Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination | Infectious Diseases | JAMA | JAMA Network
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Figure.  Neutralizing Antibody Responses Against SARS-CoV-2 Variants
Neutralizing Antibody Responses Against SARS-CoV-2 Variants

A, Data from 20 patients with acute COVID-19 infection (5-19 days after symptom onset). B, Data from 20 convalescent COVID-19 individuals (32-94 days after symptom onset). C, Data from 14 healthy individuals (aged 18-55 years) who received the Moderna (mRNA-1273) vaccine, 100-μg dose, on day 14 (post–second dose). The geometric mean titers (GMTs) with 95% CI are shown for samples against the A.1, B.1, B.1.1.7, and N501Y variants. The horizontal dashed lines indicate the limit of detection (FRNT50 GMT = 20). Statistical significance was determined with the Kruskal-Wallis test to compare GMTs between the variants, followed by the Dunn’s multiple comparison post hoc test. For A (acutely infected patients) and B (convalescent individuals), no comparisons were statistically significant. For C (vaccinated individuals), significant differences were found for variant A.1 vs B.1 (P < .001), variant A.1 vs B.1.1.7 (P = .02), and variant A.1 vs N501Y (P = .02). FRNT50 indicates live-virus focus reduction neutralization tests with the reciprocal dilution of serum that neutralizes 50% of the input virus.

1.
Suthar  MS, Zimmerman  MG, Kauffman  RC,  et al.  Rapid generation of neutralizing antibody responses in COVID-19 patients.   Cell Rep Med. 2020;1(3):100040. doi:10.1016/j.xcrm.2020.100040PubMedGoogle Scholar
2.
Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
3.
Dan  JM, Mateus  J, Kato  Y,  et al.  Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.   Science. 2021;371(6529):eabf4063. doi:10.1126/science.abf4063PubMedGoogle Scholar
4.
Widge  AT, Rouphael  NG, Jackson  LA,  et al; mRNA-1273 Study Group.  Durability of responses after SARS-CoV-2 mRNA-1273 vaccination.   N Engl J Med. 2021;384(1):80-82. doi:10.1056/NEJMc2032195PubMedGoogle ScholarCrossref
5.
Liu  Y, Liu  J, Xia  H,  et al.  Neutralizing activity of BNT162b2-elicited serum: preliminary report.   N Engl J Med. Published online February 17, 2021. doi:10.1056/NEJMc2102017PubMedGoogle Scholar
6.
Vanderheiden  A, Edara  VV, Floyd  K,  et al.  Development of a rapid focus reduction neutralization test assay for measuring SARS-CoV-2 neutralizing antibodies.   Curr Protoc Immunol. 2020;131(1):e116. doi:10.1002/cpim.116PubMedGoogle Scholar
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    4 Comments for this article
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    Cellular Response
    Paz Einat, Ph.D. | Dr. Paz Einat Biotechnology Projects & Consulting
    This Research Letter makes no mention of cellular response. T-cells comprise an essential part of the immune response, they potentially are less prone to decreased efficacy due to mutations and, while they are much more difficult to examine, the minimum is to address this part of the immune system in the discussion.
    CONFLICT OF INTEREST: None Reported
    Temporal Variation
    James Marzolf, MD MPH MSc | Whole Health Institute
    Very interesting study. Vaccine serum samples perhaps should have also been drawn in a time period parallel to the convalescent sera for a stronger comparison.
    CONFLICT OF INTEREST: None Reported
    Effect of SARS-CoV-2 Subspecies on Neutralizing IgG Affinity.
    Takuma Hayashi, MBBS, DMSci, GMRC, PhD. | National Hospital Organization Kyoto Medical Center
    This Research Letter is a remarkably interesting study.

    We also investigated the affinity of serum IgG to the conventional RBD, Y453F, and N501Y in COVID-19-positive patients and healthy subjects. A strong affinity for conventional RBD was shown for the serum IgG of 29 of the 41 COVID-19-positive patients. Moderate affinity for conventional RBD, Y453F, and N501Y was shown in the serum IgG of four of the COVID-19-positive patients. No affinity for conventional RBD, Y453F, or N501Y was shown in the serum IgG of the COVID-19-negative subjects.

    On January 8, 2021, Pfizer and BioNTech reported the efficacy of the
    COVID-19 vaccine against the UK and South Africa SARS-CoV-2 variants based on the results of phase I clinical trials.

