Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice

Scheaffer, Suzanne M.; Lee, Diana; Whitener, Bradley; Bai, Ying; Wu, Kai; Liang, Chieh-Yu; Jani, Hardik; Martin, Philippa; Amato, Nicholas J.; Avena, Laura E.; Berrueta, Daniela Montes; Schmidt, Stephen D.; O’Dell, Sijy; Nasir, Arshan; Chuang, Gwo-Yu; Stewart‐Jones, Guillaume; Koup, Richard A.; Doria‐Rose, Nicole A.; Carfı́, Andrea; Elbashir, Sayda M.; Thackray, Larissa B.; Edwards, Darin K.; Diamond, Michael S.

doi:10.1038/s41591-022-02092-8

Cited by 150 publications

(135 citation statements)

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“…To assess whether mice expressing FcγRs were differentially protected against SARS-CoV-2 infection by vaccine-induced immunity, animals were challenged by intranasal route with 10 3 FFU of BA.5, and infectious virus in the nasal turbinates and lungs was measured at 3 dpi ( Fig 4a ). For these experiments, we used BA.5 as the challenge virus because: (i) it encodes a mouse-adapting mutation (N501Y) that facilitates replication in mice lacking human ACE2 expression 33 ; (ii) it allowed us to assess protection against infection under conditions when high levels of neutralizing antibody are absent ( Fig 4e ); and (iii) BA.5, and other Omicron variants are circulating, so use of this strain could provide insight as to how legacy vaccines directed against ancestral spikes protect against severe BA.5 disease in humans. Notably, we observed protection against BA.5 infection in the upper and lower respiratory tract of wild-type and FcγR I KO mice but not in FcγR III KO or FcγR I/III/IV KO mice ( Fig 4f-g ).…”

Section: Resultsmentioning

confidence: 99%

“…Viruses. All SARS-CoV-2 strains used (WA1/2020 N501Y/D614G, mouse-adapted MA-10, B.1.351, and BA.5) have been previously described 25,33,62,63 . All viruses were subjected to next generation deep sequencing to confirm presence and stability of substitutions.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, we attribute the diminished control of infection of the antigenicallyshifted BA.5 strain in the turbinates and lungs of mRNA-1273 vaccinated FcγR KO mice to the loss of Fc-FcγR interactions that mediate antibody effector functions. Notwithstanding these results, antigen-matched bivalent mRNA vaccines targeting BA.1 and BA.5 spike proteins can induce higher levels of neutralizing antibodies against Omicron strains 8,33,49 , which might result in less reliance on Fc effector functions for protection against infection. We also performed cellular depletions to investigate the cell type responsible for the protection conferred by passively transferred antibody.…”

Section: Despite the Diminished Neutralizing Ability Of Vaccine-elici...mentioning

confidence: 99%

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Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

Mackin

Desai

Whitener

et al. 2022

Preprint

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Emerging SARS-CoV-2 variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Although vaccine-elicited antibodies can bind Fc gamma receptors and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical COVID-19 outcome, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and Fc-gamma receptor (FcgR) KO mice, we determined the requirement for Fc effector functions to protect against SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcgRs, especially murine FcgR III (CD16), or depleted of alveolar macrophages. After immunization with the preclinical mRNA-1273 vaccine, protection against Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcgR III. Our passive and active immunization studies in mice suggest that Fc-FcgR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Despite the Diminished Neutralizing Ability Of Vaccine-elici...mentioning

confidence: 99%

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Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

Mackin

Desai

Whitener

et al. 2022

Preprint

Self Cite

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“…These results suggest an abbreviated efficacy of Pfizer BNT162b2 vaccine against the three variants, extending our previous results with BA.1 and BA.5 16 . The advantage of administrating monovalent or bivalent boosters is under scrutiny 25,27 56 57 . Preliminary preprints using lentiviral pseudotypes indicated that BA.5, BA.4.6 or BA.2.75 titers were comparable after monovalent or BA.5 bivalent boosters 25,27 .…”

Section: Discussionmentioning

confidence: 99%

Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

Planas

Bruel

Staropoli

et al. 2022

Preprint

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Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs.

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“…[4][5][6] As such, Omicron-containing, bivalent boosters are currently available in multiple geographies to address COVID-19 caused by omicron variants. 7,8…”

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confidence: 99%

Three-month Antibody Persistence of a Bivalent Omicron-containing Booster Vaccine Against COVID-19

Chalkias

Harper

Vrbicky

et al. 2022

Preprint

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We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study comparing the Omicron-BA.1-containing bivalent vaccine mRNA-1273.214 (50-µg) to the 50-µg mRNA-1273 booster in adults who previously received the mRNA-1273 primary series (100-µg) and mRNA-1273 first booster (50-µg) dose. Here we present day 91 post-booster results. Participants were sequentially enrolled to receive 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. In participants with no pre-booster severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-neutralizing antibody titers that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar between boosters against ancestral SARS-CoV-2 at day 91. mRNA-1273.214 also induced higher binding antibody responses against Omicron BA.1 and alpha, gamma and delta variants than mRNA-1273. Safety profiles were similar for both vaccines. The Omicron-BA.1 bivalent vaccine induced improved antibody persistence compared to mRNA-1273.

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Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice

Cited by 150 publications

References 50 publications

Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies

Three-month Antibody Persistence of a Bivalent Omicron-containing Booster Vaccine Against COVID-19

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