Omicron infection increases IgG binding to spike protein of predecessor variants

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in India in 2020-2022 was driven predominantly by Wild (Wuhan-Hu-1 and D614G), Delta, and Omicron variants. The aim of this study was to examine the effect of infections on the humoral immune response and cross-reactivity to spike proteins of Wuhan-Hu-1, Delta, C.1.2., and Omicron. Residual archival sera (N = 81) received between January 2020 and March 2022 were included. Infection status was inferred by a positive SARS-CoV-2 RT-PCR and/or serology (anti-N and anti-S antibodies) and sequencing of contemporaneous samples (N = 18) to infer lineage. We estimated the levels and cross-reactivity of infection-induced sera including Wild, Delta, Omicron as well as vaccine breakthrough infections (Delta and Omicron). We found an approximately two-fold increase in spike-specific IgG antibody binding in post-Omicron infection compared with the pre-Omicron period, whilst the change in pre- and post-Delta infections were similar. Further investigation of Omicron-specific humoral responses revealed primary Omicron infection as an inducer of cross-reactive antibodies against predecessor variants, in spite of the weaker degree of humoral response compared to Wuhan-Hu-1 and Delta infection. Intriguingly, Omicron vaccine-breakthrough infections when compared with primary infections, exhibited increased humoral responses against RBD (7.7-fold) and Trimeric S (Trimeric form of spike protein) (34.6-fold) in addition to increased binding of IgGs towards previously circulating variants (4.2 - 6.5-fold). Despite Delta breakthrough infections showing a higher level of humoral response against RBD (2.9-fold) and Trimeric S (5.7-fold) compared to primary Delta sera, a demonstrably reduced binding (36%-49%) was observed to Omicron spike protein. Omicron vaccine breakthrough infection results in increased intensity of humoral response and wider breadth of IgG binding to spike proteins of antigenically-distinct, predecessor variants.

Keywords: Breakthrough infection; Delta; Humoral immunity; Immune responses; Omicron; SARS coronavirus; SARS-CoV-2 spike variants.

Figure 1

Prevalence and waves of SARS‐CoV‐2 variants in Indian population. (A) Schematic representation of this study, (B) Graphical representation and mutational profile of spike variants, (C) MCC phylogeny of SARS‐CoV‐2 spike gene from 2020 to 2022 in Vellore (City of Tamil Nadu) and India with the sample collection date.

Figure 2

The levels and cross‐reactivity of humoral response induced by pre‐Delta and Delta, pre‐Omicron, and Omicron infections towards heterologous spike proteins. The levels of (A&E) anti‐N, (B&F) anti‐RBD, (C&G) anti‐Trimeric S antibodies, and (D&H) Median OD value (of antibody binding) against different spike variants in respective serum groups.

Figure 3

Humoral responses induced by Delta and Omicron infection is cross‐reactive towards heterologous spike proteins. The level of antibodies against (A) N protein, (B) RBD & Trimeric S protein. Levels of IgG binding towards spike variants in (C) Wild, (D) Delta and (E) Omicron Infected sera. (F) The GM ratio of IgGs binding to the variants (%).

Figure 4

Delta and Omicron infections elicited differential immune imprinting in vaccinated individuals. Level of (A) anti‐N, (B) anti‐RBD & anti‐Trimeric S antibodies in serum groups. The IgG antibody binding towards spike variants in (C) vaccinated, breakthrough infections including (D) Vaccine+Delta and (E) Vaccine+Omicron infected sera, (F) the GM ratio between the spike variants to the type of infection (%).

Figure 5

Differences in the levels and cross‐reactivity of humoral responses in primary and breakthrough infections. Geometric mean ratio of (A) level of antibodies against RBD & Trimeric S and (B) Binding of IgGs against spike variants, between indicated groups.