Immune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage

The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023-24. However, the increase in infections was not accompanied by increases in COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases infected with BA.2.86-derived lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86-derived lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted and BA.4/BA.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86-derived lineages experienced greater numbers of documented prior SARS-CoV-2 infections. These associations of BA.2.86-derived lineages with immune escape were confirmed when comparing cases diagnosed during periods when JN.1 was the predominant circulating lineage to cases diagnosed during November, 2023. Cases infected with BA.2.86-derived lineages, or during periods when JN.1 was the predominant circulating lineage, also experienced lower risk of progression to severe clinical outcomes requiring emergency department consultations or hospital admission. Sensitivity analyses suggested under-ascertainment of prior infections, even if differential between cases infected with BA.2.86-derived lineages and non-BA.2.86 lineages, could not explain this apparent attenuation of severity. Our findings implicate escape from immunity acquired from prior vaccination or infection in the emergence of the JN.1 lineage and suggest infections with this lineage are less likely to experience clinically-severe disease. Monitoring of immune escape and clinical severity in emerging SARS-CoV-2 variants remains a priority to inform responses. ### Competing Interest Statement JAL discloses receipt of grant funding and consulting fees from Pfizer, Inc., both unrelated to this work. SYT discloses receipt of grant funding from Pfizer, Inc. unrelated to this work. ### Funding Statement This study was funded by the US Centers for Disease Control and Prevention (SYT) and the US National Institutes of Health (R01-AI148336 to JAL). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Kaiser Permanente Southern California Institutional Review Board gave ethical approval for this work. This work was also reviewed by the US Centers for Disease Control and Prevention (CDC) and was conducted consistent with applicable federal law and CDC policy (45 CFR part 46, 21 CFR part 56; 42 USC Sect. 241 (d); 5 USC Sect. 552a; 44 USC Sect. 3501 et seq.). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Individual-level testing and clinical outcomes data reported in this study are not publicly shared due to privacy protections for patient electronic health records. Individuals wishing to access disaggregated data, including data reported in this study, should submit requests for access to sara.y.tartof@kp.org. Requests will receive a response within 14 days. De-identified data (including, as applicable, participant data and relevant data dictionaries) will be shared upon approval of analysis proposals with signed data-access agreements in place. Analysis code is available from GitHub (https://github.com/joelewnard/jn1).