Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge

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.