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.

Study: Impaired CD4+ T cell response in older adults is related to reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination. Image Credit: Jo Panuwat D/Shutterstock

Background

Old age raises the chance for severe COVID-19 because age decreases one’s immune competence. Within the adaptive arm of the immune system, T cells play an important role in eliciting antibody response and cytotoxicity to specific pathogen-infected cells. Nevertheless, their production, composition, and performance begin to dysregulate and decline with age.

Despite their limited advantages and reduced efficacy within the elderly, they’re advised to receive vaccines considering the numerous role T cells play in inducing response to vaccines and their decreased effectiveness of adaptive immunity. Perhaps that is why it’s crucial to elucidate age-related differences in T-cell responses to mRNA vaccines.

Concerning the study

In the current study, researchers recruited 216 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve Japanese participants comprising adults and older adults aged lower than and above 65 years, respectively. All of them had received a primary vaccination series of BNT162b2 inside a mean of 21 days.

The team collected blood samples before the vaccination (pre), two weeks after the primary dose (post 1), two weeks after the second dose (post 2), and followed up until three months after the primary 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 through the study duration. Nevertheless, 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 primary dose. These levels remained the identical 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. Nevertheless, the identical 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 primary dose but reached the identical level as adults after the second dose and again exhibited significantly lower levels at three months.

Furthermore, older adults induced lower levels of type 1 T helper (Th1) cells and CXCR3+ T follicular helper cells (Tfh) cells after the primary 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 primary 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 importance of CD4+ T cell responses to the primary vaccine dose in improving the consequences of vaccination and that older individuals had a defective process.

One other key remark was that the cell sizes of S-specific CD4+ T cells after the primary vaccine dose within the elderly were significantly reduced than in adults. Yet again, it pointed to a clumsy 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’s currently not understood which of those T cell defects leads to a lower induction of CD4+ T cell responses to mRNA COVID-19 vaccines.

Moreover, 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 on the maximal response, indicating its inhibitory role. It’s unknown whether the improved PD-1 expression levels represented higher activation or exhaustion in older adults.

There may be a possibility of no causal relation between the upper expression of PD-1 on 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 within the frequencies of S-specific T cells throughout 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 greater vaccine schedule for the elderly.

On 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 primary vaccine dose, in addition they had decreased induction of CD4+ T cells. These findings could prove a useful proxy for his or her lower CD8+ T cell response, neutralizing antibody response, and systemic reactogenicity, though mechanisms underlying the identical remain to be determined.