Memory SARS-CoV-2 T-cell response in convalescent COVID-19 patients with undetectable specific IgG antibodies: a comparative study

Front Immunol. 2023 Apr 26;14:1142918. doi: 10.3389/fimmu.2023.1142918. eCollection 2023.


Background: During the COVID-19 pandemic, a variable percentage of patients with SARS-CoV-2 infection failed to elicit humoral response. This study investigates whether patients with undetectable SARS-CoV-2 IgG are able to generate SARS-CoV-2 memory T cells with proliferative capacity upon stimulation.

Methods: This cross-sectional study was conducted with convalescent COVID-19 patients, diagnosed with a positive real-time PCR (RT-PCR) from nasal and pharyngeal swab specimens. COVID-19 patients were enrolled ≥3 months after the last PCR positive. Proliferative T-cell response after whole blood stimulation was assessed using the FASCIA assay.

Results: A total of 119 participants (86 PCR-confirmed COVID-19 patients and 33 healthy controls) were randomly filtered from an initial cohort. Of these 86 patients, 59 had detectable (seropositive) and 27 had undetectable (seronegative) SARS-CoV-2 IgG. Seropositive patients were subclassified as asymptomatic/mild or severe according to the oxygen supplementation requirement. SARS-CoV-2 CD3+ and CD4+ T cells showed significantly lower proliferative response in seronegative than in seropositive patients. The ROC curve analysis indicated that ≥ 5 CD4+ blasts/μL of blood defined a "positive SARS-CoV-2 T cell response". According to this cut-off, 93.2% of seropositive patients had a positive T-cell response compared to 50% of seronegative patients and 20% of negative controls (chi-square; p < 0.001).

Conclusions: This proliferative assay is useful not only to discriminate convalescent patients from negative controls, but also to distinguish seropositive patients from those with undetectable SARS-CoV-2 IgG antibodies. Memory T cells in seronegative patients are able to respond to SARSCoV-2 peptides, although at a lower magnitude than seropositive patients.

Keywords: COVID-19; FASCIA assay; SARS-CoV-2; proliferative T-cell response; undetectable SARS-CoV-2 IgG.

MeSH terms

  • Antibodies, Viral
  • COVID-19*
  • Cross-Sectional Studies
  • Humans
  • Immunoglobulin G
  • Memory T Cells
  • Pandemics
  • SARS-CoV-2


  • Immunoglobulin G
  • Antibodies, Viral

Grants and funding

This work was supported by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucia (grant number CV20/81659 to SC) and co‐financed by the European Development Regional Fund “A way to achieve Europe” Smart Growth Operational Program 2014–2020. This research was also supported by CIBER – Consorcio Centro de Investigación Biomédica en Red (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU. Funds for open access publication fees were received from the University of Cordoba (UCO).