ Local reactions, such as pain or swelling at the injection site, tended to be mild and self-limited. There was no evidence of an excess rate of fever in vaccine recipients compared with those who received a placebo.

Since licensure, Merck and the Food and Drug Administration have collected postmarketing reports of adverse experiences temporally associated with vaccine administration.^8,9 These passive reporting systems cannot determine the true incidence of significant reactions. In addition, data are often insufficient to determine whether the relationship between the vaccine and the adverse event was just a temporal association or a causative one. Nonetheless, the information gives us a window into the vaccine's safety profile. The major safety concerns are related to the fact that it is a live viral vaccine.

Can the vaccine cause chickenpox? Yes. In prelicensure studies, a varicella-like rash occurred in up to 7% of vaccinated children.⁷ The rash is called "varicella-like" because, while it may be vesicular, it is oftentimes maculopapular. The rash may either occur at the injection site or be generalized. It is usually very mild, however; the median number of skin lesions is two to five. A common scenario is that a child develops two bumps on the arm that are not even recognized as being vaccine related.

Postmarketing safety data through April 1999, by which time approximately 16.1 million vaccine doses had been distributed, reveal reports of 1,349 children who developed a rash (about 40% of which were "varicella-like") within six weeks after vaccination.⁸ Clinical specimens from 97 children with vesicular lesions were available for polymerase chain reaction (PCR) analysis, and the virus type was identified in 62 cases. In 38 of these, the rash was caused by wild-type VZV, indicating that these children had been infected with chickenpox, usually shortly before vaccination. The median number of lesions in these children was 100 (range: 10-1,000) and the median time of onset was eight days (range: 1-24 days) after vaccination.

The vaccine strain of VZV was identified from the remaining 24 children. The median number of skin lesions in these children was only 51 (range: 1-500) and the median time of onset was 21 days (range: 5-42 days) after vaccination. Thus, the number of lesions and the timing of the onset of rash can suggest whether a child who develops a rash after vaccination has been infected with the wild-type virus or has developed a rash from the vaccine (Figure 1).

Have serious vaccine reactions been reported? Clinicians are encouraged to report all clinically significant reactions following the administration of any vaccine (and are required to report certain adverse events) to the Vaccine Adverse Event Reporting System (VAERS). Reporting can be done either via the Internet at www.vaers.org or by phone at 800-822-7967. (Possible serious reactions to varicella vaccine can also be reported directly to Merck at 800-672-6372, and it will forward the report to VAERS.)

Among the rare adverse reactions reported after varicella vaccination are anaphylaxis, Stevens-Johnson syndrome, Guillain-Barré syndrome, encephalitis, immune thrombocytopenic purpura, and death.^8,9 For many of these cases, limited data are available to assess whether or not the vaccine caused the reaction, while in other cases alternative etiologies are likely. For example, one child who developed encephalitis 27 days after vaccination grew an enterovirus from her cerebrospinal fluid (CSF).⁸ In the case of another child, who died of encephalitis four days after vaccination, PCR detected wild-type VZV in the brain at autopsy.^8,9

Nonetheless, on rare occasions the vaccine itself may cause significant adverse reactions. For example, through April 1999 there were 24 reports of acute cerebellar ataxia that occurred one to 61 days after vaccination.⁸ Half were associated with rash or fever (although in the one case where PCR of the CSF was performed, the wild-type virus was identified). Since chickenpox can cause acute cerebellar ataxia, it seems reasonable to believe that the vaccine caused the condition in at least some of these cases.

There were 15 reports of thrombocytopenia that occurred five to 41 days (median: 21 days) after vaccination.⁸ Platelet counts ranged from 2,000 to 120,000 (median: 5,500), and one child died as a result of an intracranial bleed. He was an 18-month-old boy with a preceding upper respiratory infection who developed thrombocytopenia four days after receiving varicella, DTaP, and oral polio vaccines.⁹ PCR analyses of kidney and brain tissue were negative for vaccine virus.

