. 2022 Apr 28;185(9):1539-1548.e5.

doi: 10.1016/j.cell.2022.03.019. Epub 2022 Mar 18.

Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants

Venice Servellita¹, Abdullah M Syed², Mary Kate Morris³, Noah Brazer¹, Prachi Saldhi¹, Miguel Garcia-Knight⁴, Bharath Sreekumar⁵, Mir M Khalid⁵, Alison Ciling², Pei-Yi Chen⁵, G Renuka Kumar⁵, Amelia S Gliwa¹, Jenny Nguyen¹, Alicia Sotomayor-Gonzalez¹, Yueyuan Zhang¹, Edwin Frias⁶, John Prostko⁶, John Hackett Jr⁶, Raul Andino⁴, Debra A Wadford³, Carl Hanson⁷, Jennifer Doudna⁸, Melanie Ott⁹, Charles Y Chiu¹⁰

Affiliations

¹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
² Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
³ Viral and Rickettsial Disease Laboratory, California Department of Public Health, Richmond, CA, USA.
⁴ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institutes, San Francisco, CA, USA.
⁶ Abbott Laboratories, Abbott Park, IL, USA.
⁷ Viral and Rickettsial Disease Laboratory, California Department of Public Health, Richmond, CA, USA. Electronic address: carl.hanson@cdph.ca.gov.
⁸ Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. Electronic address: doudna@berkeley.edu.
⁹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA; Gladstone Institutes, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: melanie.ott@gladstone.ucsf.edu.
¹⁰ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: charles.chiu@ucsf.edu.

PMID: 35429436
PMCID: PMC8930394
DOI: 10.1016/j.cell.2022.03.019

Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants

Venice Servellita et al. Cell. 2022.

. 2022 Apr 28;185(9):1539-1548.e5.

doi: 10.1016/j.cell.2022.03.019. Epub 2022 Mar 18.

Authors

Affiliations

¹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
² Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
³ Viral and Rickettsial Disease Laboratory, California Department of Public Health, Richmond, CA, USA.
⁴ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institutes, San Francisco, CA, USA.
⁶ Abbott Laboratories, Abbott Park, IL, USA.
⁷ Viral and Rickettsial Disease Laboratory, California Department of Public Health, Richmond, CA, USA. Electronic address: carl.hanson@cdph.ca.gov.
⁸ Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. Electronic address: doudna@berkeley.edu.
⁹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA; Gladstone Institutes, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: melanie.ott@gladstone.ucsf.edu.
¹⁰ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA; UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: charles.chiu@ucsf.edu.

PMID: 35429436
PMCID: PMC8930394
DOI: 10.1016/j.cell.2022.03.019

Abstract

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Keywords: B.1.1.529; B.1.617.2; COVID-19; Delta variant; Omicron variant; SARS-CoV-2; VLP; antibody neutralization; boosted breakthrough infection; breakthrough infection; humoral immunity; pseudovirus infectivity studies; quantitative antibody assay; variant of concern; variant severity; virus-like particle.

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Conflict of interest statement

Declaration of interests C.Y.C. is the director of the UCSF-Abbott Viral Diagnostics and Discovery and receives research support for SARS-CoV-2 studies from Abbott Laboratories. The other authors declare no competing interests.

Figures

**Figure 1**
Neutralizing antibody levels in fully vaccinated, uninfected individuals (A and D) Box-violin plots showing median neutralizing antibody titers using VLP (left) and live virus (right) assays against the SARS-CoV-2 WA-1 ancestral lineage (wild type [WT]) and Delta variant in vaccinated, unboosted (A) and vaccinated, boosted (D) individuals. (B and E) Box-violin plots of titers against the WT and Omicron variant in vaccinated, unboosted (B) and vaccinated, boosted (E) individuals. (C and F) Cumulative distribution function plots of titers to WT, Delta, and Omicron using VLP (left) and live virus (right) assays in vaccinated, unboosted (C) and vaccinated, boosted (F) individuals, showing the proportion of samples at or above a given titer. (G) Longitudinal box-violin plots of VLP titers to Delta (top) and Omicron (bottom) stratified by time ranges following completion of a primary vaccine series. For box-violin plots, the median is represented by a thick black line inside the box, boxes represent the first to third quartiles, whiskers represent the minimum and maximum values, and the width of each curve corresponds with the approximate frequency of data points in each region.

