LAUSR

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.