Immunogenicity of JN.1 and KP.2 COVID-19 mRNA vaccines against emerging SARS-CoV-2 variants

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to evolve five years after the initial outbreak. Although mRNA vaccines encoding the JN.1 and KP.2 Spike proteins were authorized in fall 2024, it remains unclear whether vaccine updates will be necessary for variants containing antigenically closely related Spike proteins. In this study, we evaluated the immunogenicity of JN.1 and KP.2 mRNA boosters in participants from Germany and the United States, respectively. Both vaccines induced robust and similar neutralizing antibody (NAb) responses against JN.1, KP.2, and other globally relevant variants such as LP.8.1.1 and NB.1.8.1. These data suggest that updating the vaccine formulation to closely related strains will likely offer only modest additional benefits against currently circulating variants.

Introduction

In fall 2024, the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approved COVID-19 mRNA vaccines expressing SARS-CoV-2 Spike from the JN.1 and KP.2 variants, respectively. Initial reports indicate that these vaccines successfully raise neutralizing antibody (NAb) titers against various JN.1 sublineages and provide protection against severe disease^1–5. However, a debate has emerged regarding the comparative immunogenicity of antigenically related COVID-19 vaccines and the potential utility of updating COVID-19 vaccines for closely related variants, such as current circulating SARS-CoV-2 variants (Fig. S1). In this study, we evaluated the immunogenicity of the JN.1 and KP.2 COVID-19 mRNA boosters.

Results and Discussion

We assessed immune responses in 40 individuals who received the JN.1 mRNA booster in Hannover, Germany and in 63 individuals who received the KP.2 mRNA booster in Boston, USA in fall 2024 (Tables S1, S2). Participants had a median of 5 COVID-19 vaccine doses prior to the JN.1 or KP.2 mRNA booster, and at least 90% of participants in the JN.1 cohort and 69% in the KP.2 cohort had at least one documented SARS-CoV-2 infection, although we expect the true rate of natural infection to be substantially higher⁶.

We evaluated NAb responses in participants who received the KP.2 mRNA boost against historical SARS-CoV-2 variants as well as JN.1, KP.2, and recently circulating subvariants LB.1, XEC, LP.8.1.1, and NB.1.8.1 (Fig. 1A). NAb responses increased at 3 weeks after the boost against all tested variants (Fig. 1A), with a 2.6- and 4.5-fold increase against JN.1 and KP.2, respectively, and a 20.1- and 23.8-fold increase in NAb titers against LP.8.1.1 and NB.1.8.1, respectively (Fig. 1B). In participants who received the KP.2 mRNA boost, NAb titers similarly increased against all tested variants (Fig. 1C), with a 15.3- and 11.7-fold increase against JN.1 and KP.2, respectively, and a 6.0- and 13.7-fold increase in NAb titers against LP.8.1.1 and NB.1.8.1, respectively (Fig. 1D). These data demonstrate that both the JN.1 and KP.2 mRNA vaccines boosted peripheral NAb responses against all current circulating variants tested. The different fold increases in the two cohorts likely reflected the higher baseline NAb titers against JN.1 and KP.2 in the JN.1 booster cohort, presumably reflecting differences in natural infection history.

Figure 1. Serum neutralizing antibody responses of the JN.1 and KP.2-adapted COVID-19 mRNA vaccines against emerging SARS-CoV-2 variants.

Plasma neutralizing antibody (NAb) titers against the WA1/2020, BA.5, XBB.1.5, JN.2, KP.2, KP.3, KP.3.1.1, KZ.1.1.1, LP.1, XEC, LP.8.1.1, and NB.1.8.1 variants by luciferase-based pseudovirus neutralization assays at baseline and at 3 weeks post JN.1 boosting in fall 2024 (A) and a paired analysis (B). Also shown are NAb titers against the above variants in participants who received a KP.2 mRNA booster in fall 2024 (C) and a paired analysis (D). Horizontal red bars reflect median values. Paired samples are connected by lines, and fold change is shown numerically at the top. Dotted lines reflect the limit of quantitation.

We next assessed NAb responses to other sarbecoviruses, including SARS-1, WIV-1, Rs4874, BANAL-20–103, PCoV-GD1–2019, and hCoV-NL63. Both cohorts showed antibodies against these diverse sarbecoviruses at baseline, suggesting acquired natural immunity, but these responses were not substantially increased by mRNA boosting (Fig. S2). These data suggest that a broad pan-sarbecovirus vaccine will likely require a different antigen strategy than sequential SARS-CoV-2 boosters. We also evaluated binding IgG responses against SARS-CoV-2 WA1/2020, B.1.617.2, BA.5, XBB.1.5, JN.1 and KP.2 by ELISA and ECLA assays, which showed substantial increases to all variants following both JN.1 and KP.2 mRNA boosting (Figs. S3, S4). In contrast, we observed no increases in WA1/2020, BA.5, XBB.1.5, or JN.1 Spike-specific cellular immune responses following KP.2 mRNA boosting (Fig. S5), consistent with prior reports^7,8.

As mucosal immunity is likely important for preventing SARS-CoV-2 acquisition, we evaluated mucosal NAb responses in nasal swabs following JN.1 or KP.2 mRNA boosting and observed minimal to no increases in nasal NAb titers (Fig. 2), similar to previous findings⁸. We observed a modest increase in mucosal IgG but no increase in mucosal IgA (Fig. S6), indicating that current intramuscular COVID-19 vaccines do not induce robust mucosal antibody responses⁸.

Figure 2. Mucosal NAb responses of the JN.1 and KP.2-adapted COVID-19 mRNA vaccines against emerging SARS-CoV-2 variants.

Mucosal NAb responses by luciferase-based pseudovirus neutralization assays at baseline and 3 weeks post boost in JN.1 vaccinees (A) and KP.2 vaccinees (B) are shown. Horizontal red bars reflect median values. Dotted lines reflect the limit of quantitation.

Finally, we evaluated the durability of humoral immune responses at 6 months following KP.2 mRNA boosting. NAb responses waned over this period but remained higher in individuals who received the boost compared with individuals who did not receive a boost, including against currently circulating variants (Fig. 3). These data suggest that it may not be necessary to time boosting precisely in populations with high levels of baseline immunity.

Figure 3. Durability of serum NAb responses of the KP.2-adapted COVID-19 mRNA vaccines against emerging SARS-CoV-2 variants.

The durability of serum NAb responses at 6 months in people who did (A) or did not get a KP.2 mRNA booster (B) are shown. The horizontal red bar reflects median values. The dotted line reflects the limit of quantitation.

Our findings indicate that both the JN.1 and KP.2 mRNA vaccines substantially increased peripheral, but not mucosal, antibody responses against current circulating SARS-CoV-2 variants, including LP.8.1.1 and NB.1.8.1. The similar profile of NAb responses induced by these two antigenically related mRNA vaccines suggests that minor differences in the vaccine antigen sequence, especially for variants within the same antigenic cluster as defined by antigenic cartography^9–11, may not have a major impact on immunogenicity. These data suggest that vaccine strain updates may not be necessary for closely related circulating variants in the absence of a major antigenic shift. The FDA and EMA suggested manufacturers produce any JN.1 lineage vaccines for fall 2025 and consider LP.8.1^12,13. Our data support these recommendations, and the immunologic cross-reactivity between JN.1, KP.2, LP.8.1, and JN.1-related variants suggest that minor strain updates for variants within the same antigenic cluster may provide only modest additional benefits in the context of widespread hybrid immunity.