Insights From Studies of the Genetics, Pathogenesis, and Immunogenicity of the Varicella Vaccine

Abstract

While the varicella vaccine was created with approaches established for other live attenuated viral vaccines, novel methods to probe virus-host interactions have been used to explore the genetics, pathogenesis, and immunogenicity of the vaccine compared to wild-type varicella-zoster virus (VZV). As summarized here, a mechanism-based understanding of the safety and efficacy of the varicella vaccine has been achieved through these investigations.

Keywords: herpesvirus; varicella vaccine; varicella-zoster virus; varicella-zoster virus pathogenesis.

Figure 1.

Evaluation of the pathogenic potential of the varicella vaccine in human T-cell xenografts in the SCID mouse model. A, Viral replication in T cells from xenografts inoculated with wild type or vOka was determined by infectious foci assay using Vero cell monolayers to test T cells obtained at 0, 7, 14, and 21 days; the geometric mean titers are shown with bars representing the standard error of the mean. The dotted line is the level of detection of the assay. Histologic analysis of xenografts at 21 days showed massive T-cell loss, accounting for the failure to detect infectious virus. B, T cells were analyzed by flow cytometry at 7 days after inoculation with wild type, vOka, or uninfected cells; the percentage of infected T cells with subpopulations was determined by staining with antibodies to VZV proteins and antibodies to CD4, CD8, and CD4/CD8 T-cell surface markers; background fluorescence is shown for nonimmune serum. Abbreviations: SCID, severe combined immunodeficiency; vOka, vaccine Oka virus; VZV, varicella-zoster virus. Adapted from Moffat et al, J Virol 1995 [24].

Figure 2.

Evaluation of the pathogenic potential of the varicella vaccine in human skin xenografts in the SCID mouse model. A–C, Skin xenografts were infected with mock-infected (A), pOka (B), or vOka infected (C) and fixed, paraffin-embedded sections were tested for the presence of VZV DNA by in situ hybridization and counterstained with hematoxylin (magnification: ×61). At day 21 postinfection, large pOka skin lesions were present and VZV DNA was detected deep within dermal fibroblasts (arrow) (B) whereas the basement membrane remained intact in vOka lesions (arrows) (C) and virus did not penetrate into the dermis; mock-infected skin had a normal appearance and VZV DNA was not detected. D, Infectious virus yields (infectious foci/mL) (y-axis) were compared from xenografts inoculated with pOka and vOka at 14, 21, and 28 day time points (x-axis). The geometric mean titers are shown with bars representing the standard error of the mean. Abbreviations: pOka, parent Oka virus; vOka, vaccine Oka virus; VZV, varicella-zoster virus. Adapted from Moffat et al, J Virol 1995 [25].

Figure 3.

Schematic of the attenuation of varicella vaccine. When varicella vaccines are given by subcutaneous inoculation, vOka encounters the robust intrinsic host cell defenses characteristic of human dermal and epidermal cells, mediated in particular by triggering the type I interferon signaling pathway. These defenses are present and function to control vOka at the vaccination site in both immunocompetent and immunocompromised individuals. VZV-specific T-cell immunity is typically induced shortly after vaccination in immunocompetent vaccinees, followed by IgG antibodies to VZV, both of which persist as memory immune responses. Varicella vaccination is contraindicated in immunocompromised children. However, delayed cellular immunity may allow continued vOka replication if the vaccine is given inadvertently or before the diagnosis of an immunodeficiency. Because vOka retains T-cell tropism, T cells trafficking into skin may become infected, causing viremia and the risk of vOka dissemination to lungs, liver, and other organs. Under these circumstances, the sensitivity of vOka genomes to acyclovir means that antiviral treatment can compensate for the delayed VZV-specific immunity, with eventual acquisition of VZV-specific immunity in most cases. Abbreviations: IgG, immunoglobulin G; vOka, vaccine Oka virus; VZV, varicella-zoster virus.