{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T08:22:45Z","timestamp":1761898965546,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: While host immune responses to SARS-CoV-2 vaccination are routinely assessed through IgG measurements, less is known about the temporal dynamics of vaccine-induced cellular immunity, particularly in individuals who fail to develop detectable IgG antibodies after COVID-19 vaccination. Objective: To investigate the development and timing of T-cell immunity following SARS-CoV-2 vaccination in antibody-non-responders to COVID-19 vaccination. Methods: A cross-sectional analysis was conducted on COVID-19-naive individuals who had received full SARS-CoV-2 vaccination, categorized by SARS-CoV-2 IgG serostatus. T-cell response was evaluated using the IGRA methodology T-SPOT\u00ae.COVID (Oxford Immunotec, Abingdon, Oxfordshire, UK). T-cell response rates and levels were compared between SARS-CoV-2 seropositive and seronegative groups, and a temporal cutoff analysis was applied to examine trends in T-cell response over time. Results: Within the seronegative group, IgG levels showed a strong negative correlation with time since vaccination (Spearman \u03c1 = \u22120.65, p &lt; 0.001), while T-cell response levels exhibited a weak positive time-dependent trend (\u03c1 = 0.15, p = 0.019). Temporal cutoff analysis identified a critical time-point beginning at 80 days post-vaccination, after which both T-cell response rates and levels were significantly higher. Specifically, individuals tested after 80 days showed increased median T-cell response levels (U = 4205, p &lt; 0.001) and higher positive T-cell response rate (67% vs. 38%, \u03a72 = 17.06, p &lt; 0.001). Conclusions: Cellular immunity response against SARS-CoV-2 may emerge later than expected in antibody-non-responders to COVID-19 vaccination, with the 80-day post-vaccination mark emerging as a critical time point. Our results support the inclusion of cellular assays in post-vaccination monitoring and emphasize the need to reconsider the timing and criteria for evaluating vaccine response.<\/jats:p>","DOI":"10.3390\/vaccines13111123","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:29:42Z","timestamp":1761895782000},"page":"1123","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delayed Cellular Immunity in SARS-CoV-2 Antibody-Non-Responders to COVID-19 Vaccination: Rethinking Post-Vaccine Immune Assessment"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4260-2646","authenticated-orcid":false,"given":"Dimitris","family":"Nikoloudis","sequence":"first","affiliation":[{"name":"Bioiatriki Healthcare Group, Kifisias 132 and Papada Street, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanella E.","family":"Konstantinakou","sequence":"additional","affiliation":[{"name":"Bioiatriki Healthcare Group, Kifisias 132 and Papada Street, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandros D.","family":"Konstantinidis","sequence":"additional","affiliation":[{"name":"Bioiatriki Healthcare Group, Kifisias 132 and Papada Street, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia I.","family":"Spyrou","sequence":"additional","affiliation":[{"name":"Bioiatriki Healthcare Group, Kifisias 132 and Papada Street, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene V.","family":"Vasileiou","sequence":"additional","affiliation":[{"name":"Bioiatriki Healthcare Group, Kifisias 132 and Papada Street, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanasios","family":"Tsakris","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Medical School of Athens, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1951-8489","authenticated-orcid":false,"given":"Vassiliki C.","family":"Pitiriga","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Medical School of Athens, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s40545-023-00652-y","article-title":"mRNA Vaccine Development during the COVID-19 Pandemic: A Retrospective Review from the Perspective of the Swiss Affiliate of a Global Biopharmaceutical Company","volume":"16","author":"Killeen","year":"2023","journal-title":"J. Pharm. Policy Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1016\/j.ymthe.2022.02.016","article-title":"COVID-19 mRNA vaccines: Platforms and current developments","volume":"30","author":"Mahiny","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109934","DOI":"10.1016\/j.intimp.2023.109934","article-title":"An insight overview on COVID-19 mRNA vaccines: Advantageous, pharmacology, mechanism of action, and prospective considerations","volume":"117","author":"Mirtaleb","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105577","DOI":"10.1016\/j.ebiom.2025.105577","article-title":"Longitudinal immunogenicity cohort study of SARS-CoV-2 mRNA vaccines across individuals with different immunocompromising conditions: Heterogeneity in the immune response and crucial role of Omicron-adapted booster doses","volume":"113","author":"Ciabattini","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"117936","DOI":"10.1016\/j.biopha.2025.117936","article-title":"The comprehensive insights into the B-cells-mediated immune response against COVID-19 infection amid the ongoing evolution of SARS-CoV-2","volume":"185","author":"Dhawan","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107111","DOI":"10.1016\/j.ijid.2024.107111","article-title":"Development of antibody levels and subsequent decline in individuals with vaccine induced and hybrid immunity to SARS-CoV-2","volume":"146","author":"Reekie","year":"2024","journal-title":"Int. J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pitiriga, V.C., Papamentzelopoulou, M., Konstantinakou, K.E., Vasileiou, I.V., Konstantinidis, A.D., Spyrou, N.I., and Tsakris, A. (2024). Prolonged SARS-CoV-2 T cell Responses in a Vaccinated COVID-19-Naive Population. Vaccines, 12.","DOI":"10.3390\/vaccines12030270"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s10875-022-01382-7","article-title":"COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity","volume":"43","author":"Erra","year":"2022","journal-title":"J. Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e236","DOI":"10.1016\/S2666-5247(22)00390-1","article-title":"Efficacy of SARS-CoV-2 vaccines and the dose\u2013response relationship with three major antibodies: A systematic review and meta-analysis of randomised controlled trials","volume":"4","author":"Yang","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4748","DOI":"10.1038\/s41467-025-60024-9","article-title":"Comparative duration of neutralizing responses and protections of COVID-19 vaccination and correlates of protection","volume":"16","author":"Liu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pitiriga, V.C., Papamentzelopoulou, M., Konstantinakou, K.E., Theodoridou, K., Vasileiou, I.V., and Tsakris, A. (2023). SARS-CoV-2 T-cell Immunity Responses following Natural Infection and Vaccination. Vaccines, 11.","DOI":"10.3390\/vaccines11071186"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0140-6736(20)31604-4","article-title":"Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1\/2, single-blind, randomised controlled trial","volume":"396","author":"Folegatti","year":"2020","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Paniskaki, K., Anft, M., Meister, T.L., Marheinecke, C., Pfaender, S., Skrzypczyk, S., Seibert, F.S., Thieme, C.J., Konik, M.J., and Dolff, S. (2022). Immune Response in Moderate to Critical Breakthrough COVID-19 Infection After mRNA Vaccination. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.816220"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pitiriga, V.C., Papamentzelopoulou, M., Nikoloudis, D., Saldari, C., Konstantinakou, K.E., Vasileiou, I.V., and Tsakris, A. (2025). Evaluating SARS-CoV-2 T Cell Immunity in COVID-19-Naive Vaccinated Individuals with and Without Spike Protein IgG Antibodies. Pathogens, 14.","DOI":"10.3390\/pathogens14050415"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41590-021-00902-8","article-title":"Robust SARS-CoV-2-Specific T Cell Immunity Is Maintained at 6 Months Following Primary Infection","volume":"22","author":"Zuo","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1056\/NEJMoa2028436","article-title":"Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults","volume":"383","author":"Anderson","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/s41586-020-2814-7","article-title":"COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T-cell responses","volume":"586","author":"Sahin","year":"2020","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15447","DOI":"10.1038\/s41598-022-19581-y","article-title":"SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2: A 9 months longitudinal study","volume":"12","author":"Takeuchi","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.cell.2022.01.015","article-title":"SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron","volume":"185","author":"Tarke","year":"2022","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eabo2202","DOI":"10.1126\/sciimmunol.abo2202","article-title":"Divergent SARS-CoV-2 Omicron\u2013reactive T and B cell responses in COVID-19 vaccine recipients","volume":"7","author":"GeurtsvanKessel","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3201\/eid2701.203611","article-title":"Intrafamilial Exposure to SARS-CoV-2 Associated with Cellular Immune Response without Seroconversion, France","volume":"27","author":"Gallais","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.immuni.2020.11.016","article-title":"Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19","volume":"53","author":"Bacher","year":"2020","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1111\/bjh.17877","article-title":"T-cell immune response after mRNA SARS-CoV-2 vaccines is frequently detected also in the absence of seroconversion in patients with lymphoid malignancies","volume":"196","author":"Marasco","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jay, C., Ratcliff, J., Turtle, L., Goulder, P., and Klenerman, P. (2023). Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1092910"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1038\/s41591-021-01507-2","article-title":"Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy","volume":"27","author":"Apostolidis","year":"2021","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e41836","DOI":"10.1016\/j.heliyon.2025.e41836","article-title":"Human immune system: Exploring diversity across individuals and populations","volume":"11","author":"Le","year":"2025","journal-title":"Heliyon"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.3201\/eid2708.211145","article-title":"Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly, Germany","volume":"27","author":"Schwarz","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"COVID-19 Host Genetics Initiative (2020). The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet., 28, 715\u2013718.","DOI":"10.1038\/s41431-020-0636-6"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5888","DOI":"10.7150\/thno.75904","article-title":"Antigen transfer and its effect on vaccine-induced immune amplification and tolerance","volume":"12","author":"Shi","year":"2022","journal-title":"Theranostics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4569","DOI":"10.1038\/s41467-021-24824-z","article-title":"Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization","volume":"12","author":"Pathak","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1002\/jmv.27688","article-title":"Characterization of the significant decline in humoral immune response six months post-SARS-CoV-2 mRNA vaccination: A systematic review","volume":"94","author":"Notarte","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"abm0829","DOI":"10.1126\/science.abm0829","article-title":"mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern","volume":"374","author":"Goel","year":"2021","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.xcrm.2021.100355","article-title":"Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals","volume":"2","author":"Tarke","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1038\/s41591-021-01540-1","article-title":"Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection","volume":"27","author":"Feng","year":"2021","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Rostoker, G., Rouanet, S., Merzoug, M., Chakaroun, H., Griuncelli, M., Loridon, C., Boulahia, G., and Gagnon, L. (2025). Serological Correlate of Protection Established by Neutralizing Antibodies Differs Among Dialysis Patients with SARS-CoV-2 Variants of Concern. Vaccines, 13.","DOI":"10.3390\/vaccines13050518"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/11\/1123\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:39:12Z","timestamp":1761896352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/11\/1123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["vaccines13111123"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13111123","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}