mRNA vaccines have proven to be pivotal in the fight against COVID-19. A recommended booster, given 3 to 4 weeks post the initial vaccination, can substantially amplify protective antibody levels. Here, we show that, compared to contralateral boost, ipsilateral boost of the SARS-CoV-2 mRNA vaccine induces more germinal center B cells (GCBCs) specific to the receptor binding domain (RBD) and generates more bone marrow plasma cells. Ipsilateral boost can more rapidly generate high-affinity RBD-specific antibodies with improved cross-reactivity to the Omicron variant. Mechanistically, the ipsilateral boost promotes the positive selection and plasma cell differentiation of pre-existing GCBCs from the prior vaccination, associated with the expansion of T follicular helper cells. Furthermore, we show that ipsilateral immunization with an unrelated antigen after a prior mRNA vaccination enhances the germinal center and antibody responses to the new antigen compared to contralateral immunization. These findings propose feasible approaches to optimize vaccine effectiveness. Display omitted •Ipsilateral boost of mRNA vaccine induces superior GC and plasma cell responses•Ipsilateral boost more rapidly induces high-affinity antibodies with improved breadth•Ipsilateral boost directly activates the ongoing GCs from the prior vaccination•Ipsilateral new antigen immunization post mRNA vaccination improves humoral responses COVID-19 mRNA vaccines require a prime-boost approach to stimulate robust levels of protective antibodies. Jiang et al. demonstrate that receiving the booster shot or a different vaccine on the same side following a prior mRNA vaccination may result in more optimal B cell and antibody responses.