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Cross-reactive neutralizing antibody response triggered by SARS-CoV-2 501Y.V2 (B.1.351)



To the editor:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 501Y.V2 lineage (also known as B.1.351), first identified in South Africa in October 2020,1 have mutations that confer increased resistance to plasma from convalescent patients and vaccine recipients as well as to some monoclonal antibodies.2-4 However, the immune response to 501Y.V2 is unknown. Similarly, the ability of antibodies induced by 501Y.V2 infection to cross-react with other variants is unknown, but such cross-reactivity would have implications for the ability of second-generation vaccines based on the 501

Y.V2 spike protein to protect against infection with the original and new SARS-CoV-2 lines.5

We characterized SARS-CoV-2 infections in a cohort of patients with coronavirus disease 2019 (Covid-19) admitted to Groote Schuur Hospital, Cape Town (Table S1 in the supplementary appendix, available with the full text of this letter at NEJM.org) after the emergence and dominance of 501Y.V2 in South Africa. Blood samples were obtained from 89 patients between 31 December 2020 and 15 January 2021; of these patients, 28 (31%) were randomly selected for SARS-CoV-2 sequencing, all of whom were shown by phylogenetic analysis to be infected with 501Y.V2 (Fig. S1A). In addition, the epidemic in Cape Town (Fig. S1B) and in South Africa as a whole was dominated by 501Y.V2, which accounted for more than 90% of infections. No patients in our study previously reported SARS-CoV-2 infection.

We first assessed the binding and neutralizing antibody responses from these patients to the 501Y.V2 spike protein. As with the original variant (D614G), 501Y.V2 elicited high titer binding and neutralizing antibody responses (Fig. S2). Furthermore, titers of binding antibodies to the receptor binding domain (including all subdomain 1) and the full spike protein in the original variant were strongly correlated with titers of binding antibodies to the corresponding proteins in the 501Y.V2 variant. Titration of a subset of 46 samples revealed that plasma samples had higher titers for the spike protein of 501Y.V2 than for the spike protein from the original variant (mean 1.7 times as high), but high level binding to the original variant remained (Fig. S3).

Cross-reactivity of neutralizing antibody responses.

Plasma samples from patients infected with the original variant (D614G) (Panel A) and from patients in the Groote Schuur Hospital (GSH) cohort infected with the 501Y.V2 variant (panels B, C and D) were compared for their neutralization cross-reactivity against other variants. One assay (Panel C) was limited to samples from the 22 patients who had positive titers of binding antibodies and in which sequencing had confirmed infection with 501Y.V2. A subset of 10 samples (panel D) was analyzed against 501Y.V3 pseudovirus. Neutralizing antibody response elicited by 501Y.V2 infection was more cross-reactive than those elicited by infection with the original variant. Plasma from patients infected with the original variant elicited titers against 501Y.V2, which averaged approx. a ninth of the titer evoked against the original variant (Panel A). In contrast, plasma from patients who had been infected with 501Y.V2 elicited responses against the original variant, which was one-third (Panel B) and one-fourth (Panel C) of those who developed the 501Y.V2 variant. Plasma from some of the patients infected with 501Y.V2 elicited an even greater response to 501Y.V3 than to 501Y.V2 (approximately three times as high) (Panel D). In each graph, the orange line indicates the slope between the tested samples median neutralization powers. In the pie chart, blue indicates the percentage of samples with neutralizing activity and red indicates the percentage of samples without detectable neutralizing activity. The neutralization assay detection threshold is a 50% inhibitory dilution (ID)50) of 20. All experiments were performed in duplicate and the mean values ​​are shown. Data for the original variant plasma are from Wibmer et al.2

We previously reported that plasma from individuals infected with the original variant showed significantly lower neutralization of the 501Y.V2 variant than of the original variant (Figure 1A and S4A).2 In the current study, we performed the reverse experiment by evaluating the cross-reactivity of plasma neutralizing responses in the Groote Schuur Hospital cohort of patients with 501Y.V2 infection against the original variant and against 501Y.V3 (P.1), variant first described in Brazil. We first tested 57 plasma samples from patients at Groote Schuur Hospital against both 501Y.V2 and the original variant and found that 53 out of 57 samples maintained neutralization activity against the original variant with a geometric mean titer of 203 (95% confidence interval, 141 to 292), ca. one third of the titer against the 501Y.V2 variant (Figure 1B and S5A). When we limited the assay to the 22 donors who had sequencing-confirmed infection with 501Y.V2 and had positive titers of binding antibodies, we observed the same pattern (Figure 1C). Finally, we tested a subset of 10 plasma samples against the 501Y.V3 (P.1) variant and found high levels of neutralization of this variant, with some samples showing higher potency against 501Y.V3 (P.1) than against 501Y. V2, a finding that may be due to the very different N-terminal domains in these variants (Figure 1D).

