Pathogenesis of infection with varicella vaccine

Because of its exanthem, the disease varicella has been known since antiquity. Even late in the 19th century, however, there remained considerable confusion between mild smallpox and chickenpox. The name varicella itself is an irregular diminutive form of variola. Yet, early in the 20th century, detailed histologic studies began to differentiate the exanthems. The investigation of the varicella vesicle by Tyzzer 90 years ago remains a classic example (see Fig. 2). Although the pathogenesis of varicella vaccine virus infection appears to mimic that of wt VZV infection, a vaccine virus-related exanthem is more common in immunized children with an underlying immunosuppressive condition, such as leukemia, than in normal children. Those immunized children who never develop a rash presumably have an abrogated infection in which the host immune response has eliminated the virus prior to a major viremic spread. There may be a correlation between the presence of an exanthem and the ability of an immunized child to spread the varicella vaccine virus. The differences in capsid structure and assembly may explain in part the attenuation of the vaccine strain. Because the majority of varicella vaccine virus particles in the nucleus have aberrant cores lacking an electron-dense center, they are never enveloped. Therefore, they do not become infectious virions. In a recent article, Grose et al applied the technique of three-dimensional (3-D) computer modeling in an attempt to reconstruct an aberrant VZV capsid with the hubcap or pinwheel core. Each 3-D model was then sliced by computer to obtain a series of two-dimensional models that represented the images commonly seen by traditional electron microscopy. The 3-D model that best represented the capsid with a pinwheel core contained particulate matter in each of the 12 vertices of the icosahedral capsid (Fig. 14). This model strongly suggested that VZV may form in the nucleus an intermediary or end-stage capsid with an aberrant distribution of assembly protein or viral DNA within its core. Herpes simplex viral particles with pinwheel cores are rarely seen in cell culture, so this type of aberrant capsid appears to be associated mainly with VZV replication. Thus, the strategy of Takahashi and colleagues to serially passage the varicella vaccine virus in human embryonic lung cells, guinea pig embryo cells, and Wistar Institute strain 38 (WI-38) cells may have exploited in as yet unknown ways the profound cell-associated nature of VZV to achieve an end product with attenuated pathogenic potential.