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The phenomena of “vaccine encephalopathy” and post-vaccine developmental and epileptic encephalopathy (DEE) have been discussed for some time, though less so after the recognition that infants diagnosed with vaccine encephalopathy usually have Dravet syndrome secondary to SCN1A pathogenic variants.[1] However, for children with immunodeficiency, live-attenuated vaccines, including the measles-mumps-rubella (MMR) vaccine, can contribute to significant disease, which could include DEE. We present a boy who developed seizures and encephalopathy post-vaccination, evolving into infantile epileptic spasms syndrome (IESS, formerly West syndrome); genetic testing identified homozygous IFNAR2 (OMIM 602376) pathogenic variants.