The establishment of immune protection against a CNS viral challenge (VIR1P.1157)

Abstract

Abstract The neuroinvasive rabies virus (RABV) requires CD4 T and B cell infiltration into CNS tissue and local production of virus neutralizing antibody (VNA) in order to be successfully cleared. This occurs during attenuated but not in wild-type dog RABV infection. Effective protection against a CNS challenge with dog RABV is only established by a vaccination regimen that delivers RABV-specific immune effectors to the CNS. Mice that recover from an attenuated RABV of the CNS are protected long term against subsequent CNS challenge by pathogenic dog RABV, whereas long term protection is not seen in mice that received attenuated RABV in the gastrocnemius. This difference is likely to be due to the increased formation of memory like cells which remain in the brain following a direct CNS vaccination, resulting in a more robust and effective response during CNS challenge. Since the blood-brain barrier (BBB) evidently remains intact during dog RABV infection, it is likely that immune memory cells capable of reactivating to produce VNA upon challenge must be resident in the CNS rather than enter from the periphery. In support of this concept, adoptive transfer of RABV immune cells fails to protect against a dog RABV infection of the CNS. A robust CNS immune response during initial vaccination appears to be the only effective way to establish long term protection against a pathogenic RABV infection that reaches the CNS.