Human cytotoxic T-cell memory: long-lived responses to vaccinia virus

Abstract

Peripheral T lymphocytes can be classified into two groups: naive and memory T cells. The focus of this study was to examine the duration of T-cell memory in humans. Vaccinia virus replicates in the cytoplasm of infected cells and is not thought to persist or become latent after the acute phase of infection. We identified long-lived vaccinia virus-specific memory cytotoxic T cells in adults who had been immunized against smallpox as children. Initially, we detected vaccinia virus-specific T cells in peripheral blood mononuclear cells while screening for human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses in HIV-1-seropositive subjects. These individuals had not had contact with vaccinia virus since their primary immunization in early childhood. Several vaccinia virus-specific CD4 ؉ T-cell clones were derived from these donors and characterized. Healthy, HIV-1-seronegative donors who had been immunized against smallpox many (35 to 50) years earlier were also screened for vaccinia virus-specific T-cell immunity. We found significant CD8 ؉ and CD4 ؉ cytotoxic T-cell responses to vaccinia virus after in vitro stimulation, indicating that these memory cells are maintained in vivo for many years. The peripheral blood mononuclear cells of young adults with no history of immunization against smallpox did not develop vaccinia virus-specific T-cell responses after in vitro stimulation. Precursor frequency analysis of the vaccinia virus-specific memory CD4 ؉ T cells from a donor immunized with vaccinia virus 35 years earlier revealed a frequency of 1 in 65,920 CD4 ؉ T cells. We concluded that specific vaccinia virus T-cell immunity can persist for up to 50 years after immunization against smallpox in childhood in the presumed absence of exposure to vaccinia virus.

Immunogenicity and protection efficacy of monovalent and polyvalent poxvirus vaccines that include the D8 antigen

“…First, the polyvalent poxvirus vaccine formulations and vaccinia vaccines also included EEV antigens and thus EEV-mediated neutralizing antibodies may play an important role for part of the protection as reported by previous studies (Appleyard et al, 1971;Boulter and Appleyard, 1973;Fogg et al, 2004;Galmiche et al, 1999;Hooper et al, 2003Hooper et al, , 2004Law and Smith, 2001). Second, cell-mediated immunity (CMI) may also be critical for protection against smallpox infection (Demkowicz et al, 1996;Ennis et al, 2002;Frey et al, 2002;Kennedy et al, 2004). The finding that the increased IMV neutralizing antibody did not correlate with increased protection will have important impact to the design of subunit-based poxvirus vaccines.…”

“…However, more studies are still needed to establish the scale-up production of these vaccines and to confirm their safety profile in larger human populations. Although vaccinia virus is a potent vaccine and has the distinct ability to produce long lasting immunity in humans (Crotty et al, 2003;Demkowicz et al, 1996), the nature of its protective antigens has just begun to be revealed (Fogg et al, 2004;Hooper et al, 2004;Pulford et al, 2004). The corresponding epitopes involved in the activation of host immune responses at the B and T cell level that lead to protective immunity are much less understood.…”

Critical Role of Perforin-dependent CD8+ T Cell Immunity for Rapid Protective Vaccination in a Murine Model for Human Smallpox

“…Mass immunization with VACV during the smallpox eradication program indicated a critical role for cellular immune responses, since severe complications could occur in patients with T cell deficiencies [31][32][33]. However very little information is available on the role of cell-mediated immunity in protective VACV vaccination, although more recent analyses suggest that humans maintain VACV specific T cells for decades after vaccination [34][35][36].…”

LC16m8: An attenuated smallpox vaccine

“…The duration of humoral and cell-mediated protective immunity afforded by smallpox vaccination remains unknown, yet there is both empirical [96,97] and experimental [43,[98][99][100] evidence that some degree of immunity to smallpox persists for several decades postvaccination. In addition, Hammarlund and colleagues recently reported that smallpox vaccination as much as 48 years pre-exposure conferred immunity to humans exposed to monkeypox [101].…”