Virological characteristics of the SARS-CoV-2 JN.1 variant

The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the current circulating SARS-CoV-2 omicron XBB lineages, including EG.5.1 and HK.3. Compared with XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike protein, indicating a high potential for immune evasion.1Uriu K Ito J Kosugi Y et al.Transmissibility, infectivity, and immune evasion of the SARS-CoV-2 BA.2.86 variant.Lancet Infect Dis. 2023; 23: e460-e461Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 2Wang Q Guo Y Liu L et al.Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.Nature. 2023; (published online Oct 23.)https://doi.org/10.1038/s41586-023-06750-wGoogle Scholar, 3Sheward DJ Yang Y Westerberg M et al.Sensitivity of the SARS-CoV-2 BA.2.86 variant to prevailing neutralising antibody responses.Lancet Infect Dis. 2023; 23: e462-e463Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 4Yang S Yu Y Jian F et al.Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86.Lancet Infect Dis. 2023; 23: e457-e459Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbours Leu455Ser and three mutations in non-spike proteins (appendix pp 17–18). Spike protein mutation Leu455Ser is a hallmark mutation of JN.1: we have recently shown that HK.3 and other flip variants carry Leu455Phe, which contributes to increased transmissibility and immune escape ability compared with the parental EG.5.1 variant.5Kosugi Y Plianchaisuk A Putri O et al.Virological characteristics of the SARS-CoV-2 omicron HK.3 variant harboring the “FLip” substitution.BioRxiv. 2023; (published online Nov 15.) (preprint)https://doi.org/10.1101/2023.11.14.566985Google Scholar Here, we investigated the virological properties of JN.1. We estimated the relative effective reproductive number of JN.1 using genomic surveillance data from France, the UK, and Spain, where more than 25 sequences of JN.1 have been reported, using a Bayesian multinomial logistic model (appendix pp 10–15, 17–18).6Yamasoba D Kimura I Nasser H et al.Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike.Cell. 2022; 185 (15.e19): 2103Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar The reproductive number of JN.1 in these three countries was higher than that of BA.2.86.1 and HK.3, one of the XBB lineages with the highest growth advantage at the end of November, 2023 (appendix pp 17–18).5Kosugi Y Plianchaisuk A Putri O et al.Virological characteristics of the SARS-CoV-2 omicron HK.3 variant harboring the “FLip” substitution.BioRxiv. 2023; (published online Nov 15.) (preprint)https://doi.org/10.1101/2023.11.14.566985Google Scholar These results suggest that JN.1 might soon become the dominant lineage worldwide. Indeed, by the end of November 2023, JN.1 had already overtaken HK.3 in France and Spain (appendix pp 17–18). The in vitro ACE2 binding assay7Uriu K Ito J Zahradnik J et al.Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant.Lancet Infect Dis. 2023; 23: 280-281Summary Full Text Full Text PDF PubMed Google Scholar showed that the dissociation constant value of the JN.1 receptor-binding domain (RBD) was significantly higher than that of the BA.2.86 RBD (appendix pp 17–18), suggesting that Leu455Ser decreases binding affinity to the human ACE2 receptor. In contrast, the pseudovirus assay showed that the infectivity of JN.1 was significantly higher than that of BA.2.86 (appendix pp 17–18). This discrepancy could be due to the difference between monomeric RBD and trimerised whole spike protein (appendix pp 2, 17–18). We then performed a neutralisation assay using rodent sera infected with BA.2.86 or immunised with BA.2.86 spike protein. In both cases, the 50% neutralisation titre (NT50) against JN.1 was similar to that against BA.2.86 (appendix 17–18), suggesting that Leu455Ser does not affect the antigenicity of BA.2.86. On the other hand, the NT50 of breakthrough infection sera with XBB.1.5 and EG.5.1 against JN.1 was significantly lower than that of HK.3 (2·6-fold to 3·1-fold) and BA.2.86 (3·8-fold; appendix pp 17–18). Furthermore, JN.1 shows robust resistance to monovalent XBB.1.5 vaccine sera compared with BA.2.86 (appendix 17–18). Taken together, these results suggest that JN.1 is one of the most immune-evading variants to date. Our results suggest that Leu455Ser contributes to increased immune evasion, which partly explains the increased reproductive number of JN.1. KJI and KS are supported in part by AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA and by AMED SCARDA Program on R&D of new generation vaccine including new modality application. The G2P-Japan Consortium and KS are supported by AMED Research Program on Emerging and Re-emerging Infectious Diseases and by the JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research). KS received funding from the AMED Research Program on HIV/AIDS, JST CREST, JSPS Core-to-Core Program, The Tokyo Biochemical Research Foundation, and The Mitsubishi Foundation; received consulting fees from Moderna Japan and Takeda Pharmaceutical; and honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. JI received funding from JST PRESTO and JSPS KAKENHI Grant-in-Aid for Early-Career Scientists; and received consulting fees and honoraria for lectures from Takeda Pharmaceutical. KU is a JSPS Research Fellow DC2. YKo is a JSPS Research Fellow DC1. JZ is funded by the International Joint Research Project of the Institute of Medical Science, the University of Tokyo and the project of National Institute of Virology and Bacteriology, Programme EXCELES, that is funded by the European Union, Next Generation EU. The other authors declare no competing interests. We thank CEU Universities and Santander Bank (Ayudas a la movilidad internacional de los investigadores en formación de la CEINDO) and to the Federation of European Biochemical Societies for their financial support to MP-B during the first and second part of his internship period at BIOCEV. Download .pdf (.69 MB) Help with pdf files Supplementary appendix