Longitudinal Innate and Heterologous Adaptive Immune Responses to SARS-CoV-2 JN.1 in Transplant Recipients With Prior Omicron Infection: Limited Neutralization but Robust CD4+ T-Cell Activity.

Abstract

Background: Solid organ transplant (SOT) recipients are at increased risk for severe COVID-19 and often exhibit reduced vaccine efficacy due to chronic immunosuppression. As new SARS-CoV-2 variants emerge, understanding immune responses following natural infection remains critical for informing protection strategies in this vulnerable population. We conducted a longitudinal study of SOT recipients who had recovered from Omicron BA.1 or BA.2 infection, evaluating immune responses to the JN.1 subvariant at 4-6 weeks and 1 year postinfection.

Methods: Neutralizing antibodies to JN.1 were measured using a pseudovirus neutralization assay, and JN.1-specific T-cell responses were assessed by flow cytometry. Frequencies of bulk T-cells and innate immune cells, identified via flow cytometry, and their correlation with adaptive responses were also analyzed.

Results: At 4-6 weeks, 30% of participants had detectable JN.1-neutralizing antibodies, rising to 43% at one year, although titers remained low. In contrast, CD4⁺ T-cell responses were robust and detected in 75%-83% of participants at 4-6 weeks, increasing to 75%-93% by 1 year. CD8⁺ T-cell responses were observed less frequently. Exploratory correlations between innate and bulk T-cell subsets with heterologous adaptive immune responses were investigated but did not reveal statistically significant relationships.

Conclusion: These findings offer important insights into the durability and breadth of immunity following natural infection in immunocompromised transplant recipients. While heterologous neutralizing antibodies were limited, sustained CD4⁺ T-cell responses may help mitigate severe disease following exposure to JN.1-derived variants, which continue to dominate the SARS-CoV-2 landscape.