Disseminated disease caused by the vaccine strain has been reported in three immunocompromised vaccine recipients. A 13-month-old boy with a three-month history of thrush developed a vesicular rash 15 days and again 38 days postvaccination. He was hospitalized 83 days after vaccination for pneumonia with a diffuse nodular pattern on chest X-ray. Lung biopsy showed multinucleated giant cells and PCR was positive for the vaccine strain of VZV. He was subsequently diagnosed with human immunodeficiency virus infection.⁸

Another 13-month-old male with a history of failure to thrive, chronic diarrhea, and thrush was hospitalized two weeks after vaccination with respiratory distress, elevated liver enzymes, and hepatomegaly. A liver biopsy showed multifocal areas of necrosis and grew the vaccine strain of VZV. The child was subsequently diagnosed with severe combined immunodeficiency.¹⁰

Finally, a 5-year-old boy with multiple medical problems including asthma was vaccinated seven days after finishing a steroid taper, and was then restarted on steroids eight days after vaccination. Two days later he developed a rash, and a week later pneumonia. The Oka strain of VZV was identified by PCR from endotracheal secretions.⁸

What about zoster? The varicella vaccine is unique in that it is the only licensed herpes virus vaccine. All herpes viruses can establish latency and, after chickenpox resolves, VZV can become latent in the dorsal root and sensory ganglia. Years or decades later, the virus can reactivate as zoster, usually when the individual becomes elderly or immunocompromised.

Since this is a live viral vaccine, one would guess that the vaccine virus could also establish latency and thereby cause zoster. Indeed, there have been documented cases of zoster caused by the vaccine strain. Of 205 reports of zoster in vaccine recipients, clinical specimens were available from 56 patients for PCR analysis. Of the 32 in which the virus could be identified, 10 were found to be the wild-type virus and 22 were the vaccine strain. The median time to onset of zoster after vaccination in the 22 vaccine-related cases was 193 days (range: 47-1,249). Three of those patients had had a vesicular rash after vaccination, and 10 patients developed zoster at the injection site.⁸

Thus far, the rate of reported—not necessarily confirmed—zoster following vaccination is much lower than would be expected following natural disease. Furthermore, studies in children with leukemia have shown that those who are vaccinated are at significantly lower risk of zoster than those who have had chickenpox.^11,12

So, while studies are necessary to determine the long-term impact of vaccination on the incidence of zoster, evidence to date suggests that the risk of developing zoster is lower in those who are immunized than in those who have had chickenpox. It is thought that VZV establishes latency during viremia or by tracking back from the skin. Since the vaccine virus is less likely than VZV to result in viremia and to cause a rash, it should be less likely to establish latency. If there's no latency, there's no zoster.

In fact, since zoster occurs when a person's cell-mediated immunity wanes and since the live viral vaccine induces cell-mediated immunity, it is possible that vaccinating the elderly may actually boost their immunity and reduce their risk of zoster.¹³ A large-scale study in the elderly is underway to see if the chickenpox vaccine may indeed prevent zoster. Results should be available in several years.

What's the bottom line on safety? The live attenuated varicella vaccine can in rare circumstances cause disease similar to that caused by the wild-type virus. But the risk of serious complications from chickenpox far exceeds the risk of complications from the vaccine. For example, acute cerebellar ataxia is reported to occur in about one in 4,000 cases of chickenpox. In contrast, a large, postmarketing evaluation of the vaccine's safety in almost 90,000 children and adults found not a single case of acute cerebellar ataxia following vaccination.¹⁴

Vaccine virus transmission

As discussed, the vaccine can cause mild chickenpox in some children. If the rash is vesicular and you unroof a vesicle, you can sometimes culture vaccine virus from the lesion. Therefore, children who develop a rash may be contagious.

What do the data show? Before licensure, the varicella vaccine was extensively evaluated in children with leukemia. Because these children are immunocompromised, they are more likely to develop rashes after vaccination, and studies showed that they could transmit the vaccine virus to close contacts. In one study, 15 of 88 susceptible siblings (17%) were infected when the child with leukemia developed a postvaccination rash.¹⁵ Infection in the otherwise healthy sibling was usually subclinical or resulted in mild disease; the sibling developed few skin lesions, rarely had fever, and recovered rapidly. Significantly, there were no cases of transmission among children with leukemia who did not develop a rash.

Before vaccine licensure, there were no cases of transmission from healthy children given the vaccine.⁷ After licensure through April 1999, there were 92 reports of possible secondary transmission occurring 10 to 56 days after vaccination of the index case.⁸ Of 29 specimens obtained from contacts who had suspected secondary disease, five were negative for VZV and three were inadequate for analysis. Interestingly, 18 revealed wild-type virus, which again highlights the difficulty in assessing whether the vaccine is responsible when there is still substantial circulation of wild-type virus. Only three of 29 specimens confirmed the Oka strain of VZV.

