Optimizing allocation of vaccine, a highly scarce resource, is an urgent and critical issue during fighting against on‐going COVID‐19 epidemic. Prior studies suggested that vaccine should be prioritized by age and risk groups, but few of them have considered the spatial prioritization strategy. This study aims to examine the spatial heterogeneity of COVID‐19 transmission in the city naturally, and optimize vaccine distribution strategies considering spatial prioritization. We proposed an integrated spatial model of agent‐based model and SEIR (susceptible‐exposed‐infected‐recovered). It simulated spatiotemporal process of COVID‐19 transmission in a realistic urban context. Individual movements were represented by trajectories of 8,146 randomly sampled mobile phone users on December 28, 2016 in Guangzhou, China, 90% of whom aged 18–60. Simulations were conducted under seven scenarios. Scenarios 1 and 2 examined natural spreading process of COVID‐19 and its final state of herd immunity. Scenarios 3–6 applied four vaccination strategies (random strategy, age strategy, space strategy, and space & age strategy), and identified the optimal vaccine strategy. Scenario 7 assessed the most appropriate vaccine coverage. The results demonstrates herd immunity is heterogeneously distributed in space, thus, vaccine intervention strategies should be spatialized. Among four strategies, space & age strategy is substantially most efficient, with 7.7% fewer in attack rate and 44 days longer than random strategy under 20% vaccine uptake. Space & age strategy requires 30%–40% vaccine coverage to control the epidemic, while the coverage for a random strategy is 60%–70% as a comparison. The application of our research would greatly improves the effectiveness of the vaccine usability.