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 it is spreading rapidly in the United States and has been found in at least 25 other countries (see updates at https://www.gisaid.org/hcov19-variants/). This variant contains three spike mutations that are major targets for antibody neutralization; one mutation (L452R) is located in the receptor-binding motif and the other (W152C) in the N-terminal domain supercity. This has raised concerns about a possible escape of the immune system, which could jeopardize the effectiveness of the vaccine and increase the risk of re-infection. We measured the neutralizing activity of serum samples obtained from 14 convalescent individuals and from 49 recipients of one of two different precision-based vaccines: mRNA vaccine (mRNA-1273 [Moderna]; 26 recipients)2 and a protein nanoparticle vaccine (NVX-CoV2373 [Novavax]; 23 recipients).3 We selected mRNA-1273 samples that represented high, medium, and low neutralization titers. Samples of NVX-CoV2373 were randomly selected and not previously selected based on antibody titer.
The neutralizing activity of all serum samples was tested against variant B.1.429 and the concerned variant that first appeared in South Africa (B.1.351, also named 20H / 501Y.V2). We compared this neutralizing activity with the activity of serum samples in relation to the prototype variant D614G. Compared to variant D614G, we found that B.1.429 was approximately 2 to 3 times less susceptible to neutralization by convalescent serum and serum samples obtained from vaccinated individuals, while B.1.351 was approximately 9 to 14 times less sensitive to neutralization.
Convalescent serum samples were obtained from infected individuals 1 to 8 weeks after resolving coronavirus disease infection 2019 or 2 to 10 weeks after the latest positive SARS-CoV-2 test. Serum samples were taken from Moderna vaccine recipients on day 57 (28 days after the second dose of vaccine) and Novavax serum samples from vaccine recipients on day 35 (14 days after the second dose of vaccine). The results are presented as the difference in the neutralization titers of the respective samples (panels A and B) and as the difference in the titers relative to variant D614G (titer ratio to the specified variant) for each set of samples (plate C). Lower values indicate stronger cross-neutralization of the virus variant. The dashed thin lines on plates A and B represent the individual patterns, and the thick black lines represent the geometric means of each group of patterns, as shown on the right. The thick black bands on plate C represent the geometric mean differences in titers for the sample sets, which are also marked above each set. The circles on plate C represent differences in titers relative to D614G for individual samples. P values for comparison of reciprocal neutralization titers at 50% inhibitory dilution (ID50) and 80% inhibitory dilution (ID80) are comparative comparisons of the data shown on plates A and B, calculated using the Wilcoxon test with a rank signature. Values of P less than 0.001 correlate with Q (adjusted P) values less than 0.0019 (see Table S2 in Appendix 2). Differences in neutralization titers between the three sets of samples shown in panel C were not significant (P> 0.05 by the Wilcoxon rank sum test).
We constructed pseudoviruses only with the spike mutation D614G (as a comparative variant) or in combination with 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 virus test on spike-pseudotyped virus in 293T cells that were stably converted to angiotensin-converting enzyme overexpression 2.4 Variant B.1.429 was neutralized with convalescent serum and serum obtained from vaccinated individuals, resulting in an inhibitory dilution of 50% (ID50) geometric mean titers from 225 to 495 (Figure 1Aand Table S1 in Appendix 1, available with the full text of this letter at NEJM.org). ID50 and ID80 titers against variant B.1.429 for convalescent serum and for serum of subjects who received one of the vaccines were significantly lower than those against D614G (P <0.001)Figure 1A and 1Band Table S2 in Appendix 2). Geometric mean ID50 titers against B.1.429 were 3.1-fold (range, 1.4 to 8.8) lower than those against D614G for convalescent serum and were 2.0 and 2.5-fold lower (ranges, 0.7 and 8, 6) lower than D614G for serum from subjects who received mRNA-1273 and NVX-CoV2373 vaccines (Figure 1C and Table C1). Geometric mean ID50 the titer against B.1.351 was 13.1 times lower than against D614G for convalescent serum and 9.7 times and 14.5 times lower than against D614G for serum from persons who received mRNA-1273 and NVX-CoV2373 vaccines (Figure 1C). Our findings regarding neutralization of variant B.1.351 with serum obtained from recipients of the mRNA-1273 vaccine are consistent with those previously reported.5
The moderately lower value in neutralization titers compared to variant B.1.429, seen in this study, is similar to that previously seen when neutralization of variant B.1.1.7 was tested by the same test, using serum samples obtained from mRNA-1273 and NVX recipients. -CoV2373 vaccine.4 These results and the high efficacy shown by these vaccines suggest that neutralizing antibodies induced by the vaccine are likely to remain effective against variant B.1.429. The magnitude of resistance seen in variant B.1.351 is more of a concern given current vaccines.
Xiaoying Shen, Ph.D.
Haili Tang, MS
Duke University, Durham, NC
Dr. Rolando Pajon
Modern, Cambridge, MA
Gale Smith, Ph.D.
Gregory M. Glenn, Ph.D. Med
Novavax, Gaithersburg, dr. Med
Wei Shi, Ph.D.
National Institute of Allergy and Infectious Diseases, Bethesda, et al. Med
Bette Korber, Ph.D.
Los Alamos National Laboratory, Los Alamos, NM
David C. Montefiori, Ph.D.
Duke University, Durham, NC
Dr. Shen and Montefiori are supported by a grant (3UM1-AI068618-14S1) from
Forms for publishing data submitted by the authors are available with the full text of this letter at NEJM.org.
This letter was published on April 7, 2021 on NEJM.org.
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2 Anderson EJ,, Rouphael NG,, Widge AT, et al. Safety and immunogenicity of the SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020; 3832427–2438.
3 Keech C,, Albert G,, Cho I, et al. Phase 1-2 study of the SARS-CoV-2 recombinant protein nanoparticle vaccine. N Engl J Med 2020; 3832320–2332.
4. Shen X,, Tang H,, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralization of antibodies that cause ancestor of the spike vaccine. The host of microbes 2021 March 05 (Epub before printing).
5. Wu K,, Werner AP,, Koch M, et al. Serum neutralization activity induced by mRNA-1273 vaccine. N Engl J Med. DOI: 10.1056 / NEJMc2102179.