    Our results also suggest that SARS-CoV-2 subspecies with the RBD mutations Y453F or N501Y partially escaped detection by 4 neutralizing monoclonal antibodies and 21 neutralizing antibodies in sera derived from COVID-19-positive patients. Infection with SARS-CoV-2 subspecies that cause serious symptoms in humans may spread globally.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Vaccine derived vs post-infection immunity against mutant SARS-CoV-2
    Jeremiah Stanley, PhD | Yokohama City University
    Edara and colleagues have assessed the neutralizing antibody (nAb) response against SARS-CoV-2 variants after infection and vaccination with the mRNA-1273 vaccine. But this paper has several weaknesses.

    As of April 8th 2021, the US CDC reports five variants of concern (VoC) of SARS-CoV-2 in circulation which differ from the original strain in terms of transmissibility, disease severity, evasion from neutralization, and failure of treatments and vaccines. Of the five VoC, the authors have tested only one, the B.1.1.7 from the United Kingdom which possesses the N510Y mutation that confers high transmissibility yet has minimal impact on neutralization by convalescent
    and post-vaccination sera. On the other hand, two of the other VoC were not tested: B.1.351 from South Africa and P.1 from Brazil/Japan which are known to possess an additional E484K mutation that is responsible for viral evasion from infection or vaccine-derived nAbs (https://doi.org/10.1101/2021.01.25.428137).

    The authors have used two groups for comparison and both have several flaws that hamper their purpose. The first comprises sera of acutely ill patients with severe COVID-19 and the second had convalescent sera from mild to moderate illness. Surprisingly, both the comparative groups had similar levels of geometric mean titers (GMT) of nAbs which might probably be due to improper timing of sample collection. Antibody levels are higher and peak levels are attained later in severe COVID-19 (doi:10.1038/s41467-020-19943-y). In the severe disease group, samples were collected 5-19 days after symptom onset, which is too early and could possibly be the reason for lower nAb levels and high proportion nAb negatives in this group. Nearly 40% of the convalescent individuals may not possess nAbs either due to absence of production, production of undetectable levels or due to rapid waning (doi:10.1016/S2666-5247(21)00025-2). This trend was not reflected in the convalescent group.

    Overall, both the comparator groups represented primary humoral response, while the vaccine group comprised secondary response. This could possibly be the reason why the GMTs of vaccine-derived nAbs against all mutants were higher (on the order of 103) compared to post-infection nAbs (on the order of 102). Also, IgA-mediated mucosal immunity that occurs following infection might not be expected from the injectable vaccine. There were no negatives encountered in the vaccine group probably due to the low sample size. The above factors must be taken into consideration in vaccine efficacy studies to avoid skewing of results.

    Despite the lacunae, the data suggests that two rounds of vaccine elicit a more robust protective immune response compared to a single round of infection. It would be interesting to see if the vaccine could similarly achieve higher nAb titers for E484K mutants compared to that obtained post-infection. If so, vaccine-induced immunity could still be a better option than infection immunity in limiting systemic viremia and not mucosal colonization. Although developing a new vaccine to cover these escape mutants should be the ideal goal, the old vaccine might still offer some benefit in the meantime, if the above phenomenon could be proven using a proper comparator group.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    March 19, 2021

    Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination

    Author Affiliations
    • 1Emory University Department of Pediatrics, Atlanta, Georgia
    • 2Emory Vaccine Center, Atlanta, Georgia
    • 3University of Texas Medical Branch, Galveston
    JAMA. 2021;325(18):1896-1898. doi:10.1001/jama.2021.4388

    Serum neutralizing antibodies rapidly appear after SARS-CoV-2 infection1 and vaccination2 and are maintained for several months.3,4 The emergence of SARS-CoV-2 variants has raised concerns about the breadth of neutralizing-antibody responses. We compared the neutralizing-antibody response to 4 variants in infected and vaccinated individuals to determine how mutations within the spike protein are associated with virus neutralization.

    Methods

    Serum samples were obtained from 3 groups of individuals. At Emory University, hospitalized adults with SARS-CoV-2 infection (polymerase chain reaction confirmed) were enrolled 5 to 19 days after symptom onset (July 2020). Infected convalescent individuals (polymerase chain reaction or antigen test confirmed) were enrolled 32 to 94 days after symptom onset (March to August 2020). Deidentified serum samples drawn 14 days after the second dose (100-μg cohort) from individuals in the mRNA-1273 phase 1 clinical trial2 were obtained from the National Institutes of Health. See the eAppendix in the Supplement for participant details. Institutional review board approval was obtained from Emory University and Advarra; all participants provided written informed consent.

