mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 omicron variant

Edara, Venkata-Viswanadh; Manning, Kelly; Ellis, Madison; Lai, Lilin; Moore, Kathryn M.; Foster, Stephanie L.; Floyd, Katharine; Davis-Gardner, Meredith E.; Mantus, Grace; Nyhoff, Lindsay E.; Bechnak, Sarah; Alaaeddine, Ghina; Naji, Amal; Samaha, Hady; Lee, Matthew; Bristow, Laurel; Gagné, Matthew; Roberts-Torres, Jesmine; Henry, Amy R.; Godbole, Sucheta; Grakoui, Arash; Saxton, Marybeth; Piantadosi, Anne; Waggoner, Jesse J.; Douek, Daniel C.; Rouphael, Nadine; Wrammert, Jens; Suthar, Mehul S.

doi:10.1016/j.xcrm.2022.100529

Cited by 182 publications

(178 citation statements)

References 12 publications

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“…WT-immunized sera had comparably high titers against Alpha (ID50 = 15,176) and Delta (ID50 = 13,985) RBDs but presented decreased activities against Beta (ID50 = 10,763; by 35%) and more substantially against Omicron (ID50 = 6,201; by 69%). The magnitudes of antibody evasion by VOCs were consistent with clinical data [3][4][5][6][7][8] , indicating that the RBD immunodominance hierarchy is similar between mouse and human.…”

Section: Omicron Mutations Lead To a Drastic And Systemic Reduction I...supporting

confidence: 79%

Reduced antigenicity of Omicron lowers host serologic response

Tubiana

Xiang

Fan

et al. 2022

Preprint

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SARS-CoV-2 Omicron variant of concern (VOC) contains fifteen mutations on the receptor binding domain (RBD), evading most neutralizing antibodies from vaccinated sera. Emerging evidence suggests that Omicron breakthrough cases are associated with substantially lower antibody titers than other VOC cases. However, the mechanism remains unclear. Here, using a novel geometric deep-learning model, we discovered that the antigenic profile of Omicron RBD is distinct from the prior VOCs, featuring reduced antigenicity in its remodeled receptor binding sites (RBS). To substantiate our deep-learning prediction, we immunized mice with different recombinant RBD variants and found that the Omicron's extensive mutations can lead to a drastically attenuated serologic response with limited neutralizing activity in vivo, while the T cell response remains potent. Analyses of serum cross-reactivity and competitive ELISA with epitope-specific nanobodies revealed that the antibody response to Omicron was reduced across RBD epitopes, including both the variable RBS and epitopes without any known VOC mutations. Moreover, computational modeling confirmed that the RBS is highly versatile with a capacity to further decrease antigenicity while retaining efficient receptor binding. Longitudinal analysis showed that this evolutionary trend of decrease in antigenicity was also found in hCoV229E, a common cold coronavirus that has been circulating in humans for decades. Thus, our study provided unprecedented insights into the reduced antibody titers associated with Omicron infection, revealed a possible trajectory of future viral evolution and may inform the vaccine development against future outbreaks.

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Section: Omicron Mutations Lead To a Drastic And Systemic Reduction I...supporting

confidence: 79%

Reduced antigenicity of Omicron lowers host serologic response

Tubiana

Xiang

Fan

et al. 2022

Preprint

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“…Here, viral titers were low in the lungs and low to undetectable in the upper airway. Second, neutralizing antibody titers in NHP are 5-to 10-fold greater than in humans that received the same dose and regimen of mRNA-1273 with a boost (Edara et al, 2021a; Pajon et al, 2022). Third, a second dose of mRNA-Omicron may elicit a population of B cells specific only for Omicron.…”

Section: Discussionmentioning

confidence: 98%

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron

Gagné

Moliva

Foulds

et al. 2022

Preprint

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SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.

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“… 124 However, a significant increase in neutralizing antibody levels was observed after a booster dose. 125 , 126 , 127 After a single dose of BNT162b2 booster, neutralizing activity could be detected among all participants and increased sharply (by > 100‐fold). Notably, it was even higher than that against WT after two doses of BNT162b2.…”

Section: Strategies Against the Omicron Variantmentioning

confidence: 99%

SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

Lan

et al. 2022

MedComm

101

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New genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) constantly emerge through unmitigated spread of the virus in the ongoing Coronavirus disease 2019 pandemic. Omicron (B.1.1.529), the latest variant of concern (VOC), has so far shown exceptional spread and infectivity and has established itself as the dominant variant in recent months. The SARS‐CoV‐2 spike glycoprotein is a key component for the recognition and binding to host cell angiotensin‐converting enzyme 2 receptors. The Omicron variant harbors a cluster of substitutions/deletions/insertions, and more than 30 mutations are located in spike. Some noticeable mutations, including K417N, T478K, N501Y, and P681H, are shared with the previous VOCs Alpha, Beta, Gamma, or Delta variants and have been proven to be associated with higher transmissibility, viral infectivity, and immune evasion potential. Studies have revealed that the Omicron variant is partially resistant to the neutralizing activity of therapeutic antibodies and convalescent sera, which poses significant challenges for the clinical effectiveness of the current vaccines and therapeutic antibodies. We provide a comprehensive analysis and summary of the epidemiology and immune escape mechanisms of the Omicron variant. We also suggest some therapeutic strategies against the Omicron variant. This review, therefore, aims to provide information for further research efforts to prevent and contain the impact of new VOCs during the ongoing pandemic.

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mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 omicron variant

Cited by 182 publications

References 12 publications

Reduced antigenicity of Omicron lowers host serologic response

Reduced antigenicity of Omicron lowers host serologic response

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron

SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

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