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.
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We thank B. Moss (US National Institute of Health (NIH)) for providing rVACV expressing EGFP and OT-I T cell epitope OVA257–264, as well as WR-VACV. We thank K. Rock (University of Massachusetts Medical School) for providing the MO5 cell line and M. Seaman (Beth Israel Hospital) for providing the MVA stocks. FTY720 was provided by V. Brinkmann at Novartis Pharmaceuticals. This work was supported by NIH–US National Institute of Allergy and Infectious Diseases grants R01 AI042124 and R37 AI025082 to T.S.K. and NIH grant U19AI57330 subcontracted to T.S.K., a Dermatology Foundation Research Career Development Award to L.L. and a Career Development Award and a New Opportunities Grant to L.L. from US National Institute of Allergy and Infectious Diseases–New England Regional Center of Excellence/Biodefense and Emerging Infectious Disease (AI057159).
Supplementary Figures 1–8 and Supplementary Methods