Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.
Varicella zoster virus (VZV) causes chickenpox and establishes a life-long latent infection in humans. VZV can reactivate years later to cause shingles, a debilitating and painful disease. Vaccines against both chickenpox and shingles are available but not 100% efficacious. Two doses of the chickenpox vaccine are required to provide adequate protection and the shingles vaccine reduces the incidence of this disease by 51%. To improve these vaccines, we must identify the components of the immune system that are important for the control of VZV replication. However, the contribution of T versus B cell responses is unknown. Infection of rhesus macaques with simian varicella virus is a robust model of VZV infection. Here, we used this unique animal model to show for the first time that the absence of B cells does not alter disease severity and that the loss of CD8 T cells only results in a mild increase in disease severity. In sharp contrast, the lack of CD4 T cells leads to disseminated varicella. These data highlight the importance of CD4 T cells and suggest that novel vaccines that focus on engendering a more robust CD4 T cell response against VZV might provide better protection from chickenpox and shingles.