Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case

Background: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2. Methods: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor. Findings: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants. Interpretation: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants. Funding: This work was supported by grants fromAMED (JP23ym0126048,JP22ym0126048,JP21ym0126048,JP23wm0125002,JP233fa627001,JP223fa627009,JP24jf0126002, andJP22fk0108572), and theJSPS (JP21H02970,JK23K20041, andJPJSCCA20240006).