One of the confirmed cases was a 12-month-boy who developed a generalized rash with about 30 lesions after vaccination. He transmitted the vaccine virus to his susceptible mother who developed a generalized rash with about 100 lesions. Unfortunately, she was pregnant at the time, and she chose to abort the fetus. Evaluation of the fetus showed no evidence of infection with the vaccine strain.¹⁶

In each of the two other confirmed cases, a 1-year-old developed a vesicular rash after vaccination and transmitted the vaccine virus to a close household contact.⁸ In one case, the contact was a 4-month-old brother who developed 25 lesions. In the other case, the child's 35-year-old father developed more than 100 lesions.

Recently, transmission of the vaccine virus was also confirmed from a 3-year-old boy who developed zoster five months postvaccination. Two weeks later, his otherwise healthy brother developed a mild case of chickenpox with about 50 lesions.¹⁷

What's the bottom line on transmission? It does occur, but very rarely. Evidence to date suggests that vaccine recipients must have a rash (either vaccine-related chickenpox or zoster) to be contagious. How contagious they are depends on two factors: One, the extent of the rash—a child with a generalized rash with 30 to 50 skin lesions is much more contagious than a child with two bumps on the arm—and two, the extent of the contact—household contacts are at much higher risk than casual contacts.

What should you do if you want to vaccinate a 12-month-old who lives with a susceptible, high-risk person, perhaps a child with leukemia or a pregnant woman? It comes down to a choice. Either you do not vaccinate the healthy child, in which case he will be at risk for chickenpox, which would in turn put his sibling or parent at very high risk for contracting the disease. Or you vaccinate the child, which would dramatically reduce his chances of getting chickenpox and thereby help protect the high-risk person. If you weigh the potential risks and benefits, vaccination is the way to go.^18,19

Children who have close contact with immunocompromised individuals and other high-risk persons should be vaccinated.¹⁹ If they develop a rash, they should avoid contact with the high-risk person if possible. Should the immunocompromised person develop vaccine-related chickenpox, it is likely to be mild and can be treated with acyclovir.

Vaccine effectiveness

More than 95% of children 12 years of age and younger respond to a single dose of varicella vaccine. Among persons 13 years of age and older, however, an average of only about 80% respond, and even among those who do, antibody levels are much lower than in younger individuals. With most vaccines, children respond better than adults. That is why, for example, the hepatitis A and hepatitis B vaccines come in adult and pediatric formulations. The adult formulations contain twice as much vaccine as the pediatric versions.

To overcome the diminished response in adolescents and adults to the varicella vaccine, a second dose is recommended. With this dose, the overall response rate exceeds 95%; those who did not respond vigorously to the first shot mount a good booster response and develop high levels of antibodies.

Still, while we measure antibodies as an indicator of a vaccine's effectiveness, what really matters is whether the vaccine protects the recipient.

Can a child still get chickenpox after vaccination? The short answer is yes: Since some children do not respond to the vaccine, they may develop full-blown chickenpox if infected with the wild-type virus. Even children who do mount an antibody response to the vaccine may, rarely, develop chickenpox if they come in contact with someone who has the disease. This "breakthrough" disease is caused by the wild-type virus²⁰ and is most common among children who have the lowest antibody levels after vaccination.²¹ It occurs in 1% to 4% of vaccinated children per year but tends to be a mild, modified form of disease characterized by few skin lesions (median: 30-50), low rates of fever, and a rapid recovery.²²

How protective is the vaccine? Clinical studies conducted before the vaccine was licensed showed that it was 70% to 90% effective. This means that 70% to 90% of children who would otherwise have come down with the disease following exposure were completely protected—they developed no signs or symptoms of chickenpox. In addition, most children who were "not protected" developed the mild, modified form of disease. Therefore, the vaccine was more than 95% protective against severe chickenpox.

Since vaccine licensure, studies in child-care centers and pediatric practices have evaluated the vaccine's effectiveness in the "real world"^23-28 (Table 1). During an outbreak in a child-care center in Georgia,²³ for example, chickenpox occurred in nine of 66 (14%) vaccinated children vs. 72 of 82 (88%) unvaccinated children. The vaccine's effectiveness against all forms of disease was 86%, and since all nine children who developed chickenpox despite vaccination had mild disease (fewer than 50 skin lesions), the vaccine was 100% effective against moderate to severe disease.