    Four variants were examined, chosen to represent the original SARS-CoV-2 strain and emerging variants with mutations in the spike protein. The first variant, nCoV/USA_WA1/2020 (A.1 lineage), closely resembled the original Wuhan strain and the spike used in the mRNA-1273 vaccine, and was propagated from an infectious SARS-CoV-2 clone. The second variant, EHC-083E (B.1 lineage), containing a D614G mutation within the spike, was the predominant circulating strain at the time of the study and was isolated from a residual nasopharyngeal swab from a patient in Atlanta, Georgia, in March 2020 (SARS-CoV-2/human/USA/GA-EHC-083E/2020). The third variant, B.1.1.7 (SARS-CoV-2/human/USA/CA_CDC_5574/2020), was originally identified in the UK and of concern because of increased transmissibility. It contained several spike mutations and was isolated from a residual nasopharyngeal swab from a patient in San Diego, California, in December 2020. The fourth variant, N501Y SARS-CoV-2 virus, containing a mutation in the critical receptor binding domain of the spike that is present across multiple emerging variants, including the B.1.1.7 variant in this study, was generated from an infectious clone as previously described.5 This virus is not found in nature.

    Live-virus focus reduction neutralization tests (FRNTs) were performed as previously described.6 See the eAppendix in the Supplement for details on the laboratory methods. FRNT50 titers, which represent the reciprocal dilution of serum that neutralizes 50% of the input virus, were interpolated with a 4-parameter nonlinear regression, and geometric mean titers (GMTs) were calculated with 95% CI in GraphPad Prism version 8.4.3. Kruskal-Wallis test was used to compare FRNT50 GMTs between the variants, followed by Dunn’s multiple comparison post hoc test. We determined P < .05 (2 sided) to define statistical significance.

    Results

    Twenty acutely infected COVID-19 patients provided serum samples (mean age, 56.6 years; 50% men). The FRNT50 GMT for the A.1 variant was 186 (95% CI, 90-383); for B.1, 110 (95% CI, 57-209); for B.1.1.7, 116 (95% CI, 62-215); and for N501Y, 141 (95% CI, 74-269). Comparison of the FRNT50 GMT of the variants was not statistically significant (Figure).

    Twenty convalescent individuals provided serum samples (mean age, 45 years; 55% men). The FRNT50 GMT for the A.1 variant was 168 (95% CI, 113-249); for B.1, 91 (95% CI, 60-138); for B.1.1.7, 145 (95% CI, 96-220); and for N501Y, 145 (95% CI, 76-172). Comparison of the FRNT50 GMT of the variants was not statistically significant.

    Serum samples were available for 14 mRNA-1273 vaccinated individuals2 (age range, 18-55 years; 43% men). The FRNT50 GMT for the A.1 variant was 1709 (95% CI, 1412-2069); for B.1, 804 (95% CI, 632-1023); for B.1.1.7, 965 (95% CI, 695-1341); and for N501Y, 994 (95% CI, 777-1272). Comparisons of the FRNT50 GMT of B.1, B.1.1.7, and the N501Y variant were not statistically significant. The FRNT50 GMTs for the B.1 (P < .001), B.1.1.7 (P = .02), and N501Y (P = .02) variants were statistically significantly lower than that for the A.1 variant.

    Discussion

    This study found neutralizing activity of infection- and vaccine-elicited antibodies against 4 SARS-CoV-2 variants, including B.1, B.1.1.7, and N501Y. Because neutralization studies measure the ability of antibodies to block virus infection, these results suggest that infection- and vaccine-induced immunity may be retained against the B.1.1.7 variant. As additional variants emerge, neutralizing-antibody responses after infection and vaccination should be monitored.

    Limitations include the small sample size, possible selection bias, lack of clinical outcomes, and how neutralization titers correlate with protection.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Mehul S. Suthar, PhD, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Room 2022, Atlanta, GA 30329-4208 (msuthar@emory.edu).

    Accepted for Publication: March 8, 2021.

    Published Online: March 19, 2021. doi:10.1001/jama.2021.4388

    Author Contributions: Dr Suthar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Edara, Ahmed, Suthar.

    Acquisition, analysis, or interpretation of data: Edara, Hudson, Xie, Suthar.

    Drafting of the manuscript: Edara, Suthar.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Edara, Hudson, Suthar.

    Obtained funding: Suthar.

    Administrative, technical, or material support: Xie, Suthar.

    Supervision: Edara, Ahmed, Suthar.

