Wei J. Chen, Kristin Tompkins, Ian W. Windsor, Lyndsey T. Martinez, Minah Ramos, Weiqiang Li, Shikha Shrivastava, Swati Rajput, Jeanne S. Chang, Parag V. Sahasrabudhe, Kimberly F. Fennell, Thomas J. McLellan, Graham M. West, Kristianne P. Dizon, Aaron Yam, Siddartha Mitra, Subrata Saha, Daiana Sharaf, Andrew McKeen, Carla I. Cadima, Alexander Muik, Wesley Swanson, R.M. Girón Moreno, P. Daroca, Uğur Şahin, Annaliesa S. Anderson, Huixian Wu, Kena A. Swanson, Kayvon Modjarrad
The rise in prevalence of the SARS-CoV-2 JN.1 lineage in 2023 and subsequent derivative sublineages coincided with reduced neutralizing activity and effectiveness of XBB.1.5-adapted vaccines. Here, we characterize the biophysical and immunologic attributes of BNT162b2 JN.1- and KP.2-adapted mRNA vaccine-encoded spike (S) proteins. We reveal the structural consequences of key amino acid substitutions in S and a potential molecular mechanism of immune escape employed by JN.1 and KP.2 viruses. The two vaccines, administered as fourth or fifth doses in BNT162b2-experienced mice, or as a primary series in naïve mice, confer improved neutralizing responses over the BNT162b2 XBB.1.5-adapted vaccine against a broad panel of JN.1 sublineages. Mapping of neutralizing responses indicate greater antigenic overlap of JN.1 and KP.2 vaccines with JN.1 sublineages, while CD4+ and CD8+ T cell responses are conserved across all three vaccines. These data support the selection of JN.1- or KP.2-adapted vaccines for the 2024-25 COVID-19 vaccine formula. Variation in SARS-CoV-2 viruses results in newly emergent virus lineages. Here, the authors characterize the BNT162b2 mRNA vaccines, adapted to two SARS-CoV-2 lineages, JN.1 and KP.2, measure responses elicited by these vaccines against contemporary and older SARS-CoV-2 variants in naive and antigen experienced animal models and describe the biophysical and structural properties of the spike proteins expressed by these vaccines.