TABLE 1
Effectiveness of varicella vaccine in child-care centers and pediatric practices

Postlicensure findings are remarkably consistent—the vaccine is about 85% protective against chickenpox. As with certain other vaccines, such as influenza and pertussis, it may not completely prevent disease. It is highly effective at preventing serious disease, however.

Now that the vaccine has been available for almost six years, there is evidence that it is having a major impact. Active surveillance for chickenpox has been conducted since 1995 at sites in Pennsylvania, Texas, and California in a CDC- sponsored study.²⁹ In 1998, vaccine coverage among 1- to 2-year-olds was 60% to 70%. Overall, cases of varicella declined 70% to 90% between 1995 and 1999, with the greatest decrease in children 1 to 4 years of age. Cases also declined in all other age groups, including infants younger than 12 months and adults, suggesting herd immunity. The varicella vaccine works—we just need to vaccinate more children.

Duration of immunity

For many clinicians, "How long will protection last?" is the major question concerning the chickenpox vaccine. If protection wanes, the vaccine could decrease the incidence of disease in children but, theoretically, increase the incidence of disease in adults. Since chickenpox tends to be more serious in adults, this would be an unfortunate consequence of routine childhood immunization. As with any vaccine, only long-term studies can determine the true duration of protection afforded by the varicella vaccine.

What do we know so far about duration of antibodies? Antibody levels have been followed for at least 10 years in children given the currently licensed vaccine³⁰ and for more than 20 years in children given earlier formulations.³¹ Nearly all children maintain antibody levels for as long as 20 years after vaccination. The persistence of antibodies observed in studies to date may not reflect what will happen in the years ahead, however.

Although live varicella vaccines have been available in several countries, including Japan, for a number of years, the US is the first country to recommend universal childhood immunization. Therefore, children who were vaccinated 10, 15, or 20 years ago lived in communities where there was still a lot of chickenpox. When exposed to a close contact with the disease, some became infected. Although usually subclinical, these infections served as a natural boost to their antibody levels. Indeed, children often had higher antibody levels 10 years after vaccination than they did one to two years after vaccination.³⁰

As more and more children are vaccinated and chickenpox becomes less common, opportunities for antibody levels to be boosted by exposure to chickenpox will diminish. Levels will begin to fall shortly after vaccination and continue to decline over the years. One-year-olds vaccinated today will very likely have much lower antibody levels at 25 years of age than do 25-year-olds today—just as young adults today have much lower antibody levels against measles than did young adults in the pre-measles-vaccine era.³²

Is there another way to boost? A recent article suggests that children may not need exposures to chickenpox to experience a boost in antibody levels.³³ The authors analyzed a computer database containing serial antibody levels and infection rates for more than 4,600 children immunized before vaccine licensure. They found that children with the lowest antibody levels were not only most likely to develop breakthrough disease but also most likely to increase their antibody titers over time. Furthermore, the rate of asymptomatic "boosting" in this group was significantly higher than would be expected from exposure to wild-type chickenpox. The authors suggest that the vaccine virus may silently reactivate and boost antibody levels. Further studies are needed to confirm or refute this theory.

How significant are antibody levels? Although it is very likely that antibody levels will be lower in young adults 25 years from now and that some children vaccinated today will no longer have measurable antibodies, this does not necessarily mean that these individuals will be without immunity. The critical issue is not whether antibodies last, but whether protection lasts. And while we commonly consider antibody levels a marker for protection, they are not the only, and may not be the best, indicator.

The live varicella vaccine induces not only a humoral (antibody) response but also a cell-mediated (T cell-mediated) immune response.³⁴ Although antibodies may wane, cell-mediated immunity persists, and it is this immune memory that should provide long-term protection. Since chickenpox has an incubation period of about two weeks, immune memory allows time for an anamnestic response—an infected individual has two weeks to rapidly boost his antibody levels to prevent or ameliorate disease.

What evidence suggests that protection will be durable? While the chickenpox vaccine has not been around long enough to know definitively how long immunity will last, we can draw on our experiences with two other, similar live attenuated viral vaccines: measles and rubella.

