<b>PRISMA checklists</b>

Brucellosis is a major zoonosis that threatens both public health and livestock production worldwide. Current live vaccines (e.g., S19, RB51, A19) have limitations in safety and field applicability. Numerous Brucella abortus S2308-derived gene-deletion mutants have been developed as vaccine candidates, but their protective efficacy relative to conventional vaccines has not been quantitatively summarized. We performed a systematic review and meta-analysis of murine studies comparing S2308-derived gene-deletion mutants with conventional vaccines, using the mean difference (MD) in post-challenge splenic bacterial burden (log10 CFU) between groups as the primary effect measure. Fifteen studies met the inclusion criteria and were included in the quantitative synthesis. Random-effects models were used, and subgroup analysis and meta-regression were conducted to explore between-study heterogeneity. Overall, the pooled effect showed no statistically significant difference between S2308-derived mutants and conventional vaccines (MD = 0.38, 95% CI: −0.07 to 0.84; p = 0.11), with substantial overall heterogeneity (I² = 95.38%). Heterogeneity was partially explained by mouse strain and age, functional categories of deleted genes, number of deletions, and challenge dose. Univariable meta-regression showed that mutants targeting signal-regulatory genes exhibited lower splenic bacterial loads than mutants targeting genes involved in LPS biosynthesis. Collectively, current evidence supports S2308-derived gene-deletion mutants as promising candidates for next-generation Brucella vaccines. Future studies should prioritize deletions targeting signal-regulatory genes and evaluate their protective efficacy in target livestock models.