088 Skin delivery of modified vaccinia ankara (MVA) virus generates superior protective pulmonary immunity

Abstract

No viral infection has shaped human history more profoundly than smallpox (Variola major). Although it was eradicated in vivo by a world-wide vaccination program by 1980, it remains a potential threat via bioterrorism, as most of the world’s population has never been immunized. There is an unacceptable incidence of morbidity after vaccinia virus (VACV) vaccination, particularly in individuals with atopic disorders. Therefore, a less virulent replication deficient variant of VACV, called MVA, has been developed. In all prior studies in humans, MVA has been delivered via intramuscular (im) injection. Variola major is transmitted by respiratory droplets, and successful immune response to V. major are T cell rather than antibody mediated. We showed that MVA as low as 1.8 X 106 pfu delivered by skin scarification (ss) elicited strong T cell mediated responses that completely protected mice against lethal respiratory challenge. MVA could be safely inoculated to skin of immunocompromised mice without any morbidity. Nearly equivalent numbers of lung tissue TRM could be generated via MVA ss compared to direct pulmonary infection; both were sufficient to protect mice against lethal pulmonary challenge with WT VACV. Strikingly, MVA ss-generated activated T cells exhibiting similar global gene transcriptional profile with those generated via pulmonary infection. Moreover, comparisons of ss with other vaccine delivery routes employed in clinic (id, sc or im) showed that MVA ss-generated T cells were both more abundant and qualitatively superior. Specifically, MVA ss produced more lung CD8+ TRM and was superior in protecting mice against lethal respiratory challenge. Mice genetically deficient in LC and Langerin+ DC demonstrated that both are required for generating an optimal CD8+ T cell response. Our data show that ss with MVA generates robust pulmonary protective immunity, and could be used as a safe and superior vaccine strategy against smallpox. This may be the preferred mode of delivery for MVA as a vaccine vector for other infectious and malignant diseases.