"Abstract
Introduction: Evidence is scant regarding the long-term humoral and cellular responses ... triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in cancer patients after repeated booster doses. The possibility of T-cell exhaustion following these booster doses in this population has not yet been fully studied and remains uncertain.
Methods: In this single-center prospective observational study, we explored the specific humoral and cellular response to S1 antigen in 36 patients with solid malignancies at baseline, and after the second and third doses of the mRNA-1273 vaccine.
Results: A dual behavior was observed: 24 (66.7%) patients showed partial specific IFN-γ response after the second dose that was further enhanced after the third dose; and 11 (30.5%) already showed an optimal response after the second dose and experienced a marked fall-off of specific IFN-γ production after the third (4 patients negativization), which might suggest T cell exhaustion due to repetitive priming to the same antigen. One (2.8%) patient had persistently negative responses after all three doses... The patients with decreased cellular response after the booster had a higher expression of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells compared with those with an increased cellular response both in vivo and in vitro. The proportion of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells inversely correlated with IFN-γ production...
Introduction
... Published literature suggests that adaptive immune response plays an important role in disease severity, viral clearance, and disease resolution. It has also been shown that variants of concern can partially escape the humoral response elicited by mRNA vaccines, but not T-cell mediated response...
Cancer patients and other immunocompromised populations were also excluded or underrepresented in the clinical trials for the SARS-CoV-2 mRNA vaccines...
Discussion
... A concerning phenomenon was the loss of cellular responses, which may be due, among other factors, to increased expression of T cell inhibitory molecules after the third vaccine dose, suggesting T cell exhaustion after SARS-CoV-2 vaccination with additional booster and may account for the lack of capacity of these cells to control viral replication. T cell exhaustion is a dysfunctional state of T cells characterized by the high expression level of immune-checkpoint (IC) receptors, such as PD-1 (exhaustion) and CD57 terminal effector cells (senescence) markers, decreased proliferation and production of cytotoxic cytokines, and altered transcriptional and metabolic profiles. These IC immune receptors have been previously demonstrated to control antiviral and antitumor CD8+ T-cell effector function in experimental models of lymphocytic choriomeningitis virus (LCMV) and in humans with advanced melanoma...
Our findings have potential implications on vaccine responses in advanced immune engaging cancer therapy patients who have particularly blunted cellular vaccine responses despite multiple doses (up to 43% of patients after the third dose of the BNT162b2 mRNA COVID-19 vaccine)."
© 2022 Benitez Fuentes, Mohamed Mohamed, de Luna Aguilar, Jimenez ́Garcıa, Guevara-Hoyer, Fernandez-Arquero, Rodriguez de la Peña, Garciia Bravo, Jimenez Ortega, Flores Navarro, Bartolome Arcilla, Alonso Arenilla, ́Baos Muñoz, Delgado-Iribarren Garcıa-Campero, Montealegre Sanz, ́Sanchez-Ramon, and Perez Segura.
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