Live attenuated measles vaccine has been available for more than 30 years. As with the varicella vaccine, the measles vaccine induces cell-mediated immunity. As with chickenpox, measles has a fairly long incubation period. After measles vaccination, antibody levels decline but protection lasts. During the US measles outbreak of 1989 to 1991, some vaccinated people did develop measles; however, their likelihood of developing measles was not related to how long ago they had been vaccinated.³⁵ There was no evidence that protection had waned.

There continues to be no evidence that a booster dose of measles vaccine is needed. Nonetheless, two doses of measles vaccine are now recommended for all children in the US. The major reason is that a small proportion of children fails to respond to the first dose and remains susceptible. The second dose is given to overcome these primary vaccine failures. It is likely that a two-dose regimen will eventually be recommended for varicella vaccine for the same reason. This will probably not occur until a combination measles-mumps- rubella-varicella (MMRV) vaccine becomes available.

Our experience with the rubella vaccine should also allay concerns about waning immunity. As with chickenpox, rubella has much graver consequences in adults, because of the risk of congenital rubella syndrome if a pregnant woman becomes infected. How can we protect adult women from rubella? One strategy is to immunize all teenage girls. Some countries have adopted this strategy, the success of which depends on achieving very high vaccination levels among teens. While these countries have witnessed a significant reduction in the number of rubella cases, congenital rubella syndrome continues to occur.

In contrast, the US adopted a strategy of routine infant immunization, supplemented by targeting susceptible postpubertal girls and women. The result: Congenital rubella has almost disappeared. This strategy works for two reasons. First, protection is durable after immunization with the live attenuated rubella vaccine, so most adults are still protected as a result of the shot they received as a young child. Second, even those adults who are susceptible, either because they did not respond to the vaccine or never received it, are unlikely to be exposed to rubella virus. Since most children are vaccinated, there is very little wild-type rubella virus circulating in the US.

The lesson from the rubella experience, therefore, is that the best way to protect adults from a potentially serious viral infection is routine childhood immunization. Everything we know about the varicella vaccine and similar vaccines suggests that protection will be durable. While questions about duration of protection are legitimate, they should not prevent us from immunizing our children.

Are we creating a self-fulfilling prophecy? Concerns that routine childhood immunization will produce a population of susceptible adults could lead to the very thing we fear most—more adult disease. As more and more children are vaccinated, less and less wild-type VZV is circulating in our communities. When a critical mass (for example, 50% to 70%) of children are vaccinated, those who are unvaccinated are much less likely to be exposed to natural chickenpox. In that way, we may shift the age distribution of chickenpox upward by creating a cohort of susceptible teens and young adults—and in turn more adult disease.

Could this really happen? The experience in Greece with the rubella vaccine suggests that it could. Greece began giving MMR vaccine to 1-year-olds in the mid-1970s. There were no systematic policies in place to ensure compliance, however, and vaccination levels remained at about 50% through the 1980s. As a result, the age distribution of rubella cases shifted to teenagers and, in 1993, cases of congenital rubella increased to levels not seen since the 1950s.³⁶

The potentially self-fulfilling prophecy of creating more adults susceptible to chickenpox can be avoided by vaccinating all appropriate children.

Recommendations

In addition to routine preexposure vaccination of all children 1 year of age and older, the CDC and the American Academy of Pediatrics (AAP) now recommend the varicella vaccine as postexposure prophylaxis.^1,37

Preexposure. The vaccine is recommended for routine administration to children 12 to 18 months of age who have not had chickenpox. Older children can be vaccinated at any visit but should certainly be vaccinated no later than 11 to 12 years of age because of the higher risk of complications in adolescents and young adults.

Susceptible adults should also be vaccinated, particularly those at high risk for exposure or transmission (Table 2). Two doses, given four to eight weeks apart, are recommended for people 13 years of age and older.

TABLE 2
Vaccination of persons 13 years or older

Varicella vaccine is recommended for susceptible persons at high risk for exposure or transmission:

Persons who live or work in environments where transmission of VZV is likely (for example, teachers of young children, child-care center employees, and residents and staff members in institutional settings)

Persons who live and work in environments where transmission can occur (for example, college students, inmates and staff members of correctional institutions, and military personnel)

Nonpregnant women of child-bearing age

Adolescents and adults living in households with children

International travelers

In 1999, the CDC recommended that states pass legislation requiring vaccination or proof of immunity for entrance into child-care centers and elementary schools. Evidence of immunity should consist of physician-diagnosed disease, a reliable history of chickenpox, or a positive serology. As of October 20, 2000, 18 states plus the District of Columbia had passed such legislation for both day care and school entry (Figure 2).

