#5150-0021). 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 contamination 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, improving with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against SRT 1460 BA.1 and BA.2 Rabbit polyclonal to Aquaporin10 contamination. 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, improving with mRNA-1273 or?mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured. Keywords: mRNA vaccine, booster, SARS-CoV-2, mice, Omicron, pathogenesis, immunity, antibody, neutralization Graphical abstract Open in a separate windows 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 SRT 1460 observed in mice boosted with the BA.1-matched vaccine. Introduction Since the inception of the SARS-CoV-2 pandemic in late 2019, almost 460 million infections and 6.1 million deaths have been recorded (https://covid19.who.int). Several vaccines targeting the SARS-CoV-2 spike protein were developed and deployed rapidly with billions of doses administered (https://covid19.who.int). These vaccines use the SARS-CoV-2 spike protein from historical strains that circulated during the early phases of the pandemic in 2020 and have reduced the numbers of infections, hospitalizations, and COVID-19-related deaths. Despite the success of COVID-19 vaccines, the continued evolution of more transmissible SARS-CoV-2 variants with amino acid substitutions, deletions, and insertions in the spike protein jeopardizes the efficacy of global vaccination campaigns (Krause et?al., 2021). The SARS-CoV-2 spike protein engages angiotensin-converting enzyme 2 (ACE2) on the surface of human cells to facilitate access and contamination (Letko et?al., 2020). The S1 fragment of the spike protein contains the N-terminal (NTD) and receptor binding (RBD) domains, which are targets of neutralizing monoclonal (Barnes et?al., 2020; Cao SRT 1460 et?al., 2020; Pinto et?al., 2020; Tortorici et?al., 2020; Zost et?al., 2020) and polyclonal antibodies (Rathe et?al., 2021). In late November of 2021, the Omicron (BA.1) variant emerged, SRT 1460 which has the largest number (>30) of amino acid substitutions, deletions, or insertions in the spike protein described to date. These changes in the spike raise concerns for escape from protection by existing vaccines that target early?pandemic spike proteins. Indeed, reduced serum neutralization of BA.1 (B.1.1.529) and BA.1.1 (B.1.1.529 with an additional R346K spike substitution) Omicron viruses (Edara et?al., 2022; Pajon et?al., 2022) and large numbers of symptomatic breakthrough infections have been reported in vaccinated individuals (Buchan et?al., 2022; Christensen et?al., 2022; Elliott et?al., 2021). Here, we evaluated the antibody responses and protective activity against Omicron variants of a preclinical version of the current Moderna vaccine, mRNA-1273, or an Omicron-targeted vaccine, mRNA-1273.529, designed with sequences from your historical Wuhan-1 or BA.1 spike genes, respectively, in the context of a primary (two-dose) immunization series or third-dose boosters. We hoped to determine serum antibody correlates of protection against Omicron variants, determine the likelihood and significance of breakthrough infections, determine the differences in immunogenicity and protection of SRT 1460 homologous and heterologous mRNA vaccine boosters, and evaluate the activity of mRNA-1273.529 in the context of a primary immunization series against historical strains and variants of concern that emerged prior to Omicron. In particular, we assessed whether improving with.