tetano
Editor, Senior Moderator
Front Immunol
. 2025 Sep 5:16:1657082.
doi: 10.3389/fimmu.2025.1657082. eCollection 2025. Reduced spike specific T-cell responses in COVID-19 vaccinated subjects undergoing SARS-CoV-2 breakthrough infection
Stefania Varchetta[SUP] 1 [/SUP], Federica Sole Golfetto[SUP] 1 [/SUP], Patrizia Bono[SUP] 2 [/SUP], Annapaola Callegaro[SUP] 2 [/SUP], Tanya Fabbris[SUP] 3 [/SUP], Andrea Favalli[SUP] 3 [/SUP], Mariacristina Crosti[SUP] 3 [/SUP], Tullia Maria De Feo[SUP] 4 [/SUP], Nathalie Iannotti[SUP] 1 [/SUP], Giorgio Bozzi[SUP] 1 [/SUP], Valeria Castelli[SUP] 1 [/SUP], Bianca Mariani[SUP] 1 [/SUP], Antonio Muscatello[SUP] 1 [/SUP], Sergio Abrignani[SUP] 3 5 [/SUP], Renata Grifantini[SUP] 3 [/SUP], Alessandra Bandera[SUP] 1 6 [/SUP], Andrea Lombardi[SUP] 1 6 [/SUP]
Affiliations
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[SUP]+[/SUP] NKG2C[SUP]+[/SUP] 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[SUP]+[/SUP] CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T-cells. A positive correlation was observed between AIM[SUP]+[/SUP] CD4[SUP]+[/SUP] T-cells and NKG2C[SUP]+[/SUP] NK cells at T2 in PVI subjects. Following natural infection, T-cell responses were enhanced and associated with an expansion of NKG2C[SUP]+[/SUP] NK cells.
Conclusions: Individuals experiencing PVI displayed impaired booster-induced CD4[SUP]+[/SUP] 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.
Keywords: LAG-3; SARS-CoV-2; T cell immune responses; breakthrough infection; natural killercells; vaccine.
. 2025 Sep 5:16:1657082.
doi: 10.3389/fimmu.2025.1657082. eCollection 2025. Reduced spike specific T-cell responses in COVID-19 vaccinated subjects undergoing SARS-CoV-2 breakthrough infection
Stefania Varchetta[SUP] 1 [/SUP], Federica Sole Golfetto[SUP] 1 [/SUP], Patrizia Bono[SUP] 2 [/SUP], Annapaola Callegaro[SUP] 2 [/SUP], Tanya Fabbris[SUP] 3 [/SUP], Andrea Favalli[SUP] 3 [/SUP], Mariacristina Crosti[SUP] 3 [/SUP], Tullia Maria De Feo[SUP] 4 [/SUP], Nathalie Iannotti[SUP] 1 [/SUP], Giorgio Bozzi[SUP] 1 [/SUP], Valeria Castelli[SUP] 1 [/SUP], Bianca Mariani[SUP] 1 [/SUP], Antonio Muscatello[SUP] 1 [/SUP], Sergio Abrignani[SUP] 3 5 [/SUP], Renata Grifantini[SUP] 3 [/SUP], Alessandra Bandera[SUP] 1 6 [/SUP], Andrea Lombardi[SUP] 1 6 [/SUP]
Affiliations
- PMID: 40977733
- PMCID: PMC12446237
- DOI: 10.3389/fimmu.2025.1657082
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[SUP]+[/SUP] NKG2C[SUP]+[/SUP] 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[SUP]+[/SUP] CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T-cells. A positive correlation was observed between AIM[SUP]+[/SUP] CD4[SUP]+[/SUP] T-cells and NKG2C[SUP]+[/SUP] NK cells at T2 in PVI subjects. Following natural infection, T-cell responses were enhanced and associated with an expansion of NKG2C[SUP]+[/SUP] NK cells.
Conclusions: Individuals experiencing PVI displayed impaired booster-induced CD4[SUP]+[/SUP] 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.
Keywords: LAG-3; SARS-CoV-2; T cell immune responses; breakthrough infection; natural killercells; vaccine.