Overall, we found that 501Y.V2 elicits robust neutralizing antibody responses to both the original variant and 501Y.V3 (P.1), indicating high levels of cross-reactivity. Our data indicate that vaccines built on the spike protein of 501Y.V2 may be promising candidates for eliciting cross-reactive neutralizing antibody responses to SARS-CoV-2.

Thandeka Moyo-Gwete, Ph.D.
Mashudu Madzivhandila, Ph.D.
Zanele Makhado, M.Sc.
Frances Ayres, M.Sc.
Donald Mhlanga, M.Sc.
Brent Oosthuysen, M.Sc.
Bronwen E. Lambson, Ph.D.
Prudence Kgagudi, B.Sc.
National Institute for Communicable Diseases, Johannesburg, South Africa

Houriiyah Tegally, M.Sc.
KwaZulu-Natal Research Innovation and Sequencing Platform, Durban, South Africa

Arash Iranzadeh, B.Sc.
Deelan Doolabh, M.Sc.
Lynn Tyers, M.Sc.
Lionel R. Chinhoyi, M.Sc.
Mathilda Mennen, MD
Sango Skelem, B. nursing
Gert Marais, MD
University of Cape Town, Cape Town, South Africa

Constantinos K. Wibmer, Ph.D.
Jinal N. Bhiman, Ph.D.
National Institute for Communicable Diseases, Johannesburg, South Africa

Veronica Ueckermann, MD
Steve Biko Academic Hospital, Pretoria, South Africa

Theresa Rossouw, MD, Ph.D.
University of Pretoria, Pretoria, South Africa

Michael Boswell, MD, D.Phil.
Steve Biko Academic Hospital, Pretoria, South Africa

Tulio de Oliveira, Ph.D.
KwaZulu-Natal Research Innovation and Sequencing Platform, Durban, South Africa

Carolyn Williamson, Ph.D.
Wendy A. Burgers, Ph.D.
Ntobeko Ntusi, MD, D.Phil.
University of Cape Town, Cape Town, South Africa

Lynn Morris, D. Phil.
Penny L. Moore, Ph.D.
National Institute for Communicable Diseases, Johannesburg, South Africa
[email protected]

Supported by South African Medical Research Council (grant 96825, SHIPNCD 76756 and DST / CON 0250/2012), the Centers for Disease Control and Prevention (grant 5 U01IP001048-05-00), the ELMA South Africa Foundation (grant 20-ESA011) and the Wellcome Center for Infectious Disease Research in Africa, which are supported of core funding from the Wellcome Trust (grant 203135 / Z / 16 / Z). Dr. Wibmer is supported by the Fogarty International Center of the National Institutes of Health (award number R21TW011454) and the FLAIR Fellowship program (award number FLR R1 201782). Dr. Burgers are supported by the European and Developing Countries Clinical Trial Partnership 2 of the European Union’s Horizon 2020 program (grant TMA2016SF-1535-CaTCH-22). Dr. Moore is supported by the South African Research Chairs Initiative from the Department of Science and Innovation and the National Research Foundation (grant 98341).

Publication forms provided by the authors are available in full text of this letter at NEJM.org.

This letter was published on April 7, 2021 on NEJM.org.

Dr. Moyo-Gwete and Madzivhandila also contributed to this letter.

  1. 1. Tegally H, Wilkinson E, Giovanetti Met al. Emergence of a SARS-CoV-2 variant concerned with mutations in peak glycoprotein. Nature 2021 March 9 (Epub before printing).

  2. 2. Wibmer CK, Ayres F, Hermanus Tet al. SARS-CoV-2 501Y.V2 avoids neutralization of South African COVID-19 donor plasma. Nat Med 2021 March 2 (Epub before printing).

  3. 3. Wang P., Nair MS, Liu L.et al. Antibody resistance for SARS-CoV-2 variants B.1.351 and B.1.1.7. February 12, 2021 (https://www.biorxiv.org/content/10.1101/2021.01.25.428137v3). pre-print.

  4. 4. S, Gasser I., Jackson L.et al. Escape of SARS-CoV-2 501Y.V2 from neutralization with convalescent plasma. Nature 2021 March 29 (Epub before printing).

  5. 5. Fontanet A, Autran B., Lina B., Kieny MP, Karim SSA, Sridhar D.. SARS-CoV-2 variants and termination of the COVID-19 pandemic. Lancet 2021397:952954.


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