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Immune imprinting is now evident in COVID-19 vaccinated people. This phenomenon may impair the development of effective neutralizing antibodies against variants of concern (VoCs), mainly Omicron and its subvariants. Consequently, the boost doses with bivalent vaccines have not shown a significant gain of function regarding the neutralization of Omicron. The approach to design COVID-19 vaccines must be revised to improve the effectiveness against VoCs. Here, we took advantage of the self-amplifying characteristic of RepRNA and developed a polyvalent formulation composed of mRNA from five VoCs. LION/RepRNA Polyvalent induced neutralizing antibodies in mice previously immunized with LION/RepRNA D614G and reduced the imprinted phenotype associated with low neutralization capacity of Omicron B.1.1.529 pseudoviruses. The polyvalent vaccine can be a strategy to handle the low neutralization of Omicron VoC, despite booster doses with either monovalent or bivalent vaccines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.V.P.C.R.; B.A.S.M.; B.C.B; H.C.Q.; A.M.S.F.; E.S.L.; M.E.B.; C.S.M.; L.M.S.F., R.J.S.B.; and M.B.P.S. declare no conflict of interest., (© 2024 The Author(s).)