Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s s ) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses Comparisons of s s with intradermal, subcutaneous, or intramuscular routes showed that MVA(OVA) s s -generated T cells were both more abundant and transcriptionally unique MVA(OVA) s s produced greater numbers of lung Ova-specific CD8(+) T(RM) and was superior in protecting mice against lethal VACV(OVA) respiratory challenge Nearly as many lung T(RM) were generated with MVA(OVA) s s immunization compared to intra-tracheal immunization with MVA(OVA) and both routes vaccination protected mice against lethal pulmonary challenge with VACV(OVA) Strikingly, MVA(OVA) s s -generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization Overall, our data suggest that heterologous MVA vectors immunized via s s are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19 In addition, MVA delivered via s s could represent a more effective dose-sparing smallpox vaccine