Varicella Vaccine: Rare Serious Problems—but the Benefits Still Outweigh the Risks

Included in this issue of the Journal are 2 case reports involving children who developed severe complications after immunization with the Oka strain of live attenuated varicella vaccine. Levy et al. report an 11-year-old girl who developed life-threatening pneumonitis with a generalized varicelliform rash 5 weeks after vaccination; she was successfully treated with intravenous acyclovir (ACV) [1]. This complication, which would be classified as a vaccine-associated rash with pneumonitis, had not previously been observed in a vaccinated healthy child. Not surprisingly, this girl was eventually found to have an underlying immunodeficiency disease: a novel and rare deficiency in NK T cells. Her immunodeficiency had presented only as recurrent upper-respiratory-tract infections; no mention is made of past measles immunization, and she may not have had difficulties with this vaccine. The other child, reported by Levin et al., was a 1-year-old boy who had a prolonged and dramatic case of zoster after being vaccinated with the Oka strain of varicella-zoster virus (VZV); this complication also had not previously been reported after vaccination of healthy children [2]. This boy was originally thought to be healthy when he was vaccinated against varicella; however, 5 days after receiving the vaccine, he was diagnosed with neuroblastoma, and chemotherapy was administered. After 3 months of anticancer treatment, he developed zoster at the injection site, and, despite treatment with intensive intravenous and oral ACV as well as foscarnet, his zoster waxed and waned for almost 1 year. At one point he developed involvement of the central nervous system and had an extensive generalized skin rash. The Oka virus causing his illness was demonstrated to be resistant to ACV; eventually the infection was partially controlled by foscarnet. The boy’s VZV infection eventually cleared, but only after his chemotherapy had ended and his immune function had been restored In both of these children, diagnosis of VZV Oka-strain infection was made on the basis of polymerase chain reaction (PCR) analysis. An attempt to culture virus from 1 of these patients did not yield virus, but there is no question about the diagnosis in either of them. Both of these cases were dramatic and frightening, and it is important to try to put them into perspective. Do they suggest that one ought not to use varicella vaccine routinely, because it may be too dangerous? Past experience from formal studies of vaccination, even of immunocompromised children, indicates that events such as these are very rare. In a collaborative study of immunization of ∼600 varicella-susceptible American and Canadian children with leukemia in remission, performed between approximately 1980 and approximately 1990, extensive and prolonged severe varicelliform or zosteriform skin reactions due to the Oka strain were infrequent [3–5]. These children were among the first North Americans to be immunized with the Oka vaccine. They were vaccinated in clinical trials to determine whether it might be possible to prevent them from developing severe or fatal varicella, because, at that time, numerous children were being cured of leukemia only to die from natural chickenpox. After such children were vaccinated safely and efficaciously, interest turned to immunization of healthy, rather than immunocompromised, children. The leukemic vaccinees were in remission for ⩾1 year and were still receiving maintenance chemotherapy when they were immunized. Although as many as 25% were given ACV to control a vaccine-associated rash, <0.2% developed pneumonitis. All the complications were treated successfully; in fact, the entire study was able to be performed only because the Oka strain was sensitive to ACV [6] Zoster also is rare after immunization, even in immunocompromised children [7–9]. In the leukemic vaccinees, the incidence of zoster was 8 cases/1000 person-years, which is ∼3 times less frequent than that seen in leukemic children who have had natural varicella and 2–4 times more frequent than that seen in healthy adults after natural infection [7, 10–12]. In one study, none of 18 leukemic vaccinees with zoster, even those who had undergone bone-marrow transplantation, had a prolonged rash illness [7] (author’s unpublished data). To manifest zoster for almost 1 year is remarkable, and it is reminiscent of a reported 4-year-old child infected with human immunodeficiency virus who had zoster for >1 year, despite being treated with ACV [13]; in contrast to the patient reported by Levin et al., she had a history of natural varicella. In both of these patients with zoster, the causative VZV was resistant to treatment with ACV. This also is a rare phenomenon and has been reported, as recorded in the article by Levin et al., on <20 occasions, with the wild-type virus, and only in immunocompromised patients. It now appears that, on rare occasions, the Oka strain can also become resistant to ACV. As is suggested by Levin et al., it makes sense to suspect that, when chronic verrucous lesions develop despite what should be adequate therapy, especially in an immunocompromised patient, ACV-resistant VZV is likely to be present, and foscarnet should be considered sooner rather than later. Unfortunately, rapid laboratory assays to determine resistance to ACV are not generally available, so one must rely on clinical judgment. It is fortunate that, despite the aggressive appearance of these chronic skin lesions, the infectivity of these viruses seems to be low, both for virus isolation in cell culture and for human contact Live attenuated varicella vaccine was licensed for routine use in children in 1995, and, since that time, >40 million doses of vaccine have been distributed in the United States. At present, ∼4 million children are vaccinated annually. Zoster after vaccination of healthy children also appears to be rare, with <40 recorded cases in which the Oka strain has been found to be causative [14, 15]. It is not yet clear why this should be so; there is some experimental evidence that absence of skin lesions in the overwhelming number of vaccinees after immunization may be critical. First, the Oka strain of VZV has decreased ability to replicate in human skin, compared with the wild-type virus in the SCID-hu mouse model [16]. Second, in a model using isolated enteric guinea-pig neurons in culture, cell-free VZV is necessary to establish latent infection [17]. In human infection, the enveloped or cell-free form of VZV develops primarily in superficial layers of the skin, where virions collect, in high concentration, in vesicular fluid. After vaccination, enveloped VZV that can invade sensory nerves is rarely present in the skin. Thus, the propensity of the Oka strain not to infect the skin after vaccination [18] may prevent the virus from establishing latency. It is known from a rat model, however, that the Oka strain has the ability to establish latency after inoculation of cell-free virus into the hind limb of that animal [19, 20]. Thus, the Oka strain is capable of establishing latency but, because of its usual absence from the skin, may have a limited opportunity to do so after vaccination In healthy children, the varicella vaccine appears to be extremely safe [14], and reports such as those in this issue of the Journal should not dampen our enthusiasm for routine use of the vaccine. To assess vaccine safety accurately, it is necessary to be able to differentiate between rashes caused by the wild-type VZV and those caused by the Oka strain. Fortunately, it has been possible, from the beginning of vaccine trials in the United States, to distinguish between wild-type VZV and the Oka strain, by either culture, DNA analysis, or PCR methodology [21, 22]. Since its licensure in 1995, ∼40 million doses of varicella vaccine have been administered, but there have been only 5 reports of severe reactions in immunized children, and all were found in immunocompromised or immunodeficient vaccinees, although this was not necessarily apparent at the time of immunization; the first 3 cases have been reported elsewhere [14, 23, 24], and the other 2 are reported in this issue of the Journal. No vaccinee has died from the vaccine virus, a result that is very different than what would be predicted for wild-type VZV. Nevertheless, it is recommended that children who are known to be immunocompromised not be immunized It is not surprising, however, that a few apparently healthy immunocompromised individuals have been “unmasked” by severe reactions to varicella vaccine. This also has occurred after receipt of live attenuated measles vaccine [25–27] Today, one depends on herd immunity [28, 29], rather than on direct immunization, to protect patients who are at high risk to develop severe or fatal varicella. It is a remarkable testimony to the skills of pediatricians in the United States that they have refrained from immunizing patients who might be immunocompromised, resulting in the extreme rarity of events reported in this issue of the Journal