Cross-reactive neutralizing antibody responses elicited 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 has mutations that confer increased resistance to plasma of recovery patients and vaccine recipients, as well as for some monoclonal antibodies.^2-4 However, the immune response to 501Y.V2 is unknown. Similarly, the ability of antibodies elicited by 501Y.V2 infection to cross-react with other variants is unknown, but such cross-reactivity will have implications for the ability of second-generation vaccines, based on the 501Y.V2 spike protein, to protect. against infection. with the original and emerging SARS-CoV-2 descendants.⁵

We characterized the SARS-CoV-2 infections in a group of patients with coronavirus disease 2019 (Covid-19) who were hospitalized in the Groote Schuur Hospital, Cape Town (Table S1 in the supplementary appendix, available with the full text of this letter. on NEJM.org), after the rise and domination of 501Y.V2 in South Africa. Blood samples were obtained from 31 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). Furthermore, the epidemic in Cape Town (Fig. S1B) and in South Africa as a whole was dominated by 501Y.V2, which accounts for more than 90% of infections. No patient in our study reported previous SARS-CoV-2 infection.

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

Figure 1. Figure 1. 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) group infected with the 501Y.V2 variant (panels B, C and D) are compare for their neutralization cross-reactivity against other variants. One analysis (panel C) was limited to samples from the 22 patients who had positive titers of binding antibodies and in whom the sequence confirmed infection with 501Y.V2. A subset of ten samples (panel D) was tested against 501Y.V3 pseudoviruses. Neutralizing antibody responses elicited by 501Y.V2 infection were more cross-reactive than those induced by infection with the original variant. Plasma of patients infected with the original variant elicited titers compared to 501Y.V2, which averaged about one-ninth of the titer against the original variant (panel A). In contrast, plasma from patients infected with 501Y.V2 elicited responses against the original variant that elicited one-third (panel B) and a fourth (panel C) from those elicited against the 501Y.V2 variant. Plasma of some patients infected with 501Y.V2 elicited even greater responses 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 median neutralization potential of the tested samples. In the pie charts, blue indicates the percentage of samples with neutralizing activity and red indicates the percentage of samples without observable neutralizing activity. The detection threshold for the neutralization assay is a 50% inhibitory dilution (ID₅₀) 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 reported earlier that plasma of persons 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 present study, we performed the reverse experiment using the cross-reactivity of the plasma neutralizing reactions in the Groote Schuur hospital group of patients with 501Y.V2 infection versus the original variant and versus 501Y.V3 (P.1), the variant which was first described in Brazil. We first tested 57 plasma samples from patients at Groote Schuur Hospital on both 501Y.V2 and the original variant and found that 53 of 57 samples maintained neutralization activity compared to the original variant, with a geometric mean titer of 203 (95% confidence interval, 141 to 292), about one-third of the titer versus the 501Y.V2 variant (Figure 1B and S5A). When we limited the analysis to the 22 donors who confirmed a 501Y.V2 sequence infection 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 that there is a high level of neutralization of this variant, and some samples show a greater potential against 501Y.V3 ( P.1) as opposed to 501Y. V2, a finding that may be due to the different N-terminal domains of these variants (Figure 1D).

Overall, we found that 501Y.V2 elicited robust neutralizing antibody responses against both the original variant and 501Y.V3 (P.1), indicating high levels of cross-reactivity. Our data suggest that vaccines built on the peak protein of 501Y.V2 may be promising candidates to elicit cross-reactive neutralizing antibody response 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 of 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, Managing Director
Sango Skelem, B. Nursing
Gert Marais, managing director
University of Cape Town, Cape Town, South Africa

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

Veronica Ueckermann, Managing Director
Steve Biko Academic Hospital, Pretoria, South Africa

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

Michael Boswell, Managing Director, 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, Managing Director, D.Phil.
University of Cape Town, Cape Town, South Africa

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

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