    Data visualization: Hudson.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This work was supported in part by grants NIH P51 OD011132, 3U19AI057266-17S1 CCHI Immune Memory Supplement, U19AI090023, R01AI127799, R01AI148378, K99AI153736, and UM1AI148684 to Emory University; R00AG049092 and R24AI120942 to the University of Texas Medical Branch from the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Oliver S. and Jennie R. Donaldson Charitable Trust; the Emory Executive Vice President for Health Affairs Synergy Fund award; the Pediatric Research Alliance Center for Childhood Infections and Vaccines and Children’s Healthcare of Atlanta; COVID-Catalyst-I3 Funds from the Woodruff Health Sciences Center and Emory School of Medicine; Woodruff Health Sciences Center 2020 COVID-19 CURE Award; and the Vital Projects/Proteus funds.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

    Additional Contributions: We acknowledge the following individuals for providing reagents, discussion, and editing of the manuscript: Emory University School of Medicine, Atlanta, Georgia: Katharine Floyd, BS, Lilin Lai, MD, Meredith Gardner, PhD, Anne Piantadosi, MD, Jesse J. Waggoner, MD, Ahmed Babiker, MBBS, David S. Stephens, MD, Evan J. Anderson, MD, Srilatha Edupuganti, MD, MPH, Nadine Rouphael, MD, MSc, Grace Mantus, MS, Lindsay Nyhoff, PhD, Jens Wrammert, PhD, Max W. Adelman, MD, MSc, Rebecca Fineman, BS, Shivan Patel, MD, Rebecca Byram, ME, Dumingu Nipuni Gomes, MPH, Garett Michael, BS, BA, Hayatu Abdullahi, MD, Erin M. Scherer, PhD, Nour Beydoun, MD, Bernadine Panganiban, BS, Nina McNair, BS, Kieffer Hellmeister, BA, Jamila Pitts, BS, Joy Winters, MS, Jennifer Kleinhenz, BS, Jacob Usher, BS, and James O’Keefe, MD; UC San Diego School of Medicine, California: Louise C. Laurent, MD, PhD, Peter De Hoff, PhD, Holly Valentine, BA, MPH, Rob Knight, PhD, Phoebe Seaver, BA, MPH, Gene W. Yeo, PhD, MBA, Shashank Sathe, BTech, MS, and Aaron Carlin, MD, PhD; The Scripps Research Institute, La Jolla, California: Kristian G. Andersen, PhD, Mark Zeller, PhD, Karthik Gangavarapu, BS, Catie Anderson, BA, and Alaa Abdel Latif, BA, MPhil, BS; University of Texas Medical Branch, Galveston: Kumari Lokugamage, PhD, Vineet Menachery, PhD, Pei-Yong Shi, PhD; and Centers for Disease Control and Prevention, Atlanta, Georgia: Natalie Thornburg, PhD, Azaibi Tamin, PhD, Jennifer L. Harcourt, PhD, Maureen Diaz, PhD, Suxiang Tong, PhD, Ying Tao, PhD, Jing Zhang, PhD, Phili Wong, MS, Shilpli Jain, PhD, and Jennifer Folster, PhD. No one received financial compensation for his or her contributions. We thank the mRNA-1273 phase 1 study team and the Division of Microbiology and Infectious Diseases for providing clinical samples.

    References
    1.
    Suthar  MS, Zimmerman  MG, Kauffman  RC,  et al.  Rapid generation of neutralizing antibody responses in COVID-19 patients.   Cell Rep Med. 2020;1(3):100040. doi:10.1016/j.xcrm.2020.100040PubMedGoogle Scholar
    2.
    Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
    3.
    Dan  JM, Mateus  J, Kato  Y,  et al.  Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.   Science. 2021;371(6529):eabf4063. doi:10.1126/science.abf4063PubMedGoogle Scholar
    4.
    Widge  AT, Rouphael  NG, Jackson  LA,  et al; mRNA-1273 Study Group.  Durability of responses after SARS-CoV-2 mRNA-1273 vaccination.   N Engl J Med. 2021;384(1):80-82. doi:10.1056/NEJMc2032195PubMedGoogle ScholarCrossref
    5.
    Liu  Y, Liu  J, Xia  H,  et al.  Neutralizing activity of BNT162b2-elicited serum: preliminary report.   N Engl J Med. Published online February 17, 2021. doi:10.1056/NEJMc2102017PubMedGoogle Scholar
    6.
    Vanderheiden  A, Edara  VV, Floyd  K,  et al.  Development of a rapid focus reduction neutralization test assay for measuring SARS-CoV-2 neutralizing antibodies.   Curr Protoc Immunol. 2020;131(1):e116. doi:10.1002/cpim.116PubMedGoogle Scholar
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