Frontiers in immunology · 2025
Reduced spike specific T-cell responses in COVID-19 vaccinated subjects undergoing SARS-CoV-2 breakthrough infection.
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Varchetta Stefania, Golfetto Federica Sole, Bono Patrizia, Callegaro Annapaola, Fabbris Tanya, Favalli Andrea, Crosti Mariacristina, De Feo Tullia Maria, Iannotti Nathalie, Bozzi Giorgio, Castelli Valeria, Mariani Bianca, Muscatello Antonio, Abrignani Sergio, Grifantini Renata, Bandera Alessandra, Lombardi Andrea
Аннотация
INTRODUCTION: T-cell responses to SARS-CoV-2 remain largely preserved across variants despite waning neutralizing antibodies. However, T-cell immunity may vary with the host's immune status, and data on T-cell responses in post-vaccine infections (PVI) are limited.
METHODS: We assessed Spike-specific T-cell responses in 32 vaccinated individuals, 16 of whom experienced PVI. Immune responses were evaluated at three time points: 1 month after the second vaccine dose (T1), 1 month after the booster dose (T2), and, in the PVI group, 1-3 months after the first positive nasal swab (T3). Additionally, we evaluated anti-spike antibody levels, T-cell exhaustion markers, and natural killer cell subsets, focusing on memory-like CD57+ NKG2C+ cells.
RESULTS: Subjects who developed PVI exhibited significantly reduced Spike-specific CD4 T-cell responses following the booster dose compared to vaccinated individuals who remained uninfected. This was accompanied by increased frequencies of LAG-3+ CD4+ and CD8+ T-cells. A positive correlation was observed between AIM+ CD4+ T-cells and NKG2C+ NK cells at T2 in PVI subjects. Following natural infection, T-cell responses were enhanced and associated with an expansion of NKG2C+ NK cells.
CONCLUSIONS: Individuals experiencing PVI displayed impaired booster-induced CD4+ T-cell responses and increased expression of the immune checkpoint LAG-3. Natural infection restored and enhanced cellular immunity, particularly through the expansion of Spike-specific T-cells and memory NK cell populations. This study identifies an immune profile characterized by low spike-specific responses, which are associated with an increased susceptibility to breakthrough infections.
METHODS: We assessed Spike-specific T-cell responses in 32 vaccinated individuals, 16 of whom experienced PVI. Immune responses were evaluated at three time points: 1 month after the second vaccine dose (T1), 1 month after the booster dose (T2), and, in the PVI group, 1-3 months after the first positive nasal swab (T3). Additionally, we evaluated anti-spike antibody levels, T-cell exhaustion markers, and natural killer cell subsets, focusing on memory-like CD57+ NKG2C+ cells.
RESULTS: Subjects who developed PVI exhibited significantly reduced Spike-specific CD4 T-cell responses following the booster dose compared to vaccinated individuals who remained uninfected. This was accompanied by increased frequencies of LAG-3+ CD4+ and CD8+ T-cells. A positive correlation was observed between AIM+ CD4+ T-cells and NKG2C+ NK cells at T2 in PVI subjects. Following natural infection, T-cell responses were enhanced and associated with an expansion of NKG2C+ NK cells.
CONCLUSIONS: Individuals experiencing PVI displayed impaired booster-induced CD4+ T-cell responses and increased expression of the immune checkpoint LAG-3. Natural infection restored and enhanced cellular immunity, particularly through the expansion of Spike-specific T-cells and memory NK cell populations. This study identifies an immune profile characterized by low spike-specific responses, which are associated with an increased susceptibility to breakthrough infections.