Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

doi:10.1126/scitranslmed.abn7842

. 2022 Mar 2;14(634):eabn7842.

doi: 10.1126/scitranslmed.abn7842. Epub 2022 Mar 2.

Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

Benjamin L Sievers¹, Saborni Chakraborty², Yong Xue³, Terri Gelbart¹, Joseph C Gonzalez^{2

4}, Arianna G Cassidy⁵, Yarden Golan⁶, Mary Prahl⁷, Stephanie L Gaw⁵, Prabhu S Arunachalam⁸, Catherine A Blish^{2

4

9}, Scott D Boyd^{10

11}, Mark M Davis^{8

12

13}, Prasanna Jagannathan^{2

12}, Kari C Nadeau¹¹, Bali Pulendran⁸, Upinder Singh^{2

12}, Richard H Scheuermann^{1

14}, Matthew B Frieman¹⁵, Sanjay Vashee³, Taia T Wang^{2

4

9

12}, Gene S Tan^{1

16}

Affiliations

¹ J. Craig Venter Institute, La Jolla, CA 92037, USA.
² Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA 94305, USA.
³ J. Craig Venter Institute, Rockville, MD 20850, USA.
⁴ Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA.
⁶ Department of Bioengineering and Therapeutic Sciences, and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94115, USA.
⁷ Division of Pediatric Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94115, USA.
⁸ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
¹⁰ Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford, CA 94305, USA.
¹² Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁴ Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
¹⁵ Department of Microbiology and Immunology, Center for Pathogen Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁶ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.

PMID: 35025672
PMCID: PMC8891085
DOI: 10.1126/scitranslmed.abn7842

Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

Benjamin L Sievers et al. Sci Transl Med. 2022.

. 2022 Mar 2;14(634):eabn7842.

doi: 10.1126/scitranslmed.abn7842. Epub 2022 Mar 2.

Authors

Affiliations

¹ J. Craig Venter Institute, La Jolla, CA 92037, USA.
² Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA 94305, USA.
³ J. Craig Venter Institute, Rockville, MD 20850, USA.
⁴ Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA.
⁶ Department of Bioengineering and Therapeutic Sciences, and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94115, USA.
⁷ Division of Pediatric Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94115, USA.
⁸ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
¹⁰ Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford, CA 94305, USA.
¹² Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁴ Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
¹⁵ Department of Microbiology and Immunology, Center for Pathogen Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁶ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.

PMID: 35025672
PMCID: PMC8891085
DOI: 10.1126/scitranslmed.abn7842

Abstract

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.

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Figures

**Fig. 1.. Plasma neutralizing titers against variants of concern wane over time in samples from an outpatient COVID-19 infection cohort.**
(A) Study participants were enrolled (day 0) within three days of a positive SARS-CoV-2 PCR test (+PCR). Longitudinal plasma samples from day 28 (n=23), day 210 (n=23) and day 300 (n=8) were assessed against D614, Delta, Beta and Omicron. (B) The kinetics of half-maximal SARS-CoV-2 pseudovirus neutralizing titers (pNT₅₀) over time are shown. Dotted lines indicate baseline mean pNT₅₀ obtained from seronegative subjects. Solid lines connect samples from the same participant. (C) Mean pNT₅₀ values are shown across study time-points of all 4 pseudovirus variants. Values that were significantly different from D614 at each time point are marked with a star. (D) Ratios of pNT₅₀ values of the indicated variants of concern over D614 pNT₅₀ at each study time point are shown. Horizontal bars indicate median values. p values in (B to D) were calculated using mixed effects analysis with Geisser-Greenhouse correction and Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01.

**Fig. 2.. Plasma neutralizing titers against variants of concern increase after mRNA vaccination in a cohort of pregnant women.**
(A) Samples collected from a cohort of vaccinated pregnant women at baseline (n=9) and after 2 doses of mRNA vaccine (n=33) were assessed for neutralizing antibody against 4 SARS-CoV-2 pseudovirus strains. (B) pNT₅₀ values of paired samples at baseline and after 2 doses of mRNA vaccine (PD2) are presented. Samples from 9 participants from whom paired samples were available are shown; fold change of mean titers between the 2 time-points are indicated. (C) pNT₅₀ values against the 4 SARS-CoV-2 pseudoviral variants were measured in samples collected after 2 doses of mRNA vaccine. Fold reduction of mean pNT₅₀ compared to D614 are indicated for each variant. (D) Ratios of pNT₅₀ values of the indicated variants of concern over D614 pNT₅₀ are shown. Horizontal bars in (C and D) indicate median values. p values in (C and D) were calculated using repeated measures one way-ANOVA with Geisser Greenhouse correction and with Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, ****P < 0.0001.

