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

Kremer, Melanie; Suezer, Yasemin; Volz, Asisa; Frenz, Theresa; Majzoub, Monir; Hanschmann, Kay-Martin; Lehmann, Michael H.; Kalinke, Ulrich; Sutter, Gerd

Prophylactic use of vaccinia virus allowed eradication of human smallpox, one of the greatest successes in medicine. However there are concerns that variola virus, the infectious agent of smallpox, may be used as bioterroristic weapon and zoonotic monkeypox or cowpox remain threatening infections in humans. Thus, new developments of safe and rapidly protecting orthopoxvirus-specific vaccines have been initiated. The candidate vaccine modified vaccinia virus Ankara (MVA) was recently shown to protect against lethal systemic poxvirus disease even when applied shortly before or after infection of mice with ectromelia virus, the probably best animal model for human smallpox. Surprisingly, little is known about the protective mechanism of early immune responses elicited against orthopoxvirus infections. Here, we used the mousepox model to analyze the immunological basis of rapidly protective MVA vaccination. In contrast to common understanding of orthopoxvirus vaccine efficacy relying mainly on antibody mediated immunity, we observed unimpaired protection also in absence of B cells. Surprisingly, rapid protection by vaccination with MVA or conventional vaccinia virus was solely dependent on T cells, irrespective of the route of injection. Thus, our study suggests a key role for T cell immunity in rapidly protective immunization against orthopoxviruses and potentially other infectious agents.