SARS-CoV-2, which originated in China in late 2019, quickly fueled the global COVID-19 pandemic, profoundly impacting health and the economy worldwide. A series of vaccines, mostly based on the full SARS-CoV-2 Spike protein, were rapidly developed, showing excellent humoral and cellular responses and high efficacy against both symptomatic infection and severe disease. However, viral evolution and the waning humoral neutralizing responses strongly challenged vaccine long term effectiveness, mainly against symptomatic infection, making necessary a strategy of repeated and updated booster shots. In this repeated vaccination context, antibody repertoire diversification was evidenced, although immune imprinting after booster doses or reinfection was also demonstrated and identified as a major determinant of immunological responses to repeated antigen exposures. Considering that a small domain of the SARS-CoV-2 Spike protein, the receptor binding domain (RBD), is the major target of neutralizing antibodies and concentrates most viral mutations, the following text aims to provide insights into the ongoing debate over the best strategies for vaccine boosters. We address the relevance of developing new booster vaccines that target the evolving RBD, thus focusing on the relevant antigenic sites of the SARS-CoV-2 new variants. A combination of this strategy with immunofusing and computerized approaches could minimize immune imprinting, therefore optimizing neutralizing immune responses and booster vaccine efficacy.