**Figure 2**
Neutralizing antibody levels in Delta and Omicron breakthrough infections (A) Box-violin plots of median neutralizing antibody titers against Delta (left) and Omicron (middle) variants compared with WT, along with cumulative distribution function plots of titers against WT, Delta, and Omicron (right), showing the proportion of samples at or above a given titer, in patients with Delta breakthrough infection using a VLP neutralization assay. (B) Corresponding plots in patients with Delta breakthrough infection using a live virus neutralization assay. (C) Corresponding plots in patients with Omicron breakthrough infection using a VLP neutralization assay (D) Corresponding plots in patients with Omicron breakthrough infection using a live virus assay. For the box-violin plots, the median is represented by the thick black line inside the box, boxes represent the first to third quartiles, whiskers represent the minimum and maximum values, and the width of each curve corresponds with the approximate frequency of data points in each region. The lines connecting the paired points are color-coded based on severity of infection (blue = asymptomatic or mild infection, red = moderate to severe infection). The solid lines denote immunocompetent and the dashed lines immunocompromised patients. Boosted samples are denoted with knobs at the ends of the lines.

**Figure 3**
Comparison of neutralizing antibody titers against the WT lineage in Delta and Omicron breakthrough infections (A) All patients in the study with breakthrough infection and available samples collected from 4 to 32 days after symptom onset or SARS-CoV-2 PCR test positivity. (Left) Kernel density plot showing distribution of collection days for samples from Delta and Omicron breakthrough infections. (Middle) Box-violin plot comparing VLP-neutralizing antibody titers against the WT lineage between Delta and Omicron breakthrough infections. (Right) Box-violin plot comparing VLP-neutralizing antibody titers against the WT lineage between asymptomatic or mild and moderate to severe breakthrough infections. (B) Corresponding kernel density plot (left) and box-violin plots (middle and right) for immunocompetent, unboosted patients. (C) Longitudinal plots of VLP-neutralizing antibody titers against the WT lineage versus days after symptom onset or SARS-CoV-2 PCR test positivity for Delta (left) and Omicron (right) breakthrough infections. Serial samples from the same patient are plotted as lines, shown color-coded based on clinical severity of the breakthrough infection. Circular knobs at the ends of the lines denote boosted status, whereas dotted lines denote immunocompromised status. Singleton time points for individual patients are shown as diamonds. The insets show longitudinal plots corresponding to immunocompetent, unboosted patients, along with a regression line. For the kernel density and box-violin plots, p values for significance were determined using the Mann-Whitney U test. For the regression analysis, p values for significance were determined using a t distribution with n − 2 degrees of freedom (df). For box-violin plots, the median is represented by a thick black line inside the box, boxes represent the first to third quartiles, whiskers represent the minimum and maximum values, and the width of each curve corresponds with the approximate frequency of data points in each region.

**Figure 4**
Correlation between quantitative spike IgG and neutralizing antibody titers (A) Plots showing correlation between spike IgG titers and neutralizing antibodies directed against WT (top), Delta (middle), and Omicron (bottom) lineages using a VLP-based assay. (B) Plots showing correlation between spike IgG titers and neutralizing antibodies directed against WT (top), Delta (middle), and Omicron (bottom) lineages using a live virus-based assay. The Spearman’s rank coefficient (ρ) was used to assess the strength of correlation and to determine the p value for significance.

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References

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Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants

Affiliations

Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Miscellaneous