We developed a regression model of VZV-specific memory CD4 responses as a function of age, from early childhood to advanced adulthood, among healthy individuals who had wildtype VZV infection. This model allowed us to construct a reference curve of VZV RCF on age, against which we compared VZV RCF results of select groups of VZV-experienced hosts. Because we defined a continuous relationship between VZV RCF and age, the comparisons of the select groups with the reference group did not require exact age matching.
The reference model showed that VZV RCF was highest in young adults, despite the fact that most individuals contract VZV infection during childhood. This is contrast with other studies [20
], which failed to detect a bell shape relationship of VZV-specific cell-mediated immunity on age, perhaps because of limited sample size and use of semiquantitative or qualitative cell-mediated immunity measurements.
In our study, the majority of the VZV cell-mediated immunity data were generated prior to widespread administration of varicella vaccine, when wild-type VZV was circulating in the community. The curve of the VZV RCF as a function of age, with a peak at the age of 34 years, most likely reflects environmental boosting in response to exposure to varicella at home and in the community. Environmental boosting has been demonstrated by measuring responses in individuals after known exposures to varicella [22
] and has been suggested by modeling and case-control studies of large populations [24
]. Universal varicella vaccination may remove environmental boosting and accelerate the loss of VZV-specific memory CD4 cells that normally occurs with age. This may increase the likelihood that herpes zoster will occur earlier in life for individuals with latent wild-type VZV infection [24
After the age of 55 years, VZV-specific memory CD4 responses became undetectable in 30%–40% of subjects, contributing to the decrease of the VZV RCF estimates in the older groups. This age-specific decrease in VZV memory CD4 cells is the likely explanation for the increase in the incidence of herpes zoster with age. It is noteworthy that VZV RCF values began to decrease at ~35 years, although it is unlikely that environmental exposure ceased at that age.
An effective vaccine against herpes zoster was licensed in 2006 in the United States [28
]. Our studies of the VZV RCF responses to a vaccine similar to the licensed zoster vaccine indicate that there is an inverse relationship between age and VZV RCF responses to the vaccine, which is in agreement with other studies that used the licensed zoster vaccine [8
]. Although the VZV RCF estimate decreased with increasing age in older zoster vaccine recipients, it was significantly higher than the VZV RCF of individuals over the same age range in the reference group. It is noteworthy that elderly vaccinees aged ≤75 years had higher VZV RCF results than the young adults after wild-type infection, but this observation has to be interpreted with caution because the VZV RCF of elderly vaccinees was measured 6 months to 2 years after immunization, whereas the VZV RCF of young adults was measured after an unknown length of time from the last exposure to VZV. We previously showed that the RCF values observed in older individuals after vaccination are comparable to the RCF values after herpes zoster [29
]. The boost in VZV-specific cell-mediated immunity conferred by the vaccine is probably important for preventing or aborting reactivation of latent VZV and is the presumed explanation for the efficacy of the zoster vaccine in preventing and attenuating herpes zoster in elderly people [8
In initially seronegative varicella vaccine recipients, the VZV RCF was positively correlated with age at the time of testing. Because the VZV RCF was measured at variable times after the administration of the vaccine, environmental boosting may have contributed to the growth curve of VZV RCF on age. This was also demonstrated with measurements of VZV-specific antibodies in vaccinees followed over a decade [30
]. In these children, antibodies increased with the interval after vaccination. The comparison of VZV RCF of varicella vaccine recipients with the reference group showed lower VZV RCF in the vaccinees aged <5 years, compared with children of the same age who had wild-type VZV infection. This result is consistent with the observation that some children do not seroconvert after vaccination when seroconversion is measured with a highly specific VZV antibody test, FAMA [31
]. Our observation is also consistent with the higher incidence of varicella break-through disease in vaccine recipients, compared with the extremely low incidence of secondary cases of varicella after wild-type VZV infection [30
]. To address the varicella break-through issue, the childhood vaccination schedule currently includes a second dose of varicella vaccine at 5 or 6 years of age [33
The VZV RCF estimates were very low and did not vary with age in HIV-infected children and adolescents with previous wild-type VZV infection. In HIV-infected adults, the limitations of the available data did not support construction of a regression model of VZV RCF on age, but the differences in VZV RCF among 3 age categories (21–35, 36–50, and >50 years) were not appreciable. The flatness of the VZV RCF on age curve in HIV-infected individuals suggests a lack of environmental boosting, most likely because the underlying immunosuppression impedes significant postexposure boosts of cell-mediated immunity. The low VZV RCF values in HIV-infected individuals are consistent with the high incidence of herpes zoster in this population, which persists in the era of highly active antiretroviral therapy [34
]. The excellent VZV RCF responses to the varicella vaccine observed in HIV-infected children (see below) suggest that HIV-infected individuals with prior varicella may respond adequately to a zoster vaccine and become protected against herpes zoster.
We studied VZV RCF responses to a 2-dose varicella vaccine regimen in VZV-seronegative HIV-infected children with CD4 levels ≥20% receiving stable antiretroviral therapy. In contrast to normal hosts with wild-type infection or primary VZV vaccination, VZV RCF of HIV-infected vaccine recipients did not vary with age. Responses of HIV-infected children were uniformly assessed at the same intervals after vaccination, minimizing the potential interaction between age and environmental boost. However, it is likely that the underlying immunosuppression in these children may have also contributed to the obfuscation of the effect of age on immune responses, as it did for RCF responses after wild-type infection in HIV-infected children. Although there was a difference in the ethnic composition of HIV-infected children in this study (50% African American, 25% white, and 24% Hispanic), compared with the ethnic composition of the uninfected children in this study (5% African American, 60% white, and 20% Hispanic), this difference is unlikely to have affected the comparison of their responses to VZV, because within each group of HIV-infected or uninfected children, responses did not vary with ethnicity. VZV RCF estimates of HIV-infected vaccinees were higher than those of HIV-infected children with wild-type infection. This is most likely attributable to the fact that vaccination occurred at a time when the HIV infection was under relatively good control, with or without antiretroviral treatment, attested by CD4 levels ≥20% [6
]. In contrast, wild-type VZV infection may have occurred during or been followed by periods of profound immunosuppression, when children were unable to mount vigorous VZV RCF responses or lost specific T cell responses, respectively [5
]. VZV RCF of HIV-infected children after vaccination or chickenpox did not correlate with CD4 percentage at the time of vaccination or blood sample collection. In vaccine recipients, the RCF correlated with the plasma HIV RNA level at the time of vaccination only, whereas after varicella, the RCF correlated with the plasma HIV RNA at the time of the blood sample collection. VZV RCF estimates of HIV-infected varicella vaccine recipients did not significantly differ from those of the reference group, supporting the protective effect of the vaccine in this population of immunocompromised children and adolescents.
The magnitude of VZV RCF varied with the nature of the primary immunizing event (wild-type infection or vaccine) and the age and immunocompetence of the host. The latter are important determinants of clinically apparent VZV reactivation in individuals with latent wild-type VZV infection. The effect of aging and immunocompetence on VZV reactivation in individuals whose latent virus is of vaccine origin is uncertain.