Virological characteristics of the SARS-CoV-2 KP.3, LB.1, and KP.2.3 variants

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike-protein substitution Leu455Ser, had outcompeted the previously predominant XBB lineages by the beginning of 2024.1Kaku Y Okumura K Padilla-Blanco M et al.Virological characteristics of the SARS-CoV-2 JN.1 variant.Lancet Infect Dis. 2024; 24: e82Summary Full Text Full Text PDF PubMed Google Scholar Subsequently, JN.1 subvariants, including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional spike-protein substitutions (eg, Arg346Thr, Phe456Leu, and Gln493Glu), have emerged concurrently (appendix pp 12–13).2Kaku Y Uriu K Kosugi Y et al.Virological characteristics of the SARS-CoV-2 KP.2 variant.Lancet Infect Dis. 2024; (published online May 20.)https://doi.org/10.1016/S1473-3099(24)00298-6Summary Full Text Full Text PDF Scopus (0) Google Scholar Furthermore, JN.1 subvariants such as LB.1 (JN.1.9.2.1) and KP.2.3 (JN.1.11.1.2·3), which convergently acquired a deletion at the 31st position in S (Ser31del) in addition to the aforementioned substitutions, have emerged and spread as of June, 2024 (appendix pp 12–13). In May, 2024, we reported the virological features of KP.2;2Kaku Y Uriu K Kosugi Y et al.Virological characteristics of the SARS-CoV-2 KP.2 variant.Lancet Infect Dis. 2024; (published online May 20.)https://doi.org/10.1016/S1473-3099(24)00298-6Summary Full Text Full Text PDF Scopus (0) Google Scholar in this Correspondence, we investigate the virological properties of KP.3, LB.1, and KP.2.3. We estimated the relative effective reproduction number (Re) of KP.3, LB.1, and KP.2.3 using a Bayesian multinomial logistic model3Yamasoba D Kimura I Nasser H et al.Virological characteristics of the SARS-CoV-2 omicron BA.2 spike.Cell. 2022; 185: 2103-2115Summary Full Text Full Text PDF PubMed Scopus (190) Google Scholar based on genome surveillance data from Canada, the UK, and the USA, where these variants have spread as of May, 2024 (appendix pp 9–13). The Re of KP.3 was more than 1·2-fold higher than that of JN.1 and higher than or similar to that of KP.2 in these countries (appendix pp 12–13). Notably, the Re values of LB.1 and KP.2.3 were higher than those of KP.2 and KP.3 (appendix pp 12–13). These results suggest that the three variants we investigated will spread worldwide, in addition to KP.2.2Kaku Y Uriu K Kosugi Y et al.Virological characteristics of the SARS-CoV-2 KP.2 variant.Lancet Infect Dis. 2024; (published online May 20.)https://doi.org/10.1016/S1473-3099(24)00298-6Summary Full Text Full Text PDF Scopus (0) Google Scholar We then conducted virological and immunological experiments with pseudoviruses. The pseudovirus infectivity of KP.2 and KP.3 in human HOS-ACE2/TMPRSS2 cells was significantly lower than that of JN.1 (appendix pp 12–13). Conversely, the pseudovirus infectivity of LB.1 and KP.2.3 was similar to that of JN.1 (appendix pp 12–13). Neutralisation assay was conducted with convalescent serum samples after breakthrough infection with XBB.1.5 or EG.5, vaccination status-unknown serum samples after infection with HK.3 or JN.1, and serum samples after monovalent XBB.1.5 vaccination. In all four groups of convalescent serum samples tested, the 50% neutralisation titres against LB.1 and KP.2.3 were significantly lower than those against JN.1 (2·2-fold to 3·3-fold and 2·0-fold to 2·9-fold) and even lower than those against KP.2 (1·6-fold to 1·9-fold and 1·4-fold to 1·7-fold; appendix pp 12–13). Although KP.3 showed higher neutralisation resistance against all convalescent serum samples tested than JN.1 (1·6-fold to 2·2-fold) with statistical significance, there were no significant differences between KP.3 and KP.2 (appendix pp 12–13). In infection-naive XBB.1.5 vaccine serum samples, the 50% neutralisation titre values of JN.1 subvariants were very low (appendix pp 12–13). For XBB.1.5 vaccine serum samples after natural XBB infection, the 50% neutralisation titre values against KP.3, LB.1, and KP.2.3 were significantly lower than those of JN.1 (2·1-fold to 2·8-fold) and even lower than KP.2 after infection (1·4-fold to 2·0-fold; appendix pp 12–13). Overall, the JN.1 subvariants, including KP.2 and KP.3, showed increased immune evasion and Re compared with the parental JN.1. Moreover, LB.1 and KP.2.3 with Ser31del, showed higher pseudovirus infectivity and more robust immune resistance than KP.2. These data suggest Ser31del is crucial for increased infectivity, enhanced immune evasion, and increased Re. Continuously monitoring variants with Ser31del and assessing the effects of this deletion across various variant proteins are necessary for future studies. KS is supported by the AMED Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) Initiative for World-leading Vaccine Research and Development Centers (JP243fa627001h0003); the AMED SCARDA programme on research and development of new generation vaccine, including a new modality application (JP243fa727002); the AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP24fk0108690); the JSPS KAKENHI Grant-in-Aid for Scientific Research A (JP24H00607); and the Cooperative Research Program (Joint Usage/Research Center programme) of the Institute for Life and Medical Sciences at Kyoto University (Kyoto, Japan); receives consulting fees from Moderna Japan and Takeda Pharmaceutical; and receives honoraria for lectures from Moderna Japan and Shionogi. JI is supported by the Japan Science and Technology Agency PRESTO (JPMJPR22R1) and the JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (JP23K14526) and receives consulting fees and honoraria for lectures from Takeda Pharmaceutical. JI and KS are supported by the Mitsubishi United Financial of Japan Financial Group Vaccine Development Grant. MSY is supported by the Japanese Government Ministry of Education, Culture, Sports, Science and Technology Scholarship–Research Category (240042). JET is supported by the Japanese Government Ministry of Education, Culture, Sports, Science and Technology Scholarship–Research Category (220235). The Genotype to Phenotype Japan Consortium and KS are supported, in part, by the Japan Agency for Medical Research and Development (AMED) Adopting Sustainable Partnerships for Innovative Research Ecosystem programme (JP24jf0126002) and the Japan Society for the Promotion of Science (JSPS) KAKENHI Fund for the Promotion of Joint International Research (JP23K20041). All other authors declare no competing interests. Download .pdf (.64 MB) Help with pdf files Supplementary appendix