**Fig. 3.. Plasma neutralizing titers against variants of concern are increased after a third dose of mRNA vaccine in a cohort of healthcare workers.**
(A) Samples were collected from a cohort of healthcare workers who received 2 doses of Pfizer vaccine 21 days apart and received a 3^rd dose 242 to 324 days after the first dose. Antibody titers were assessed at 28 and 210 days post dose 1 (PD1), and 7 days and 21 to 28 days post dose 3 (PD3). (B) The kinetics of pNT₅₀ values against D614, Delta, Beta, and Omicron are shown. Dotted lines indicate baseline mean pNT₅₀ obtained from seronegative subjects. Solid lines connect samples from the same participant (C) pNT₅₀ values (left panel) and ratios of pNT₅₀ of the indicated variants of concern over D614 pNT₅₀ (right panel) are shown for samples collected 7 days after 3^rd dose of vaccine. (D) pNT₅₀ values (left panel) and ratios of pNT₅₀ of the indicated variants of concern over D614 pNT₅₀ (right panel) are shown for samples collected 21 to 28 days after 3^rd dose of vaccine. Horizontal bars in (C and D) indicate median values. p values in (C) were calculated using repeated measures one way-ANOVA with Geisser Greenhouse correction and with Tukey’s multiple comparisons test. p values in (B and D) were calculated using mixed effects analysis with Geisser-Greenhouse correction and Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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[1] Torjesen I., Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear. BMJ 375, n2943 (2021). 10.1136/bmj.n2943 - DOI - PubMed

[2] Torjesen I., Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear. BMJ 375, n2943 (2021). 10.1136/bmj.n2943 - DOI - PubMed

[3] Karim S. S. A., Karim Q. A., Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 398, 2126–2128 (2021). 10.1016/S0140-6736(21)02758-6 - DOI - PMC - PubMed

[4] Karim S. S. A., Karim Q. A., Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 398, 2126–2128 (2021). 10.1016/S0140-6736(21)02758-6 - DOI - PMC - PubMed

[5] Feng S., Phillips D. J., White T., Sayal H., Aley P. K., Bibi S., Dold C., Fuskova M., Gilbert S. C., Hirsch I., Humphries H. E., Jepson B., Kelly E. J., Plested E., Shoemaker K., Thomas K. M., Vekemans J., Villafana T. L., Lambe T., Pollard A. J., Voysey M.; Oxford COVID Vaccine Trial Group , Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat. Med. 27, 2032–2040 (2021). 10.1038/s41591-021-01540-1 - DOI - PMC - PubMed

[6] Feng S., Phillips D. J., White T., Sayal H., Aley P. K., Bibi S., Dold C., Fuskova M., Gilbert S. C., Hirsch I., Humphries H. E., Jepson B., Kelly E. J., Plested E., Shoemaker K., Thomas K. M., Vekemans J., Villafana T. L., Lambe T., Pollard A. J., Voysey M.; Oxford COVID Vaccine Trial Group , Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat. Med. 27, 2032–2040 (2021). 10.1038/s41591-021-01540-1 - DOI - PMC - PubMed

[7] McCallum M., Walls A. C., Sprouse K. R., Bowen J. E., Rosen L. E., Dang H. V., De Marco A., Franko N., Tilles S. W., Logue J., Miranda M. C., Ahlrichs M., Carter L., Snell G., Pizzuto M. S., Chu H. Y., Van Voorhis W. C., Corti D., Veesler D., Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science 374, 1621–1626 (2021). 10.1126/science.abl8506 - DOI - PubMed

[8] McCallum M., Walls A. C., Sprouse K. R., Bowen J. E., Rosen L. E., Dang H. V., De Marco A., Franko N., Tilles S. W., Logue J., Miranda M. C., Ahlrichs M., Carter L., Snell G., Pizzuto M. S., Chu H. Y., Van Voorhis W. C., Corti D., Veesler D., Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science 374, 1621–1626 (2021). 10.1126/science.abl8506 - DOI - PubMed

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Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

Affiliations

Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

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