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

Venice Servellita, Abdullah M Syed, Mary Kate Morris, Noah Brazer, Prachi Saldhi, Miguel Garcia-Knight, Bharath Sreekumar, Mir M Khalid, Alison Ciling, Pei-Yi Chen, G Renuka Kumar, Amelia S Gliwa, Jenny Nguyen, Alicia Sotomayor-Gonzalez, Yueyuan Zhang, Edwin Frias, John Prostko, John Hackett Jr, Raul Andino, Debra A Wadford, Carl Hanson, Jennifer Doudna, Melanie Ott, Charles Y Chiu, Venice Servellita, Abdullah M Syed, Mary Kate Morris, Noah Brazer, Prachi Saldhi, Miguel Garcia-Knight, Bharath Sreekumar, Mir M Khalid, Alison Ciling, Pei-Yi Chen, G Renuka Kumar, Amelia S Gliwa, Jenny Nguyen, Alicia Sotomayor-Gonzalez, Yueyuan Zhang, Edwin Frias, John Prostko, John Hackett Jr, Raul Andino, Debra A Wadford, Carl Hanson, Jennifer Doudna, Melanie Ott, Charles Y Chiu

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.

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.

Copyright © 2022 Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure S1
Figure S1
VLP and live virus neutralization assay median neutralizing antibody titers, related to Figures 1, 2, 3, and 4 Plot showing the difference in median neutralizing antibody titers to WT lineage between VLP-based and live virus-based assay.
Figure 1
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
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
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
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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