Varicella vaccine is contraindicated in persons with a history of an anaphylactic-type reaction to any vaccine component, including gelatin or neomycin. Since it is a live viral vaccine, it should not be given to pregnant women because of theoretical risks to the fetus. Furthermore, pregnancy should be avoided for at least one month after vaccination.¹⁹ It should also not be given to immunocompromised persons, including children receiving high doses of corticosteroids (2 mg/kg/day of prednisone or its equivalent) for 14 days or more. However, children with acute lymphoblastic leukemia in remission can be vaccinated under a research protocol (contact number: 484-679-2856), and the vaccine should be considered for HIV-infected children who are asymptomatic or mildly symptomatic with CD4⁺ T-lymphocyte percentages >25%.^1,37

Postexposure. Measles vaccine may provide protection against clinical disease when given within 72 hours of exposure to measles, and limited data suggest that the chickenpox vaccine may be effective postexposure as well. For example, a study of an earlier formulation of the vaccine showed that only four of 13 children immunized within five days of exposure developed chickenpox—compared with 12 of 13 children given placebo.³⁸ Furthermore, the four vaccinated children who developed chickenpox had mild disease with one, two, 20, or 50 skin lesions. Thus, the vaccine was very effective at preventing or ameliorating disease. The child who developed 50 skin lesions was vaccinated more than 72 hours postexposure. Current recommendations from the CDC's Advisory Committee on Immunization Practices (ACIP) call for vaccination within 72 hours if possible, although immunization may be effective as late as five days after exposure.

Similarly, in a study in which the licensed vaccine was given postexposure to 10 children whose siblings had chickenpox, only five of the children developed chickenpox. The mean number of skin lesions was just 13.³⁹

Finally, two cases of chickenpox in a Philadelphia homeless shelter prompted vaccination of 67 susceptible adults and children.⁴⁰ Again, the vaccine was highly effective at preventing further disease. Mild disease developed in two vaccinated children of one of the index cases. A third child, who was not vaccinated because he was erroneously reported to have had chickenpox, developed severe disease.

Although the vaccine is best used as preexposure prophylaxis, postexposure use may limit or prevent prolonged outbreaks. Parents should be advised, however, that the vaccine may not always be protective. In particular, if the child was exposed to chickenpox earlier than suspected (perhaps at the same time as the index case), she may develop a moderate to severe case within days of vaccination.

In immunocompromised children or others for whom the vaccine is contraindicated, varicella zoster immune globulin (VZIG) should be used when postexposure prophylaxis is required.

What are we waiting for?

A safe, effective vaccine against chickenpox has been available in the United States since March 1995, yet in 1999, only about 60% of children 19 to 35 months of age had been vaccinated.⁴¹ That represents a substantial improvement over previous years, but we still have a long way to go.

Since vaccine licensure, more than 20 million doses of vaccine have been distributed in the US, and we've learned a lot about the vaccine. We've learned that although this live, attenuated viral vaccine is well tolerated, it can sometimes cause disease similar to the chickenpox virus. However, the disease is usually mild and the risk of complications from the vaccine appears to be dramatically lower than the risks of natural disease. Children who develop a rash after vaccination may be contagious, but the risk of transmission is very low. The vaccine virus can establish latency and cause zoster, but it appears much less likely to do so than the wild-type virus.

Experience with the vaccine has confirmed that it is about 85% protective against chickenpox, and nearly 100% protective against severe disease. As use of the vaccine has increased, we're now seeing its impact on disease prevention. Long-term studies are in progress to determine the duration of protection, but our experience with similar live viral vaccines suggests that immunity should be durable.

Our challenges are to vaccinate the more than 40% of children who are not getting the vaccine routinely in the second year of life, and to "catch up" those unvaccinated older children who remain susceptible. Our reward will be healthier, happier children today and healthier, happier adults tomorrow.

