Evidence of exhausted lymphocytes after the third anti-SARS-CoV-2 vaccine dose in cancer patients

Abstract

IntroductionEvidence is scant regarding the long-term humoral and cellular responses Q7 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.MethodsIn 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.ResultsA 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. Seroconversion occurred in all patients after the second dose. We then studied circulating exhausted CD8+ T-cells in 4 patients from each of the two response patterns, those with increase and those with decrease in cellular response after the third booster. 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.DiscussionOur preliminary data show that the two-dose SARS-CoV-2 vaccine regimen was beneficial in all cancer patients of our study. An additional booster seems to be beneficial in suboptimal vaccine seroconverters, in contrast to maximal responders that might develop exhaustion. Our data should be interpreted with caution given the small sample size and highlight the urgent need to validate our results in other independent and larger cohorts. Altogether, our data support the relevance of immunological functional studies to personalize preventive and treatment decisions in cancer patients.

mRNA Vaccines against SARS-CoV-2: Advantages and Caveats

“…Indeed, the frequent administration of booster doses due to the loss of post-vaccination immunity is causing some experts to warn about a possible link between immune exhaustion and frequent vaccination [ 124 ]. There is some experimental evidence pointing towards this direction, as observed in a recent study of cancer patients following three doses of BNT162b2 [ 125 ].…”

SARS-CoV-2 vaccination enhances the effector qualities of spike-specific T cells induced by COVID-19

“…SARS-CoV-2 vaccination has been associated with dysfunctional T cell immunity ( 30 , 31 ). To assess this possibility in more detail, we used ex vivo peptide stimulation in conjunction with flow cytometry and scRNA-seq to profile SARS-CoV-2-specific CD4 + and CD8 + T cells functionally, phenotypically, and transcriptionally.…”

Booster mRNA vaccination post-SARS-CoV-2 infection enhances functional qualities of T cell immunity

“…Antiviral T cell exhaustion is instead a consequence of prolonged antigen stimulation, leading to an exhausted trajectory where different subsets exist to generate durable control of persistent viral infections 23 . Upregulation of inhibitory receptors during early SARS-CoV-2 infection might instead be a sign of increased recruitment of newly formed SARS-CoV-2-specific T cells 24 Repetitive stimulation through SARS-CoV-2 vaccination might negatively affect the functionality of cell-mediated immunity 26,27 . To assess this in more detail, we used peptide pool stimulations ex vivo to dissect SARS-CoV-2-specific T cell responses using both flow cytometry and scRNAseq approaches.…”