To the best of our knowledge, this is the first evidence of exhausted CD8 + T cells after repeated doses of S1 antigen following SARS-CoV-2 vaccination. We evaluated in the real-life setting the cellular and humoral immune responses after each of the three doses of mRNA-1273 vaccine in a non-selected population of solid cancer patients. We found positive specific SARS-CoV-2 cellular responses in 36.1% of cancer patients after the first vaccine dose that increased to 91.7% after the second dose. Thus, our data further confirm the efficacy of the vaccine in triggering the cellular immune responses in patients with cancer in agreement with a study by Bordry et al (16). Specific humoral responses were detected in all cancer patients after the second dose of the mRNA vaccine, in line with other studies showing that the majority of cancer patients are able to mount specific antibody responses to SARS-CoV-2 vaccines (20, 21).
Regarding the third vaccine dose (booster), our findings differentiated two groups based on the behavior of specific cellular immune response: those who further enhanced the cellular response, which coincided with a partial response after the second dose (Group 1); and those who showed a dramatic decrease or even negativization in specific anti-SARS-CoV-2 IFN-γ titres (Group 2). In addition, one patient did not mount cellular responses to any of the three vaccine doses, despìte seroconversion, suggesting T-cell independent mechanisms (22). Our data might support the relevance of alternative preventive strategies against SARS-CoV-2 in patients with non-response to a particular vaccine platform, RNA in this particular case.
Besides, a concerning phenomenon is the loss of cellular response due to increased expression of T cell inhibitory molecules after the third vaccine dose, as we have observed in a non-negligible proportion of our patients, suggesting T cell exhaustion after SARS-CoV-2 vaccination with additional booster. Madmoodpoor et al. also outlined a higher expression of PD-1 in circulating lymphocytes of patients with severe COVID-19 compared with healthy controls (6). 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, decreased proliferation and production of cytotoxic cytokines, and altered transcriptional and metabolic profiles (23). Recurrent or latent infections by many pathogens as well as several vaccines in development have shown to induce overexpression of these IC molecules, and thus exhaustion in immune cells, leading to increases in inhibitory IC signals and immune evasion (24–26). As a consequence of increased inhibitory IC receptors, T cells are exhausted, leading to viral escape from immune control (27). However, the precise mechanisms underlying the increase in exhausted CD8+ T cells after SARS-CoV-2 vaccination or infection remains to be elucidated. Another potential explanation of the loss of cellular response might be the occurrence of anti-IFN-γ antibodies described by Bastard et al (28), which were not performed.
Only one of the 12 patients with low IFN-γ presented with moderate COVID-19, which could be explained by an adequate innate immunity, as has been argued for the mild manifestations in most children, or by the presence of high specific antibody titres at the short term (29). Also, specific CD4 + T cells clones might enhance humoral responses.
This study has several limitations that should be mentioned and thus the results interpreted with caution, regarding its relatively small sample size and the heterogeneity of the cancer patients. One potential limitation regarding the baseline determination is the 5-day period pre and post vaccine established to collect the first sample that seems to slightly affect the baseline results in 5 patients of the study. Additionally, the IGRA test does not differentiate between CD4 + and CD8 + SARS-CoV-2-specific T cells. Further studies are needed to better understand the degree of each cell subset participation in the response after infection or vaccination. Therefore, we present the work as a pilot exploratory analysis.
To summarize, our preliminary study shows that the vast majority of our cancer patients develop cellular and humoral responses after two-dose SARS-CoV-2 vaccines. The third vaccine dose seems to be beneficial in non-optimal responders to SARS-CoV-2 vaccines who displayed an increase in anti-SARS-CoV-2 IFN-γ titres. Nevertheless, maximal responders might develop exhaustion by persistent antigen stimulation, which is of important concern in this patient population. Based on our data, we believe in the necessity of these functional immunological studies to better define the vaccination strategies for cancer patients.