Neutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs

Abstract

Emerging SARS-CoV-2 variants raise questions about escape from previous immunity. As the population immunity to SARS-CoV-2 has become more complex due to prior infections with different variants, vaccinations or the combination of both, understanding the antigenic relationship between variants is needed. Here, we have assessed neutralizing capacity of 120 blood specimens from convalescent individuals infected with ancestral SARS-CoV-2, Alpha, Beta, Gamma or Delta, double vaccinated individuals and patients after breakthrough infections with Delta or Omicron-BA.1. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta and Omicron-BA.1) determined by plaque-reduction neutralization assay allowed us to map the antigenic relationship of SARS-CoV-2 variants. Highest neutralization titers were observed against the homologous variant. Antigenic cartography identified Zeta and Omicron-BA.1 as separate antigenic clusters. Substantial immune escape in vaccinated individuals was detected for Omicron-BA.1 but not Zeta. Combined infection/vaccination derived immunity results in less Omicron-BA.1 immune escape. Last, breakthrough infections with Omicron-BA.1 lead to broadly neutralizing sera.

Fig. 1. Neutralization in infection-derived blood specimens against seven authentic isolates of SARS-CoV-2 variants (B.1, Alpha, Beta Gamma, Delta, Zeta, Omicron-BA.1).

Bars represent geometric mean titers (GMT) of 90% reduction endpoint titers (PRNT₉₀) with 95% confidence interval. A–E Cohorts of convalescent specimens that are derived from individuals infected with A early-pandemic SARS-CoV-2 (pre-VOC), B Alpha, C Beta, D Gamma, and E Delta. F–I Cohorts consist of individuals with F double-dose mRNA vaccination, G prior SARS-CoV-2 infection followed by double-dose mRNA vaccination H Delta breakthrough infection of double-vaccinated individuals and I Omicron-BA.1 breakthrough infection following double (n = 8) and single (n = 3) mRNA vaccination. Colored numbers above bars refer to fold change reduction of GMT versus the homologous (infecting) variant, shown as first bar of each figure. Colored numbers below each bar represent the number of specimens with complete loss of neutralization (PRNT₉₀ titer < 1). Repeated measures one-way ANOVA with Dunnett’s multiple comparisons test using log10 transformed PRNT₉₀ titers was performed to analyze the statistical significance. Source data are provided as a Source Data file.

Fig. 2. Heatmap of fold-reduction in neutralization based on PRNT₉₀ data. Values of fold-reduction in neutralization (PRNT₉₀) of B.1, Alpha, Beta, Gamma, Delta, Zeta, and Omicron-BA.1 are presented as heat maps with darker colors implying greater changes.

The immune sera/plasma were organized into cohorts of convalescent specimens that are derived from individuals infected with early-pandemic SARS-CoV-2 (pre-VOC) (n = 34), Alpha (n = 12), Beta (n = 8), Gamma (n = 10), Delta (n = 10) and cohorts consist of individuals with double-dose mRNA vaccination (n = 16), prior SARS-CoV-2 infection followed by double-dose mRNA vaccination (n = 6), Delta breakthrough infection of double-vaccinated individuals (n = 13) and, Omicron-BA.1 breakthrough infection following double (n = 8) and single (n = 3) mRNA vaccination. Source data are provided as a Source Data file.

Fig. 3. SARS-CoV-2 antigenic cartography.

Mapping of antigenic relationship using antigenic cartography for A convalescent specimens from pre-VOC SARS-CoV-2, Alpha, Beta, Gamma, and Delta infections and B post-vaccination specimens with and without prior infection and breakthrough infections with Delta or Omicron-BA.1. For graphical reasons only post vaccination specimens are shown in (B). Source data are provided as a Source Data file.