Identification, Biobanking, and Large-Scale Production of SARS-CoV-2-Specific Memory T Lymphocytes From COVID-19 Convalescent Donors

The infectious disease with a wide and diverse range of symptoms known as COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a worldwide pandemic in late 2019. In most infected patients, the virus causes mild symptoms including fever and cough. In some cases, however, the virus causes a life-threatening disease with symptoms that include pneumonia, dyspnea and a hyper inflammatory process that includes cytokine storms and systemic immune thrombosis. Patients suffering from these symptoms require hospitalization and intensive treatment1. The development of vaccines has been vigorously pursued to generate active immunity through immunization, but there is uncertainty as to the duration of the antibody-mediated immune response to COVID-192. Effective treatments are needed that can reduce severity of the symptoms, hospital stays and increase survival.

The role of adaptive immunity in COVID-19 and the protective immunity conferred by T cells is still being characterized,3 and the role of memory T cells in conferring protection against SARS-CoV-2 has not yet been properly defined. Memory T cells do appear when T cells recognize a pathogen presented by their local antigen-presenting cells. These T cells activate, proliferate, and differentiate into effector cells secreting compounds to control the infection. Once the pathogen has been cleared, most of the antigen-specific T cells disappear, and a pool of heterogeneous long-lived memory T cells persist. This population of memory T cells, defined as CD45RA or CD45RO+, is maintained over time conferring rapid and long-term immune protection against subsequent reinfections4.

Immunological memory creates a more rapid and robust secondary immune response to reinfections, which is determinant and constitutes the basis of adoptive cell therapy for viral infections in immunosuppressed patients in the context of allogeneic hematopoietic stem cell transplantation (HSCT). With this approach, the infusion of CD45RA memory T cells considerably reduces the morbidity and mortality induced by viral reactivations and simultaneously reduces the alloreactivity conferred by naïve CD45RA+ T cells5.

In this study by Ferreras et al., the authors report the presence of a SARS-CoV-2 specific T-cell population within CD45RA memory T cells from the blood of convalescent donors that can be easily, effectively, and rapidly isolated by CD45RA depletion. These specific SARS-CoV-2 CD45RA memory T cells may be able to clear virally infected cells and confer T-cell immunity for subsequent reinfections. These cells can be stored for use in moderate and severe cases of COVID-19 patients requiring hospitalization, thereby representing an off-the-shelf living drug.

The study included 6 COVID-19 convalescent donors and 2 healthy controls. The convalescent donors were all tested for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR) in nasopharyngeal samples between March and April 2020. Peripheral blood mononuclear cells (PBMCs) from healthy donors and convalescent donors were isolated from their peripheral blood by density gradient centrifugation using Ficoll-Paque. Cell Processing and Detection of SARS-CoV-2-Specific Memory T Cells by Interferon-Gamma Assay and Flow cytometry. In addition, Interleukin-15 Stimulation of Memory T Cells, Human Leukocyte Antigen Typing, Large Clinical Scale CD45RA+ T Cell Depletion,  and TCR Spectratyping was performed.

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The authors report the presence of a SARS-CoV-2-specific T-cell population within the CD45RA memory T cells of blood from convalescent donors. These cells could be easily, effectively, and rapidly isolated following a donor selection strategy based on IFN-γ expression after exposure with SARS-CoV-2-specific peptides and HLA antigen expression, thereby obtaining clinical-grade CD45RA memory T cells from the blood of convalescent donors. These cells could then be biobanked, thawed, and employed as a treatment for moderate to severe cases of COVID-19. These cells retain the memory against SARS-CoV-2 and other pathogens the donors have encountered. Unlike plasma, where the concentration decreases after infusion, memory T cells expand and proliferate and should therefore have a more lasting effect. Importantly, the data showed the presence of SARS-CoV-2 memory T cells in convalescent donors with mild symptoms, which has enormous implications for protection against further SARS-CoV-2 infections and in decreasing the severity of COVID-19. Further studies with larger cohorts are needed to determine the SARS-CoV-2 memory duration and thereby elucidate the long-term protection to SARS-CoV-2.

The authors suggest that the procedure for obtaining the cells is easy to implement for small-scale manufacture, is quick and cost-effective, and involves minimal manipulation. Also CD45RA memory T cell-based therapy is manufactured under the quality standards that apply to blood banks that perform HSCT daily with complex manipulations that are not considered advanced therapy medicinal product and can therefore be obtained without GMP condition requirements. The manufacturing of CD45RA memory T cells is carried out in closed automated systems similar to clean rooms that guarantee an aseptic process for the administration to the patient.

According to the authors, “These factors make it feasible to create a biobank or stock from the blood of convalescent donors, which would be immediately available “off the shelf” for subsequent outbreaks, increasing the therapeutic options in the current SARS-CoV-2 pandemic. These cells could provide patients with (1) a pool of SARS-CoV-2-specific T cells that will respond quickly to the infection, (2) a pool of cells for patients with severe disease presenting with lymphopenia, and (3) a pool of specific memory T cells for other pathogens from the donors encountered during their life, which are vital for eliminating other secondary infections that usually develop in patients hospitalized with COVID-19.”

References

  1. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China.Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DSClin Infect Dis. 2020 Jul 28; 71(15):762-768.
  2. T cell responses to whole SARS coronavirus in humans.Li CK, Wu H, Yan H, Ma S, Wang L, Zhang M, Tang X, Temperton NJ, Weiss RA, Brenchley JM, Douek DC, Mongkolsapaya J, Tran BH, Lin CL, Screaton GR, Hou JL, McMichael AJ, Xu XN. J Immunol. 2008 Oct 15; 181(8):5490-500.
  3. Rapid production of clinical-grade SARS-CoV-2 specific T cells.Leung W, Soh TG, Linn YC, Low JG, Loh J, Chan M, Chng WJ, Koh LP, Poon ML, Ng KP, Kuick CH, Tan TT, Tan LK, Seng MS Adv Cell Gene Ther. 2020 Jul 31; ():e101.
  4. Qualitative differences between naïve and memory T cells. Berard M, Tough DF. Immunology. 2002 Jun; 106(2):127-38.
  5. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Triplett BM, Shook DR, Eldridge P, Li Y, Kang G, Dallas M, Hartford C, Srinivasan A, Chan WK, Suwannasaen D, Inaba H, Merchant TE, Pui CH, Leung W. Bone Marrow Transplant. 2015 Jul; 50(7):968-77