Spore powder from reishi (Ganoderma lucidum) significantly strengthened the immune response to COVID-19 vaccine boosters by enhancing IFN-α activity. Participants showed higher neutralizing antibody levels 90 days after vaccination, along with increased activation of monocytes, T cells, and B cells. Single-cell multi-omics revealed that ganoderic acid H was the key compound driving this effect, suggesting reishi spores could be a powerful, natural vaccine adjuvant.