REFERENCES

1. Centers for Disease Control and Prevention: Prevention of varicella. Update of recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48:(RR-6)1

2. Meyer PA, Seward JF, Jumaan AO, et al: Varicella mortality: Trends before vaccine licensure in the United States, 1970-1994. J Infect Dis 2000;182:383

3. Vugia DJ, Peterson CL, Meyers HB, et al: Invasive group A streptococcal infections in children with varicella in Southern California. Pediatr Infect Dis J 1996;15:146

4. Laupland KB, Davies HD, Low DE, et al: Invasive group A streptococcal disease in children and association with varicella-zoster virus infection. Pediatrics 2000; 105:1

5. Centers for Disease Control and Prevention: Varicella- related deaths among adults-United States, 1997. MMWR 1997;46:409

6. Takahashi M: Vaccine development. Infect Dis Clin North Am 1996;10:469

7. White CJ: Clinical trials of varicella vaccine in healthy children. Infect Dis Clin North Am 1996;10:595

8. Sharrar RG, LaRussa P, Galea SA, et al: The postmarketing safety profile of varicella vaccine. Vaccine 2000;19:915

9. Wise RP, Salive ME, Braun MM, et al: Postlicensure safety surveillance for varicella vaccine. JAMA 2000; 284:1271

10. Ghaffer F, Carrick K, Rogers BB, et al: Disseminated infection with varicella-zoster virus vaccine strain presenting as hepatitis in a child with adenosine deaminase deficiency. Pediatr Infect Dis J 2000;19:764

11. Lawrence R, Gershon AA, Holzman R, et al: The risk of zoster after varicella vaccination in children with leukemia. N Engl J Med 1988;318:543

12. Hardy I, Gershon AA, Steinberg SP, et al: The incidence of zoster after immunization with live attenuated varicella vaccine: A study in children with leukemia. N Engl J Med 1991;325:1545

13. Gershon A, Silverstein S: Live attenuated varicella vaccine for prevention of herpes zoster. Biologicals 1997;25:227

14. Black S, Shinefield H, Ray P, et al: Postmarketing evaluation of the safety and effectiveness of varicella vaccine. Pediatr Infect Dis J 1999;18:1041

15. Tsolia M, Gershon AA, Steinberg SP, et al: Live attenuated varicella vaccine: Evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus. J Pediatr 1990; 116:184

16. Salzman MB, Sharrar RG, Steinberg S, et al: Transmission of varicella-vaccine virus from a healthy 12-month-old child to his pregnant mother. J Pediatr 1997; 131:151

17. Brunell PA, Argaw T: Chickenpox attributable to a vaccine virus contracted from a vaccinee with zoster. Pediatrics 2000;106(2). http://www.pediatrics.org/cgi/content/full/106/2/e28

18. Long SS: Toddler-to-mother transmission of varicella- vaccine virus: How bad is that? J Pediatr 1997; 131:10

19. Varicella-zoster infections, in Pickering LK (ed): 2000 Red Book: Report of the Committee on Infectious Diseases, ed 25. Elk Grove Village, IL, American Academy of Pediatrics, 2000, p 624

20. LaRussa P, Steinberg SP, Shapiro E, et al: Viral strain identification in varicella vaccinees with disseminated rashes. Pediatr Infect Dis J 2000;19:1037

21. White CJ, Kuter BJ, Ngai A, et al: Modified cases of chickenpox after varicella vaccination: Correlation of protection with antibody response. Pediatr Infect Dis J 1992; 11:19

22. Clements DA, Armstrong CB, Ursano AM, et al: Over five-year follow-up of Oka/Merck varicella vaccine recipients in 465 infants and adolescents. Pediatr Infect Dis J 1995;14:874

23. Izurieta HS, Strebel PM, Blake PA, et al: Postlicensure effectiveness of varicella vaccine during an outbreak in a child care center. JAMA 1997;278:1495

24. Shapiro E, LaRussa PS, Steinberg SP, et al: Protective efficacy of varicella vaccine. (Abstract 78). 36th Annual Meeting of the Infectious Diseases Society of America. Clin Infect Dis 1998;27:934

25. Tabony L, Kilgore P, Pelosi J, et al: Varicella vaccine effectiveness during a child-care center outbreak, Travis County, Texas, 1998. (Abstract 79). 36th Annual Meeting of the Infectious Diseases Society of America. Clin Infect Dis 1998;27:934

26. Clements DA, Moreira SP, Coplan PM, et al. Postlicensure study of varicella vaccine effectiveness in a day-care setting. Pediatr Infect Dis J 1999:18:1047

27. Buchholz U, Moolenaar R, Peterson C, et al: Varicella outbreaks after vaccine licensure: Should they make you chicken? Pediatrics 1999;104:561

