The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured. Display omitted •Primary immunization series with mRNA-1273 results in BA.1 breakthrough infection•Primary immunization with BA.1-matched vaccine neutralizes BA.1 but not Wuhan-1•Both mRNA-1273 and BA.1-matched boosters protect against BA.1 challenge•A BA.1-matched booster induces greater neutralizing antibody responses against BA.1 A comparison of the immunogenicity and efficacy of Omicron BA.1-matched and historical mRNA vaccines as boosters shows that although boosting with either vaccine increased neutralizing titers against Omicron BA.1 and BA.2, slightly greater protection against BA.1 challenge was observed in mice boosted with the BA.1-matched vaccine.