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Convergent antibody responses to SARS-CoV-2 in convalescent individuals
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Abstract
During the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has led to the infection of millions of people and has claimed hundreds of thousands of lives. The entry of the virus into cells depends on the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2. Although there is currently no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1-5. Here we report on 149 COVID-19-convalescent individuals. Plasma samples collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres; titres were less than 50 in 33% of samples, below 1,000 in 79% of samples and only 1% of samples had titres above 5,000. Antibody sequencing revealed the expansion of clones of RBD-specific memory B cells that expressed closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on the RBD neutralized the virus with half-maximal inhibitory concentrations (IC 50 values) as low as 2 ng ml-1. In conclusion, most convalescent plasma samples obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
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“The magnitude of these NAb responses appear to correlate with viral load, with higher responses reported in patients with more severe disease, and in older adults compared with younger adults26–29.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In agreement with previous reports3,6,9, there was a broad range of plasma neutralizing activity 3–14 weeks after the second vaccine dose that was similar to that elicited by natural infection in a convalescent cohort after 1.3 months, and greater than the activity at 6.2 months after infection (Fig. 1a, Extended Data Table 1).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“SARS-CoV-2 infection rapidly elicits nAbs (16, 21–24) that decline, but remain detectable, over several months (25–29).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [23]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Spike is the target of SARS-CoV-2 neutralizing antibodies, and the receptor binding domain (RBD) of Spike is the target of >90% of neutralizing antibodies in COVID-19 cases (Brouwer et al., 2020; Piccoli et al., 2020; Robbiani et al., 2020; Rogers et al., 2020; Suthar et al., 2020), with some neutralizing antibodies instead targeting the N-terminal domain (NTD) (Liu et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Robbiani et al., 2020
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Although it is unclear how long protective effects last beyond the first few months after vaccination, some studies suggest that the elicited neutralizing activity is maintained for up to 8 months after the natural infection with SARS-CoV-2 (refs. 41,42).”
From Modeling vaccination rollouts, SARS-CoV-2 variants and the requirement for non-pharmaceutical interventions in Italy (2021) · cites this paper as [41]
Experimental — accuracy not yet measured
In the citing paper
“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.”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [6]
In the citing paper
“In line with previous reports3,6,9, IgG and IgM levels were significantly higher in the vaccinated group compared to a cohort of convalescent patients assayed 1.3 and 6.2 months after infection, while IgA levels were similar (Extended Data Fig 1j–l).”
From mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021) · cites this paper as [6]
In the citing paper
“We limited our analysis to RBD because plasma RBD antibodies are strongly correlated with neutralizing activity3,10–12.”
From Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection (2021) · cites this paper as [3]
In the citing paper
“Consistent with this observation, there was an overall increase in the apparent avidity of plasma antibodies between 1.3 and 12 months3,4 (P < 0.0001) (Extended Data Fig. 7c).”
From Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection (2021) · cites this paper as [3]
In the citing paper
“In contrast to the earlier time point, 13 of 15 neutralizing antibodies obtained after 12 months interfered only with C121, a class 2 antibody3,23 (Fig. 4c, Extended Data Fig. 9).”
From Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection (2021) · cites this paper as [3]
In the citing paper
“Most serum nAb responses elicited during natural infection are directed at the RBD (21, 23, 30, 31).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [23]
In the citing paper
“Numerous neutralizing anti-RBD monoclonal antibodies (mAbs) have been characterized, the most potent of which block the RBD-ACE2 interaction (16, 17, 22–24, 32–37).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [23]
In the citing paper
“Analyses of the B cell responses to the spike generally focus on the RBD and on cells sorted with RBD baits introducing an inherent bias by omitting non-RBD targets”
From SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2 (2021) · cites this paper as Robbiani et al., 2020
In the citing paper
“The neutralizing antibodies are produced by B cells with a wide range of heavy chain and light chain V genes (Robbiani et al., 2020; Rogers et al., 2020). SARS-CoV-2 neutralizing antibodies also exhibit little to no somatic hypermutation (Gaebler et al., 2020; Robbiani et al., 2020; Rogers et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Robbiani et al., 2020
In the citing paper
“Although neutralizing antibody titers have not correlated with reduced COVID-19 severity (Dan et al., 2021; Piccoli et al., 2020; Robbiani et al., 2020), SARS-CoV-2 cTfh cell frequencies have been associated with reduced disease severity (Rydyznski Moderbacher et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Robbiani et al., 2020
In the citing paper
“This appears to hold true in the case of SARS-CoV-2, where neutralizing antibody titers (and total Spike antibody titers) have positively correlated with COVID-19 disease severity in large cohort studies (Piccoli et al., 2020; Robbiani et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Robbiani et al., 2020
In the citing paper
“However, it should also be noted that circulating SARS-CoV-2 neutralizing antibody titers are relatively low in a substantial fraction of recovered COVID-19 cases (Dan et al., 2021; Robbiani et al., 2020; Wajnberg et al., 2020), indicating that either the neutralizing antibody potency or the serum concentration is suboptimal in this subset.”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Robbiani et al., 2020
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Metadata
- Authors
- Robbiani, D. F., Gaebler, C., Muecksch, F., Lorenzi, J. C. C., Wang, Z., Cho, A., Agudelo, M., Barnes, C. O., Gazumyan, A., Finkin, S., Hägglöf, T., Oliveira, T. Y., Viant, C., Hurley, A., Hoffmann, H.-H., Millard, K. G., Kost, R. G., Cipolla, M., Gordon, K., Bianchini, F., Chen, S. T., Ramos, V., Patel, R., Dizon, J., Shimeliovich, I., Mendoza, P., Hartweger, H., Nogueira, L., Pack, M., Horowitz, J., Schmidt, F., Weisblum, Y., Michailidis, E., Ashbrook, A. W., Waltari, E., Pak, J. E., Huey-Tubman, K. E., Koranda, N., Hoffman, P. R., West, A. P., Rice, C. M., Hatziioannou, T., Bjorkman, P. J., Bieniasz, P. D., Caskey, M., & Nussenzweig, M. C.
- Affiliations
- Institute for Research in Biomedicine (CH)
- Rockefeller University (US)
- California Institute of Technology (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Robbiani, Davide F.
- Bieniasz, Paul D.
- Caskey, Marina
- Nussenzweig, Michel C.
- ORCID
- Robbiani, Davide F.
- Gaebler, Christian
- Muecksch, Frauke
- Lorenzi, Julio C. C.
- Wang, Zijun
- Cho, Alice
- Agudelo, Marianna
- Barnes, Christopher O.
- Gazumyan, Anna
- Finkin, Shlomo
- Hägglöf, Thomas
- Oliveira, Thiago Y.
- Viant, Charlotte
- Hurley, Arlene
- Hoffmann, Hans-Heinrich
- Millard, Katrina G.
- Kost, Rhonda G.
- Cipolla, Melissa
- Bianchini, Filippo
- Chen, Spencer T.
- Dizon, Juan
- Shimeliovich, Irina
- Mendoza, Pilar
- Hartweger, Harald
- Nogueira, Lilian
- Schmidt, Fabian
- Weisblum, Yiska
- Michailidis, Eleftherios
- Ashbrook, Alison W.
- Waltari, Eric
- Pak, John E.
- Koranda, Nicholas
- Hoffman, Pauline R.
- West, Anthony P.
- Rice, Charles M.
- Bjorkman, Pamela J.
- Bieniasz, Paul D.
- Caskey, Marina
- Nussenzweig, Michel C.
- Venue
- Nature
- Published
- 2020-06-18
- Volume
- 584
- Issue
- 7821
- Pages
- 437-442
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7442695
- OpenAlex
- W3036386821
- Cited by
- 1,853
- References
- 47
- Citations by year
- 2026: 49 · 2025: 79 · 2024: 115 · 2023: 194 · 2022: 403 · 2021: 691 · 2020: 321
- FWCI
- 52.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute (UL1TR001866)
- George Mason University
- California Institute of Technology
- Fast Grants
- National Institutes of Health (P01-AI138398-S1, AI150464, TR001866, UL1TR001866)
- Beckman Institute, California Institute of Technology
- National Institute of Allergy and Infectious Diseases (R01AI091707, R01AI078788, P50AI150464, U19AI111825, P01AI138938, R37AI064003, T32AI070084)
- National Center for Advancing Translational Sciences (TR001866)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, convalescent plasma, neutralizing antibodies, receptor binding domain, spike protein, antibody response, memory B cells, pseudovirus neutralization, vaccine design, antibody epitopes
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