28. Fair E, Galil K, Mountcastle N, et al: Varicella vaccine effectiveness during a day-care center outbreak in Pennsylvania, 1999-2000. [Abstract] Presented at the 38th Annual Meeting of the Infectious Diseases Society of America, New Orleans, September 2000

29. Seward J, Peterson C, Mascola L, et al: Decline in varicella disease: Evidence of vaccine impact. (Abstract). Joint meeting of the Pediatric Academic Societies and the American Academy of Pediatrics, Boston, MA, May 2000

30. Johnson CE, Stancin T, Fattlar D, et al: A long-term prospective study of varicella vaccine in healthy children. Pediatrics 1997;100:761

31. Asano Y, Suga S, Yashikawa T, et al: Experience and reason: Twenty-year follow-up of protective immunity of the Oka strain live varicella vaccine. Pediatrics 1994; 94:524

32. Markowitz LE, Albrecht P, Rhodes P, et al: Changing levels of measles antibody titers in women and children in the United States: Impact on response to vaccination. Pediatrics 1996;97:53

33. Krause PR, Klinman DM: Varicella vaccination: Evidence for frequent reactivation of the vaccine strain in healthy children. Nature Med 2000;6:451

34. Arvin AM: Immune responses to varicella-zoster virus. Infect Dis Clin North Am 1996;10:529

35. Gindler JS, Atkinson WL, Markowitz LE, et al: Epidemiology of measles in the United States in 1989 and 1990. Pediatr Infect Dis J 1992;11:841

36. Panagiotopoulos T, Antoniadou I, Valassi-Adam E: Increase in congenital rubella occurrence after immunisation in Greece: Retrospective study and systematic review. BMJ 1999;319:1462

37. American Academy of Pediatrics, Committee on Infectious Diseases: Varicella vaccine update. Pediatrics 2000;105:136

38. Arbeter AM, Starr SE, Plotkin SA: Varicella vaccine studies in healthy children and adults. Pediatrics 1986;78(suppl):748

39. Salzman MB, Garcia C: Postexposure varicella vaccination of siblings with active varicella. Pediatr Infect Dis J 1998;17:256

40. Watson B, Seward J, Yang A, et al: Postexposure effectiveness of varicella vaccine. Pediatrics 2000; 105:84

41. Centers for Disease Control and Prevention: National, state, and urban area vaccination coverage levels among children aged 19-35 months—United States, 1999. MMWR 2000;49:585

DR. LIEBERMAN is Chief, Pediatric Infectious Diseases, Miller Children's Hospital, Long Beach, CA, and Associate Professor of Pediatrics, University of California, Irvine. He is a member of Merck's Speakers Bureau and a recipient of grant support from Merck.

ACCREDITATION

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Jefferson Medical College and Medical Economics, Inc.

Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their article(s). Full disclosure of these relationships, if any, appears with the author affiliations at the beginning of the article.

CONTINUING MEDICAL EDUCATION CREDIT

This CME activity is designed for practicing pediatricians and other health-care professionals as a review of the latest information in the field. Its goal is to increase participants' ability to prevent, diagnose, and treat important pediatric problems.

Jefferson Medical College designates this continuing medical educational activity for a maximum of one hour of Category 1 credit towards the Physician's Recognition Award (PRA) of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

This credit is available for the period of January 15, 2001, to January 15, 2002. Forms received after January 15, 2002, cannot be processed.

Although forms will be processed when received, certificates for CME credits will be issued every four months, in March, July, and November. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education at 215-955-6992.

HOW TO APPLY FOR CME CREDIT

1. Each CME article is prefaced by learning objectives for participants to use to determine if the article relates to their individual learning needs.

2. Read the article carefully, paying particular attention to the tables and other illustrative materials.

3. Complete the CME Registration and Evaluation Form below. Type or print your full name and address in the space provided, and provide an evaluation of the activity as requested. In order for the form to be processed, all information must be complete and legible.

4. Send the completed form, with $20 payment if required (see Payment, below), to:

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5. Be sure to mail the Registration and Evaluation Form on or before January 15, 2002. After that date, this article will no longer be designated for credit and forms cannot be processed.

FACULTY DISCLOSURES

Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the author of "Varicella vaccine: What have we learned?"

Jay M. Lieberman, MD, is a member of Merck's Speakers Bureau and a recipient of grant support from Merck.

 

Jay Lieberman. Varicella vaccine What have we learned?. Contemporary Pediatrics 2001;1:50.