Vaccine breakthrough infection leads to distinct profiles of neutralizing antibody responses by SARS-CoV-2 variant

Abstract

Protective immunity against SARS-CoV-2 infection after COVID-19 vaccination may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. For example, among individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.

Keywords: Adaptive immunity; COVID-19; Immunoglobulins.

Figure 1. Antibody responses and viral dynamics at the time of acute infection in a breakthrough infection cohort.

(A) The logarithm of viral load at the time of infection versus the concentration of anti-Spike antibodies at the time of breakthrough. A regression line with standard error is shown, with the Pearson correlation coefficient and corresponding P value. (B) Genotype-matched neutralizing antibody titers. A regression line with standard error is shown, with the Pearson correlation coefficient and corresponding P value. (C) Anti-Spike antibody concentration at the initial study visit for culture-positive cases (+) and culture negative cases (–). Significance according to an unpaired Wilcoxon rank-sum test is shown. *P < 0.05. (D and E) Kaplan-Meier curves for time to PCR conversion by tertile of IgG responses (D) and time to culture conversion by tertile of IgG response (E). The P value represents log-rank testing comparing the subgroups.

Figure 2. Neutralizing antibody responses, as measured by NT50, against a panel of pseudoviruses.

The geometric mean is shown with a bar. Patients infected with Delta variants are shown in the top panel. Patients infected with the Omicron (BA.1) variant are shown in the bottom panel. Significance test of medians (Kruskal-Wallis) is shown. **P < 0.01. The solid bars show geometric mean for each group. Vaccination status is denoted by point shape. Subjects with seronegativity to Nucleocapsid (N) antigens at baseline are colored red; those with N seropositivity are colored blue.

Figure 3. Principal component analysis of NT50 titers.

The loadings are plotted as arrows. (A) The convex hull of the clusters according to vaccination status is shaded. Point shape denotes the infecting variant. (B) The convex hull of the clusters according to the infecting variant is shaded. Point shape denotes vaccination status at the time of infection.