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A series of vaccines, mostly based on the full SARS\u2010CoV\u20102 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\u2010CoV\u20102 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\u2010CoV\u20102 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.<\/jats:p>","DOI":"10.1111\/irv.70076","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T04:06:11Z","timestamp":1738037171000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rethinking Optimal Immunogens to Face SARS\u2010CoV\u20102 Evolution Through Vaccination"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2225-0217","authenticated-orcid":false,"given":"Juli\u00e0","family":"Blanco","sequence":"first","affiliation":[{"name":"IrsiCaixa  Badalona Catalonia Spain"},{"name":"Germans Trias i Pujol Research Institute (IGTP)  Badalona Catalonia Spain"},{"name":"CIBER de Enfermedades Infecciosas  Madrid Spain"},{"name":"Chair in Infectious Diseases and Immunity, Faculty of Medicine University of Vic\u2010Central University of Catalonia (UVic\u2010UCC)  Vic Catalonia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Trinit\u00e9","sequence":"additional","affiliation":[{"name":"IrsiCaixa  Badalona Catalonia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-0409","authenticated-orcid":false,"given":"Joan","family":"Puig\u2010Barber\u00e0","sequence":"additional","affiliation":[{"name":"\u00c1rea de Investigaci\u00f3n en Vacunas Fundaci\u00f3n para el Fomento de la Investigaci\u00f3n Sanitaria y Biom\u00e9dica de la Comunitat Valenciana  Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abp8715"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.628370"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001652"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0485-4"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1570"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.09.038"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.05.007"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5471"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.1052436"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-020-00073-5"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd0826"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2021.10.005"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15091786"},{"key":"e_1_2_12_19_1","unstructured":"International Vaccine Acces Center; WHO; CEPI \u201cResults of COVID\u201019 Vaccine Effectiveness Studies: An Ongoing Systematic Review \u201d2024 https:\/\/view\u2010hub.org\/sites\/default\/files\/2024\u201002\/COVID19%20VE%20Studies_Forest%20Plots_Omicron.pdf."},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29225-4"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl5344"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01377-8"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100253"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03647-4"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02183-8"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.972083"},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","unstructured":"A. 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