The trajectory of CD4+ T cell responses to mRNA vaccines in older individuals

By Neha MathurJan 16 2023Reviewed by Danielle Ellis, B.Sc.

In a recent study published in Nature Aging, researchers investigated how age-related T-cell defects impacted the effectiveness of messenger ribonucleic acid (mRNA)-based coronavirus disease 2019 (COVID-19) vaccines.

Background

Old age raises the risk for severe COVID-19 because age decreases one's immune competence. In the adaptive arm of the immune system, T cells play a crucial role in eliciting antibody response and cytotoxicity to specific pathogen-infected cells. However, their production, composition, and function begin to dysregulate and decline with age.

Despite their limited benefits and reduced efficacy in the elderly, they are advised to receive vaccines considering the significant role T cells play in inducing response to vaccines and their decreased effectiveness of adaptive immunity. Perhaps this is why it is crucial to elucidate age-related differences in T-cell responses to mRNA vaccines.

About the study

In the present study, researchers recruited 216 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve Japanese participants comprising adults and older adults aged less than and above 65 years, respectively. They all had received a primary vaccination series of BNT162b2 within an average of 21 days.

The team collected blood samples before the vaccination (pre), two weeks after the first dose (post 1), two weeks after the second dose (post 2), and followed up until three months after the first dose. They used activation-induced marker (AIM) and intracellular cytokine staining (ICS) assays to quantify and characterize vaccine-induced T-cell responses.

Study findings

The blood samples from adults and older adults had similar amounts of the cluster of differentiation (CD)4+ T cells that remained stable during the study duration. However, in most donors, the magnitude and frequencies of the spike (S)-specific AIM+ CD4+ T cells, CD154+ CD137+, exhibited a >10-fold increase compared with the baseline after the first dose. These levels remained the same after the second dose and declined at three months.

The effect of preexisting T cells on immune responses elicited following vaccination was limited. Before COVID-19 vaccination, CD4+ T cells also comprised cross-reactive T cell populations. Their frequency had a weak correlation post-first vaccination in older adults. However, the same was not the case after the second dose, at three months, or peak antibody titers.

Accordingly, 0.33% of older adults and 0.52% of adults had significantly fewer spike (S)-specific CD4+ T cells after the first dose but reached the same level as adults after the second dose and again exhibited significantly lower levels at three months.

Moreover, older adults induced lower levels of type 1 T helper (Th1) cells and CXCR3+ T follicular helper cells (Tfh) cells after the first but not second vaccination. The authors also noticed a correlation between these lower levels with the CD8+ T cell responses and peak antibody titers. Indeed, lower induction of CD4+ T cell responses in older adults weakened their overall adaptive immunity.

Importantly, studies have shown a poor response to the first vaccine dose in patients with solid cancer and subsequent lower antibody responses. Perhaps, the delayed development of TFH cells and subsequently neutralizing antibodies correlated with fatal COVID-19 in older adults. Together, these findings point to the significance of CD4+ T cell responses to the first vaccine dose in improving the effects of vaccination and that older individuals had a defective process.

Another key observation was that the cell sizes of S-specific CD4+ T cells after the first vaccine dose in the elderly were significantly reduced than in adults. Yet again, it pointed to an inept activation of CD4+ T cells in older adults.

Previous studies have documented T cell receptor desensitization, including a defect in antigen-presenting cells with advancing age. Had such defects not existed, people of any age would have qualitatively and quantitatively maintained the CD4+ T cell compartment. Yet, it is currently not understood which of these T cell defects results in a lower induction of CD4+ T cell responses to mRNA COVID-19 vaccines.

Furthermore, the researchers noted accelerated cell death of S-specific T cells in older adults, indicated by their early contraction. Notably, programmed death-1 (PD-1) expression in S-specific TH1 cells was higher in older adults at the maximal response, indicating its inhibitory role. It is unknown whether the enhanced PD-1 expression levels represented higher activation or exhaustion in older adults.

There is a possibility of no causal relation between the higher expression of PD-1 at the maximal response and the early contraction plus early induction of T-cell responses in older adults. Besides the age-related variations, the researchers also observed substantial individual variability amounting to around 10-fold in the frequencies of S-specific T cells within the same age groups.

Conclusions

To summarize, the study highlighted the urgent need for developing COVID-19 vaccines with higher efficacy for the older population. Also, establishing a better vaccine schedule for the elderly.

In this study,  individuals ≥ 65 years (elderly) who received two doses of mRNA vaccine BNT162b2 exhibited a lower induction and early contraction of SARS-CoV-2 S-specific T cells. Following the first vaccine dose, they also had decreased induction of CD4+ T cells. These findings could prove a useful proxy for their lower CD8+ T cell response, neutralizing antibody response, and systemic reactogenicity, though mechanisms underlying the same remain to be determined.