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

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

In a recent study published in bioRxiv*Preprint server Researchers compared immunogenicity and interaction with BNT162b2, a 2019 (COVID-19) anti-mRNA vaccine, in Japanese adults and elderly people.

Study: Delayed antigen-specific CD4+ T cell induction is associated 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, due in large part to the declining efficiency of the immune system with age. Although the mRNA vaccines were effective against COVID-19, the elderly showed lower titers of immunoglobulin G (IgG) against SARS-CoV-2 (SARS-CoV-2). The reduced ability to neutralize SARS-CoV-2 makes the elderly more susceptible to severe COVID-19.

Differentiation group 4 positive (CD4+) T lymphocytes play a vital role in regulating vaccine-induced T lymphocyte responses; However, since T-lymphocyte function and composition varies significantly with age, the association between age-related impairment in T-lymphocyte responses and interaction with or immunity to an mRNA vaccine is not clear.

about studying

In this study, researchers elucidate the pathway of T lymphocyte responses among adults and the elderly. They also explored the relationship between vaccine-induced adverse effects (AEs) and T lymphocyte immune responses.

The immunogenicity or reactivity of the COVID-19 mRNA vaccine was evaluated clonally in 107 adults and 109 elderly people <65 years of age and >65 years of age, respectively, three months after vaccination. Vaccine-induced T-helper 1 (Th1) lymphocyte and T-helper lymphocyte (Tfh) immune responses in twice-vaccinated adults and the elderly.

Peripheral blood was drawn from participants before mRNA vaccination, two weeks after the first vaccination, two weeks after the second vaccination and three months after the first vaccination. Intracellular cytokine staining (ICS) and activation-induced markers (AIM) analyzes were performed to characterize and quantify vaccine-induced T lymphocyte responses. Peripheral blood mononuclear cells (PBMCs) were assayed with overlapping peptides covering the entire SARS-CoV-2 spike (S) protein sequence. In addition, flow cytometry including forward scattering (FSC) analysis was performed using the optimized distributed random neighbor inclusion strategy (opt-SNE). Humoral responses and anti-cytomegalovirus (CMV) IgG titers were also evaluated in the two groups.


The total number of CD4+ T lymphocytes between adults and the elderly showed no significant difference and was consistent throughout the study. The frequency and antagonism of AIM + (CD137 + CD154 +) CD4 + T showed a significant increase (>10-fold) after the first vaccination, remained largely the same after the second vaccination, and decreased three months after the first vaccination. Most of the vaccine-induced T lymphocytes showed a phenotype (CD57− CD28+) and CC chemokine 7+ receptors (CCR7+ and CD45RA−) of central memory (CM) after the first vaccination, which was maintained throughout the study in both groups.

In flow cytometry analysis, vaccine-induced CD4+ T lymphocytes between adults and the elderly showed identical baseline characteristics. However, compared to adults, the elderly excreted significantly lower CD4+ T lymphocytes than vaccinated after the first vaccination, similar levels after the second vaccination, and significantly lower levels three months after the first vaccination. There were no significant associations between the frequencies of AIM+CD4+ T lymphocytes (naive and memory T lymphocytes) before vaccination with those after vaccination throughout the study period.

In the FSC analysis, the T-lymphocyte volume was largest after the first vaccination among adults and after the second vaccination among the elderly, and decreased significantly among the elderly during the systolic phase three months after the first vaccination. This indicates that the elderly showed a delayed induction and rapid contraction of vaccine-induced CD4+ T lymphocytes after vaccination.

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

Strong vaccine-induced IgG titers with peaks in the receptor-binding domain (RBD) antagonist (RBD) IgG and IgM titers were observed after the second in both groups. Both IgG and IgM at first and second vaccinations are closely related to each other, indicating that IgG and IgM were simultaneously produced independently of an individual’s age. However, peak antibody titers in the elderly were 40% lower than that in adults.

In addition, no significant differences in the frequencies of cytokine+ and AIM+ CD4 T lymphocytes were observed between matched males and females with or without anti-cytomegalovirus (CMV) IgG antibody. The exception was the increase in the frequency of AIM + T lymphocytes after the first vaccination in women. Notably, the lower number of CXCR3 expressing IFN-γ (CXC chemostimulatory receptor 3 positive) Tfh after the first vaccination correlates with lower titer of IgG antibody among the elderly.

Older adults encountered less systemic vaccination after 2nd which was associated with a delayed effect of vaccine-induced CD4+ T lymphocyte responses. Furthermore, increased levels of programmed cell death protein-1 (PD-1) in vaccine-induced Th1 lymphocytes among the elderly were associated with reduced CD8+ T lymphocyte responses.

Overall, the study results highlighted age-related differences in T-lymphocyte immune responses after the first and second BNT162b2 vaccination. The results indicated that a strong CD4+ T-lymphocyte response after the first vaccination was necessary to enhance immunity or interact with subsequent doses of BNT162b2 vaccine among the older population.

*Important note

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

2022-05-16 11:38:00

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