Exploring age-associated differences in T lymphocyte immune responses after BNT162b2 vaccination

In a recent study posted to the bioRxiv* preprint server, researchers compared the immunogenicity of, and reactogenicity to, the BNT162b2 vaccine, a coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccine, in Japanese adults and elders.

Study: Delayed antigen-specific CD4+ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly. Image Credit: PIC SNIPE/Shutterstock


Age has been reported to be the strongest predictor of COVID-19 severity, largely due to the reduction in the competency of the immune system with age. Although mRNA vaccines have been effective against COVID-19, the elder population has demonstrated lower immunoglobulin G (IgG) titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The reduced ability to neutralize SARS-CoV-2 makes the elderly more prone to severe COVID-19.

The cluster of differentiation 4 positive (CD4+) T lymphocytes plays a vital role in regulating vaccine-induced T lymphocyte responses; however, since the functionality and composition of T lymphocytes are substantially altered by age, the association between age-associated impairments in T lymphocyte responses and the reactogenicity to or immunogenicity of mRNA vaccination is not clear.

About the study

In the present study, researchers elucidated the trajectory of T lymphocyte responses among adults and elderly individuals. They also explored the association between vaccine-induced adverse effects (AEs) and the T lymphocyte immune responses.

The immunogenicity of or reactogenicity to a COVID-19 mRNA vaccine was comparatively assessed in 107 adults and 109 elders aged below 65 years and above 65 years, respectively, after three months of vaccination. The vaccine-induced T helper 1 (Th1) lymphocyte- and T follicular helper (Tfh) lymphocyte-immune responses in double vaccinated adults and elders.

Peripheral blood was drawn from the participants before the mRNA vaccination, two weeks post the first vaccination, two weeks pose the second vaccination and three months post the first vaccination. Intracellular cytokine staining (ICS) and activation-induced marker (AIM) analyses were performed to characterize and quantify the vaccine-induced T lymphocyte responses. Peripheral blood mononuclear cells (PBMCs) with overlapped peptides covering the entire SARS-CoV-2 spike (S) protein sequence were assessed. In addition, flow cytometry including the forward scatter (FSC) analysis using the optimized t-distributed stochastic neighbor embedding (opt-SNE) reduction strategy was performed. The humoral responses and the anti-cytomegalovirus (CMV) IgG titers were also assessed in the two groups.


The total CD4+ T lymphocyte count among adults and elders did not show any significant difference and was stable throughout the study. The frequency and count of vaccine-induced AIM+ (CD137+ CD154+) CD4+ T lymphocytes demonstrated a substantial increase (>10 folds) post the first vaccination, remained largely the same post the second vaccination, and decreased after three months of the first vaccination. Most of the vaccine-induced T lymphocytes demonstrated non-senescent (CD57− CD28+) and C-C chemokine receptor 7+ (CCR7+ and CD45RA−) central memory (CM) phenotype post the first vaccination, which was maintained throughout the study in both the groups.

In the flow cytometry analysis, the vaccine-induced CD4+ T lymphocytes among the adults and elders demonstrated identical fundamental characteristics. However, compared to adults, the elders elicited substantially lesser vaccine-induced CD4+ T lymphocytes post the first vaccination, similar levels post the second vaccination, and substantially lower levels three months post the first vaccination. There were no significant associations between the AIM+ CD4+ T lymphocyte (naïve and memory T lymphocytes) frequencies prior to vaccination with those post-vaccination throughout the study period.

In the FSC analysis, the size of T lymphocytes was the largest post the first vaccination among adults and post the second vaccination among elders and reduced more significantly among elders during the contraction phase post three months of the first vaccination. This indicated that the elders demonstrated delayed induction and rapid contraction of the vaccine-induced CD4+ T lymphocytes after vaccination.

The CD4+ T lymphocytes demonstrated a higher frequency of lymphocytes expressing cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and a lower frequency of lymphocytes expressing IL-4,17 among adults and elders post-vaccination. The cytokine-expressing T lymphocyte count elevated post the first vaccination and reduced thereafter in both groups. The count of IFN-γ-expressing lymphocytes was significantly lower among the adults post the first vaccination and after three months. Similar kinetics of AIM+ T lymphocytes were observed.

Robust vaccine-induced IgG titers with peaks in the anti-receptor binding domain (RBD) IgG and IgM titers post-second vaccination were noted in both groups. The IgG and IgM titers post first and second vaccination strongly correlated with each other, indicating that IgG and IgM were produced simultaneously independent of the individual’s age. However, the peak antibody titers in elders were 40% lower than those in adults.

In addition, no significant differences were observed in the cytokine+ and AIM+ CD4 T lymphocyte frequencies among age-matched males and females with or without anti-cytomegalovirus (CMV) IgG antibodies. An exception was the increase in the AIM+ T lymphocyte frequency post the first vaccination in women. Notably, the lower count of IFN-γ-expressing CXCR3+ (C–X–C motif chemokine receptor 3 positive) Tfh lymphocytes post first vaccination correlated with the lower titers of IgG antibodies among the elders.

The elders experienced substantially lesser systemic AEs post-second vaccination which was associated with the delayed induction of vaccine-induced CD4+ T lymphocyte responses. Further, increased programmed cell death protein-1 (PD-1) levels in vaccine-induced Th1 lymphocytes among elders correlated with lower CD8+ T lymphocyte responses.

Overall, the study findings highlighted the age-associated differences in T lymphocyte immune responses after the first and second BNT162b2 vaccination. The results indicated that a robust CD4+ T lymphocyte response post the first vaccination was essential to enhance the immunogenicity of or reactogenicity to the subsequent doses of the BNT162b2 vaccine among the elder population.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Norihide Jo, et al. (2022). Delayed vaccine-induced CD4+ T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly. bioRxivdoi: https://doi.org/10.1101/2022.05.10.490700 https://www.biorxiv.org/content/10.1101/2022.05.10.490700v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibodies, Antibody, Blood, CD4, Cell, Cell Death, Chemokine, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytokine, Cytokines, Cytomegalovirus, Cytometry, Flow Cytometry, Frequency, Immune System, Immunoglobulin, Interferon, Interferon-gamma, Intracellular, Lymphocyte, Necrosis, Peptides, Phenotype, Programmed Cell Death, Protein, Receptor, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, T Lymphocyte, Tumor, Tumor Necrosis Factor, Vaccine

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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