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

Abstract

Vaccination is highly effective in preventing various infectious diseases, whereas the constant threat of new emerging pathogens necessitates the development of innovative vaccination principles that also confer rapid protection in a case of emergency. Although increasing evidence points to T cell immunity playing a critical role in vaccination against viral diseases, vaccine efficacy is mostly associated with the induction of antibody responses. Here we analyze the immunological mechanism(s) of rapidly protective vaccinia virus immunization using mousepox as surrogate model for human smallpox. We found that fast protection against lethal systemic poxvirus disease solely depended on CD4 and CD8 T cell responses induced by vaccination with highly attenuated modified vaccinia virus Ankara (MVA) or conventional vaccinia virus. Of note, CD4 T cells were critically required to allow for MVA induced CD8 T cell expansion and perforin-mediated cytotoxicity was a key mechanism of MVA induced protection. In contrast, selected components of the innate immune system and B cell-mediated responses were fully dispensable for prevention of fatal disease by immunization given two days before challenge. In conclusion, our data clearly demonstrate that perforin-dependent CD8 T cell immunity plays a key role in MVA conferred short term protection against lethal mousepox. Rapid induction of T cell immunity might serve as a new paradigm for treatments that need to fit into a scenario of protective emergency vaccination.

Yeast Virus-Derived Stimulator of the Innate Immune System Augments the Efficacy of Virus Vector-Based Immunotherapy

“…To explain this prerequisite, we analyzed the infiltration of various cell types at the vaccination site. Kremer et al have reported the massive lung infiltration of monocytes, dendritic cells, neutrophils, and NK cells in the first 6 to 72 h after intranasal vaccination with MVA (39). We could demonstrate a similar scenario 24 to 48 h after subcutaneous injection of MVATG9931: neutrophils, NK cells, as well as macrophages and pDCs assembled around the injection site.…”

Discovering naturally processed antigenic determinants that confer protective T cell immunity

“…In one instance, immunization scheme I -in which priming was performed with peptide formulated with poly(I:C) plus anti-CD40 antibody -resulted in a much more robust TCD8 response against F4L [6][7][8][9][10][11][12][13][14] than that resulting from scheme II. Consequently, the former resulted in much better protection than the latter, which was essentially nonprotective (data not shown).…”

“…Moreover, when immunogenic, we also discovered that individual TCD8 specificities, despite similar functional competence, exhibited varied protective efficacy in active VACV infection. Critically, this varied protection was not directly linked to TCD8 frequency elicited by vaccination: e.g., some responders at lower frequency (A3L [192][193][194][195][196][197][198][199][200] ) were more protective than others elicited at higher frequency (F4L [6][7][8][9][10][11][12][13][14], whereas some responders (L4R [37][38][39][40][41][42][43][44][45] were not protective regardless of their frequency. It is likely that differential abundance of determinants and/or kinetics of their natural presentation define visibility of infected cells to cognate TCD8 in vivo, thus restricting protective responses to specificities that efficiently recognize infected cells.…”

“…CD8 + T cells (TCD8) play a critical role in conferring protective immunity against many infectious diseases, including those caused by respiratory viruses (7)(8)(9)(10)(11), cytomegalovirus (12), HIV (13), Plasmodium spp. (14,15), and M. tuberculosis (16,17).…”

“…In this study, we used VACV as a model, because a critical role has been attributed to TCD8 in conferring protective immunity against lethal respiratory VACV infection (10,11). Using data from a comprehensive proof-of-principle study for the identification of potent TCD8 targets from a complex virome, we report large-scale discovery and immunologic characterization of naturally processed antigenic determinants of VACV that are presented by five frequent HLA class I allotypes that represent four major class I supertypes.…”