Krause and Klinman reply

Our article examined the frequency of clinical infection and immunologic boosting in 4,631 children immunized with OkaVZV and followed annually for up to four years1. The rate of infection plus boosting in children with anti-VZV titers measured by gpELISA of less than 1.25 units was 32% per year, significantly exceeding their 12.1% annual exposure rate to wild-type VZV. This suggests that OkaVZV reactivates as immunity wanes, thereby boosting and prolonging host protection from wild-type infection. Our analysis indicates that the overwhelming majority of OkaVZV reactivations are asymptomatic. However, in children with persistently low antibody titers (∼1% of the study population), mild chickenpox-like disease developed at an annual rate of 54%, suggesting that OkaVZV reactivation could cause disease.

Seward et al., argues that the infection plus boost rates of children with low anti-VZV titers can be attributed to high rates of exposure to circulating wild type. They reference a study in which wild-type exposure rates were 16–26% in 3–6-year-olds2. Because wild-type exposure varies with age and location, we relied on results from two placebo controlled studies of seronegative recipients performed as part of the vaccine trials analyzed in our article (60 cases of chickenpox were observed over 496 patient-years of follow-up, for a cumulative rate of 12.1 ± 1.4%/yr)17,18. In response to Seward's letter, we calculated the rate of wild-type exposure among susceptible children using the data provided in their reference2. When adjusted for the precise age distribution of the children we studied (which included many outside the range of 3–6 years), the average wild-type exposure rate was 14.1%/yr. This rate approximates that observed in the placebo controlled trials, and cannot explain the 32 - 54%/yr infection plus boost rate seen in children with low and persistently low anti-VZV titers (P < .001 for both comparisons). A logical explanation for these excess infections and boosts is asymptomatic reactivation of the vaccine strain.

LaRussa et al., reports on efforts to identify VZV in pox vesicle scrapings from vaccinees with 'breakthrough' chickenpox. They identified wild type in 57/93 children from whom adequate samples were obtained, but their strain-specific PCR failed to detect OkaVZV in 36 children with disseminated disease. Because attenuated OkaVZV grows less well in vivo than does wild type19, less virus would be available for PCR amplification from lesions of children infected with OkaVZV than wild type. Thus, it is possible that OkaVZV caused illness in some of the approximately 40% of children diagnosed with breakthrough chickenpox. The alternative, proposed by LaRussa, is that trained pediatricians misdiagnose over one-third of varicella cases. It should also be noted that the sensitivity of the PCR technique reported by LaRussa was obtained using highly purified laboratory grown viral DNA assayed under optimal conditions. In PCR assays, contamination by protein and foreign DNA (present in pox vesicle scrapings) can reduce the sensitivity of such assays by orders of magnitude.

Data in our article showed that the vast majority of OkaVZV reactivations were asymptomatic, and predicted that OkaVZV caused 'breakthrough' disease only in that minority of children with persistently low anti-VZV titers. Thus, it is not surprising that LaRussa finds many cases of breakthrough disease caused by wild type. However, LaRussa failed to monitor these subject's anti-VZV titers, so that the fraction at risk from OkaVZV-induced disease cannot be determined. Moreover, children with mild OkaVZV-induced breakthrough disease may not visit their pediatricians, skewing the samples analyzed by LaRussa towards children with severe wild-type–induced disease. To resolve these uncertainties, LaRussa could prospectively identify subjects with persistently low anti-VZV titers, identify those with breakthrough disease, and analyze samples using a PCR assay of known sensitivity for OkaVZV in vesicular fluid.

We agree with LaRussa and Seward that immunologic factors in addition to anti-VZV titer (including cell-mediated immunity) may influence the rate of disseminated OkaVZV reactivation. Indeed, we found that children with persistently low anti-VZV titers developed disease at a much higher rate than children whose titers were low for shorter periods of time (54% versus 12%), suggesting that the reactivation rate is not determined solely by anti-VZV titer.

Our central finding was that OkaVZV reactivation (which is typically asymptomatic) serves to boost immunity in children with waning anti-VZV titers, thereby extending vaccine-induced protection. Neither correspondent provides a plausible explanation for the significant excess of infections plus boosts in children with low antibody titers when compared to the wild-type exposure rate. LaRussa's finding that OkaVZV causes herpes zoster is consistent with our conclusion that OkaVZV persists in vivo and can reactivate. As universal immunization reduces the frequency of wild-type exposure, ongoing studies should more precisely establish the rate at which OkaVZV reactivates to boost immunity in healthy children

See “Varicella vaccine revisited” by Seward et al.

See “Varicella vaccine revisited” by LaRussa et al.