Rapid spread of the SARS-CoV-2 JN.1 lineage is associated with increased neutralization evasion

Abstract

In July/August 2023, the highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2.86 lineage emerged and its descendant JN.1 is on track to become the dominant SARS-CoV-2 lineage globally. Compared to the spike (S) protein of the parental BA.2.86 lineage, the JN.1 S protein contains one mutation, L455S, which may affect receptor binding and antibody evasion. Here, we performed a virological assessment of the JN.1 lineage employing pseudovirus particles bearing diverse SARS-CoV-2 S proteins. Using this strategy, it was found that S protein mutation L455S confers increased neutralization resistance but reduces ACE2 binding capacity and S protein-driven cell entry efficiency. Altogether, these data suggest that the benefit of increased antibody evasion outweighs the reduced ACE2 binding capacity and further enabled the JN.1 lineage to effectively spread in the human population.

Keywords: Health sciences; Immunology; Virology.

Graphical abstract

Figure 1

Emergence and rapid spread of the SARS-CoV-2 JN.1 lineage (A) Frequencies of major SARS-CoV-2 lineages (left panels) in 2023 and trends for selected SARS-CoV-2 sublineages in late 2023 (right panels) on a global scale and for selected continents (Asia, Europe, North America, and Oceania). Graphs were generated using a seven-day sliding window and are based on data retrieved from https://cov-spectrum.org/ on 18.12.2023. Lineages suffixed with an asterisk (∗) also include their respective sublineages. (B) Recent trends in the evolution of SARS-CoV-2 BA.2 and XBB-sublineages. Evolutionary steps leading to JN.1 and XBB-sublineages JD.1.1, HV.1, and GS.4.1. S protein mutations are indicated. (C) S protein mutations (blue boxes) of B.1, BA.2.86.1, JN.1, XBB.1.5, JD.1.1, EG.5.1, HV.1, and GS.4.1 compared to the Wuhan-Hu-01 isolate (gray boxes indicate non-mutated residues). Abbreviations: NTD, N-terminal domain; RBD, receptor-binding domain, pre-S1/S2, region between RBD and S1/S2 cleavage site.

Figure 2

Cell entry and neutralization sensitivity of the SARS-CoV-2 JN.1 lineage (A) Entry efficiency of the JN.1 lineage. Pseudotype particles (_pp) harboring the indicated S proteins were inoculated onto the indicated cell lines and entry was analyzed. Presented are mean data from six biological replicates (four technical replicates), with cell entry normalized against particles harboring the B.1 S protein (=1). Error bars indicate the standard error of the mean (SEM). Further, the mean fold change in entry efficiency between BA.2.86.1_pp and JN.1_pp is indicated. See also Figure S1D. (B) ACE2 binding efficiency of the JN.1 lineage. 293T cells transiently expressing the indicated S proteins were analyzed for ACE2 binding by flow cytometry. Presented are mean data from six biological replicates (single replicates), with ACE2 binding corrected for S protein cell surface expression and normalized against the B.1 S protein (=1). Error bars indicate the SEM. Further, the mean fold change in ACE2 binding between BA.2.86.1 and JN.1 is indicated. See also Figures S1E and S1F. (C) Sensitivity of the JN.1 lineage to neutralization. Pseudotype particles harboring the indicated S proteins were incubated with plasma from vaccinated individuals without (n = 11; left) or with a history of SARS-CoV-2 infection (n = 13; right), before being inoculated onto Vero cells. Pseudovirus cell entry was normalized against samples without plasma (=0% inhibition). Presented are geometric mean titers (GMTs) from a single biological replicate (four technical replicates). Information below the graphs shows response rates (proportion of plasma samples with neutralizing activity), GMT, and median fold GMT change compared to B.1_pp. Further, the median fold change in neutralization between BA.2.86.1_pp and JN.1_pp is indicated. Please also see Table S1 and Figure S2. For (A) and (B), statistical significance was assessed by two-way analysis of variance with Tukey’s multiple comparison test, while the Friedmann test with Dunn’s multiple comparison test was used in (C) (p > 0.05, not significant [ns]; p ≤ 0.05, ∗; p ≤ 0.01, ∗∗; p ≤ 0.001, ∗∗∗).