To the editor:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.429 (also called CAL.20C or 542R.V1), first identified in California,1 spread rapidly in the United States and have been found in at least 25 other countries (see updates at https://www.gisaid.org/hcov19-variants/). This variant contains three peak mutations that are the main target of neutralizing antibodies; one mutation (L452R) is located in the receptor binding motif, and another (W152C) in the N-terminal domain supersite. This has raised concerns about possible immune escape, which may compromise vaccine effectiveness and increase the risk of reinfection. We measured the neutralizing activity of serum samples obtained from 1
The neutralizing activity of all serum samples was tested against the B.1.429 variant and a concern variant that first emerged in South Africa (B.1.351, also called 20H / 501Y.V2). We compared this neutralizing activity with the activity of the serum samples against the prototypical D614G variant. Compared to the D614G variant, we found that B.1.429 was approx. 2 to 3 times less sensitive to neutralization of convalescence serum and of serum samples obtained from vaccinated individuals, while B.1.351 was approx. 9 to 14 times less sensitive to neutralization.
Convalescent serum samples were obtained from infected individuals 1 to 8 weeks after dissolution of coronavirus disease 2019 infection or 2 to 10 weeks after the most recent positive SARS-CoV-2 test. Serum samples were obtained from recipients of the Moderna vaccine on day 57 (28 days after the second vaccine dose), and Novavax serum samples were obtained from vaccine recipients on day 35 (14 days after the second vaccine dose). The results are shown as the difference in neutralization titers for matched samples (panels A and B) and the difference in titers relative to the D614G variant (the ratio of titers to the specified variant) for each sample set (Panel C). Lower values indicate stronger spice neutralization of the variant virus. Dotted thin lines in panels A and B represent individual samples, and thick black lines represent the geometric means for each sample group, as indicated on the right. Thick black bars in panel C represent the geometric differences of titers for sample sets, which are also marked above each set. Circles in panel C represent the differences in titers relative to the D614G for individual samples. P values for comparison of the mutual neutralization titers at 50% inhibitory dilution (ID50) and 80% inhibitory dilution (ID80) are pairwise comparisons of the data shown in panels A and B, calculated using Wilcoxon signed rank tests. P values less than 0.001 correlate with Q (adjusted P) values less than 0.0019 (see Table S2 in Supplementary Appendix 2). Differences in neutralization titers among the three sample sets shown in Panel C were not significant (P> 0.05 in the Wilcoxon rank-sum test).
We constructed pseudovirus with the D614G spike mutation alone (as a comparator variant) or combined with the additional mutations found in B.1.429 (S13I, W152C and L452R) and B.1.351 (L18F, D80A, D215G, Δ242-244, R246I, K417N, E484K , N501Y and A701V). Neutralization assays were performed using a validated lentivirus-based spike-pseudotype virus assay in 293T cells that were stably transduced to overexpression of angiotensin-converting enzyme 2.4 Variant B.1.429 was neutralized with convalescent serum and of serum obtained from vaccinated individuals, resulting in 50% inhibitory dilution (ID50) geometric mean titers of 225 to 495 (Figure 1Aand Table S1 in Supplementary Appendix 1, available in full text in this letter at NEJM.org). In it50 and ID80 titers against the B.1.429 variant for convalescence serum and for serum from subjects who had received one of the vaccines were significantly lower than those against D614G (P <0.001) (Figures 1A and 1Band Table S2 in Supplementary Appendix 2). The geometric mean ID50 titers against B.1.429 were 3.1 times (range, 1.4 to 8.8) lower than those against D614G for convalescence serum and were 2.0 and 2.5 times (range, 0.7 and 8.6) lower than against D614G for serum from subjects who had received mRNA-1273 and NVX-CoV2373 vaccines respectively (Figure 1C and Table S1). The geometric mean ID50 titer against B.1.351 was 13.1-fold lower than against D614G for convalescent serum and 9.7-fold and 14.5-fold lower than against D614G for serum from subjects receiving mRNA-1273 and NVX-CoV2373, respectively (Figure 1C). Our findings regarding neutralization of the B.1.351 variant with serum obtained from recipients of the mRNA-1273 vaccine are consistent with those previously reported.5
The modestly lower value in neutralization titers against the B.1.429 variant seen in this study is similar to that we saw earlier when neutralization of the B.1.1.7 variant was tested with the same assay using serum samples obtained from recipients of mRNA. 1273 and NVX-CoV2373 vaccines.4 These results and the high efficacy shown by these vaccines suggest that vaccine-induced neutralizing antibodies are likely to remain effective against the B.1.429 variant. The magnitude of resistance seen with the B.1.351 variant is of greater concern with respect to current vaccines.
Xiaoying Shen, Ph.D.
Haili Tang, MS
Duke University, Durham, NC
Rolando Pajon, Ph.D.
Modern, Cambridge, MA
Gale Smith, Ph.D.
Gregory M. Glenn, MD
Novavax, Gaithersburg, MD
Wei Shi, Ph.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD
Bette Korber, Ph.D.
Los Alamos National Laboratory, Los Alamos, NM
David C. Montefiori, Ph.D.
Duke University, Durham, NC
Dr. Shen and Montefiori were supported by a grant (3UM1-AI068618-14S1) from
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.
1. Zhang W., Davis BD, Chen SS, Martinez JMS, Plummer JT, Vail E. Emergence of a new SARS-CoV-2 strain in Southern California, USA. January 20, 2021 (https://www.medrxiv.org/content/10.1101/2021.01.18.21249786v1). pre-print.
2. Anderson EJ, Rouphael NG, Widge ATet al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020383:2427–2438.
3. Keech C, Albert G, Because Iet al. Phase 1-2 trials with a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med 2020383:2320–2332.
4. Shen X, Tang H, McDanal Cet al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies induced by ancestral tip vaccines. Cell Host Microbe 2021 March 05 (Epub before printing).
5. Wu K, Werner AP, Kog Met al. Serum neutralizing activity induced by mRNA-1273 vaccine. N Engl J Med. DOI: 10.1056 / NEJMc2102179.