Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell–mediated immunity

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
Smallpox was eradicated by vaccination with a related poxvirus, vaccinia virus, which was applied to superficially injured skin in a process called scarification. Recombinant poxvirus–based vaccines are attractive candidates for protecting against a number of different infections, but they are nowadays usually administered intramuscularly. Thomas Kupper and his colleagues now show that the traditional route of administration, scarification, enables poxvirus-based vaccines to mediate more potent immunity compared with the intramuscular route. In particular, scarification with the poxvirus vaccines induced the sort of immune responses that are required for protection of distant tissues, including the lung mucosa. Variola major (smallpox) infection claimed hundreds of millions lives before it was eradicated by a simple vaccination strategy: epicutaneous application of the related orthopoxvirus vaccinia virus (VACV) to superficially injured skin (skin scarification, s.s.)1. However, the remarkable success of this strategy was attributed to the immunogenicity of VACV rather than to the unique mode of vaccine delivery. We now show that VACV immunization via s.s., but not conventional injection routes, is essential for the generation of superior T cell–mediated immune responses that provide complete protection against subsequent challenges, independent of neutralizing antibodies. Skin-resident effector memory T cells (TEM cells) provide complete protection against cutaneous challenge, whereas protection against lethal respiratory challenge requires both respiratory mucosal TEM cells and central memory T cells (TCM cells). Vaccination with recombinant VACV (rVACV) expressing a tumor antigen was protective against tumor challenge only if delivered via the s.s. route; it was ineffective if delivered by hypodermic injection. The clinically safer nonreplicative modified vaccinia Ankara virus (MVA) also generated far superior protective immunity when delivered via the s.s. route compared to intramuscular (i.m.) injection as used in MVA clinical trials. Thus, delivery of rVACV-based vaccines, including MVA vaccines, through physically disrupted epidermis has clear-cut advantages over conventional vaccination via hypodermic injection.