Statistical significance was defined as p?< 0

Statistical significance was defined as p?< 0.05. recently (<3?months), distantly (6C12?months), or an additional booster dose, while accounting for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinees. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron, only 4C6-fold lower than wild type, suggesting enhanced cross-reactivity of neutralizing antibody reactions. In addition, we find that Omicron pseudovirus infects more efficiently than additional variants tested. Overall, this study highlights the importance of additional mRNA doses to broaden neutralizing antibody reactions against highly divergent SARS-CoV-2 variants. Keywords: COVID-19, SARS-CoV-2, spike, variants, Omicron, Delta, vaccination, neutralizing antibodies, infectivity, breadth Graphical abstract Open in a separate windows SARS-CoV-2 Omicron variant pseudovirus exhibits escape from vaccine-induced humoral immunity. However, a third dose of COVID-19 mRNA vaccine elicited humoral immunity capable of cross-neutralizing this strain. In addition, pseudovirus produced with the Omicron spike exhibited more efficient transduction of ACE2-expressing target cells than additional variants. Intro The SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) was first detected in Botswana and reported to the World Health Business (WHO) in November 2021 like a novel variant with an unprecedented quantity of previously explained and novel mutations with immunevasive potential. A subsequent and rapid increase in Omicron instances in South Africa resulted in its designation like a novel variant of concern (VOC) from the WHO (www.who.int). This variant harbors up to 59 mutations throughout its genome, with as many as 36 of these occurring within the spike protein, the mediator of sponsor cell access and the main target of neutralizing antibodies. Studies of earlier SARS-CoV-2 variants have shown that mutations within the receptor binding website (RBD) mediate escape from vaccine-induced neutralizing antibodies (Cele et?al., 2021a; Garcia-Beltran et?al., 2021a; Zhou et?al., 2021), and in some cases, increase infectivity through enhanced affinity Mouse monoclonal to SYP for ACE2 (Tian et?al., 2021). Omicron RBD consists of 15 mutations, some of which overlap with previously analyzed variants. For example, Beta (B.1.351) and Gamma (P.1) harbor mutations in residues K417, E484, and N501 that potently diminish vaccine-induced neutralization (Garcia-Beltran et?al., 2021a), possibly the result of neutralizing antibody reactions becoming focused toward a limited set of RBD epitopes, as has been previously explained (Barnes et?al., 2020; Greaney et?al., LGK-974 2021a). In the United States, three vaccines have been authorized by the FDA or are under emergency use authorization (EUA), all of which use the initial wild-type SARS-CoV-2 spike protein 1st recognized in Wuhan, China, as the sole immunogen. These are formulated as spike-encoding mRNA in lipid nanoparticles (BNT162b2 manufactured by Pfizer-BioNTech and mRNA-1273 manufactured by Moderna) or as an adenovirus vectored vaccine (Ad26.COV2.S manufactured by Janssen/Johnson & Johnson) (Baden et?al., 2021; Polack et?al., 2020; Sadoff et?al., 2021). These SARS-CoV-2 vaccines have been amazingly successful in inducing neutralizing humoral and cellular immunity and, more importantly, reducing COVID-19 infections, hospitalizations, and deaths in clinical tests (Baden et?al., 2021; Polack et?al., 2020; Sadoff LGK-974 et?al., 2021) and during quick worldwide deployment (Tregoning et?al., 2021). However, it has now been shown that neutralizing antibody reactions and vaccine performance vary by vaccine agent, decrease with increased time post vaccination, and are negatively impacted by growing variants (Bajema et?al., 2021; Bar-On et?al., 2021; Cromer et?al., 2021; Khoury et?al., 2021; Lopez Bernal et?al., 2021; Naranbhai et?al., 2021a; Tregoning et?al., 2021). In an effort to combat waning antibody reactions and the emergence of new variants, a third dose of mRNA vaccine (boosters) has been approved for individuals vaccinated >6?weeks ago and has been shown to be very effective at inducing large neutralizing antibody titers (Bar-On et?al., 2021). In the case of Ad26.COV2.S vaccinees, cross-over mRNA doses were recommended >2?weeks from main vaccination. However, while neutralization of wild-type SARS-CoV-2 offers been shown LGK-974 to predict the effectiveness of vaccines against variants (Earle et?al., 2021; Khoury et?al., 2021), it is unclear whether this correlation will be managed among boosted individuals and for highly mutated variants like Omicron (Bajema et?al., 2021; Lopez Bernal et?al., 2021; Tregoning et?al., 2021). We previously developed and validated a high-throughput pseudovirus neutralization assay to understand variations in immunity by vaccine and sponsor characteristics against SARS-CoV-2 variants and additional coronaviruses (Garcia-Beltran.