Skin Delivery of 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. Transmission of Variola is by respiratory droplets, and MVA delivered by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with VACV than any other route of delivery, and at much lower doses. Comparisons of s.s. with intradermal, subcutaneous or intramuscular routes showed that MVA s.s.-generated T cells were both more abundant and transcriptionally distinct. MVA s.s. produced greater numbers of lung Ova-specific CD8 T and was superior in protecting mice against lethal VACV respiratory challenge. Nearly as many lung T were generated with MVA s.s. compared to direct pulmonary immunization with MVA, and both routes vaccination protected mice against lethal pulmonary challenge with VACV. Strikingly, MVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via direct pulmonary immunization. Overall, our data suggest that heterologous MVA vectors delivered via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens like COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.