Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Starr, Tyler N; Greaney, Allison J; Addetia, Amin; Hannon, William W; Choudhary, Manish; Dingens, Adam S.; Li, Jonathan Z.; Bloom, Jesse D.

doi:10.1126/science.abf9302

Cited by 761 publications

(743 citation statements)

References 34 publications

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“…These antibodies target epitopes that overlap or are closely associated with RBD residues K417, E484 and N501. They are frequently sensitive to mutation in these residues and select for K417N, E484K and N501Y mutations in SARS-CoV-2 S protein expression libraries in yeast and VSV 13,16,32 . To avert selection and escape, antibody therapies should be composed of combinations of antibodies that target non-overlapping or highly conserved epitopes 6,13,14,32, [39][40][41][42][43] .…”

Section: Discussionmentioning

confidence: 99%

“…To examine the neutralizing breadth of the monoclonal antibodies and begin to map their target epitopes we tested 17 of the most potent antibodies (Extended data Table 6), 8 of which carried IgHV3-53, against a panel of 12 SARS-CoV-2 variants: A475V is resistant to class 1 antibodies (structurally defined as described 7 ); E484K and Q493R are resistant to class 2 antibodies [5][6][7][8]13,14,31,32 ; while R346S, N439K, and N440K are resistant to class 3 antibodies 5-7,13,14,32 . Additionally, K417N, Y453F, S477R, N501Y, and D614G represent circulating variants some of which have been associated with rapidly increasing case numbers 15,16,20,[32][33][34] . Based on their neutralizing activity against the variants, all but 3 of the antibodies were provisionally assigned to a defined antibody class or a combination (Fig.…”

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

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mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Nature

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Rafael C as el la s , T he od or a Hatziioannou, Paul D. Bieniasz & M ic hel C. Nussenzweig This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

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Section: Discussionmentioning

confidence: 99%

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Nature

1,328

100

1,304

View full text Add to dashboard Cite

show abstract

“…These antibodies target epitopes that overlap or are closely associated with RBD residues K417, E484 and N501. They are frequently sensitive to mutation in these residues and select for K417N, E484K and N501Y mutations in SARS-CoV-2 S protein expression libraries in yeast and VSV 12,15,33 . To avert selection and escape, antibody therapies should be composed of combinations of antibodies that target non-overlapping or highly conserved epitopes 8,12,13,33,[40][41][42][43][44] .…”

Section: Discussionmentioning

confidence: 99%

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Preprint

280

313

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To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

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“…However, as it is derived from IGHV3-66, it will likely lose potency against variants harboring the E484K mutation (i.e. the B.1.351 and B.1.1.28 lineages), as recently shown for convalescent plasma and many NAbs 37,38 . This highlights the necessity of using NAbs cocktails targeting distinct epitopes.…”

mentioning

confidence: 99%

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Grand

Maisonnasse

Aldon

et al. 2021

Preprint

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One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed1–3. Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals4–6. Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo, a neutralizing antibody isolated from a convalescent patient7 and highly potent against the B.1.1.7. isolate8,9. In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg− 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

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Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Cited by 761 publications

References 34 publications

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

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