COVID boosters do not harm T-cell function in the vulnerable

By Dr. Priyom Bose, Ph.D.Reviewed by Lauren HardakerJun 9 2025

Contrary to public concerns, receiving frequent COVID-19 booster vaccinations will not weaken the immune system, providing reassurance to vulnerable groups facing new variants.

Study: No evidence of immune exhaustion after repeated SARS-CoV-2 vaccination in vulnerable and healthy populations. Image credit: Lucigerma/Shutterstock.com

A recent study published in Nature Communications examined the effect of repeated SARS-CoV-2 vaccination on T-cell exhaustion in both vulnerable older adults and the general healthy population in Canada.

SARS-CoV-2 vaccination and immune exhaustion

During the coronavirus disease 2019 (COVID-19) pandemic, multiple vaccines were administered to an individual within a relatively short period. Even now, with the emergence of immune-evasive SARS-CoV-2 variants, vulnerable populations such as the immunocompromised and older adults could receive multiple updated vaccinations in relatively short intervals.

However, frequent administration of vaccines has raised questions about the long-term effects on the immune system and immune exhaustion.

Immune exhaustion refers to the effects of chronic stimulation of T-cells in cases of infection or malignancy. Persistent stimulation through the T-cell receptor could upregulate PD-1, LAG-3, TIM-3, TIGIT, and other exhaustion markers. If this occurs over prolonged periods, it could lead to cytokine production and dampening of T-cell activation, thereby detecting more severely exhausted T-cells.

The differentiation between activation and exhaustion can be unclear, making it essential to consider the cytokine-producing functional capacity of T cells and the co-expression of multiple exhaustion markers.

Expression of exhaustion markers alone does not necessarily mean the cells are functionally exhausted, as these markers can be associated with T-cell activation. Therefore, surface markers and T-cell functionality were assessed.

Given the novelty of mRNA SARS-CoV-2 vaccines and their frequent administration in short intervals to vulnerable populations, it is essential to study the intricacies of T-cell immune exhaustion in this context.

About the study

This study evaluated the impact of repeated SARS-CoV-2 vaccination on circulating and spike-specific T cells. Their functional capacities after the administration of the second, third, and fourth doses were noted in healthy community-dwelling individuals (HA), individuals with rheumatoid arthritis taking immunosuppressive drugs (RA), and older adults in long-term care facilities (LTC). The expression of exhaustion markers was also studied.

The LTC cohort consisted of 23 individuals with an average age of 84. Approximately 61% of this group were female. The RA cohort consisted of 10 individuals, with an average age of 68, and included seven women. The HA cohort consisted of 43 individuals, with an average age of 47. In this group, 60.5% of the participants were female. As is evident, the cohorts differ significantly in age but not in sex distribution.

Individuals with a positive PCR test or rapid antigen test before or during the study period were excluded from the analysis. Individuals who seroconverted to become positive for anti-nucleocapsid IgG were also excluded, meaning the findings apply specifically to people without SARS-CoV-2 infection.

The mRNA-1273 (Moderna) vaccine was most commonly used in the LTC cohort in the first three doses, while the BNT162b2 (Pfizer-BioNTech) vaccine was more widely used in the HA and RA cohorts for the first, second, and third vaccine doses.

Regarding the fourth dose, the HA cohort had an even distribution of Moderna and Pfizer-BioNTech vaccines, whereas Moderna was more prevalent in the LTC and RA cohorts. Blood samples were collected 3 months after the second, third, and fourth vaccinations.

Study findings

Study participants in the LTC group exhibited greater frequencies of spike-specific CD4⁺ T-cells after the fourth vaccine dose compared to the second dose. In this group, post the third and fourth SARS-CoV-2 vaccinations, the frequencies of spike-specific CD8⁺ T-cells were also higher relative to the second dose. No such changes were noted in the RA and HA cohorts.

The surface co-expression of the exhaustion markers LAG-3, PD-1, and TIM-3 was also studied. Normal activation is indicated by a constant frequency of cells expressing these markers after repeat vaccination. Concerning CD4⁺ T-cells, no notable alterations in combined exhaustion marker expression were observed across the three cohorts.

However, following the third and fourth doses, only the LTC group showed higher PD1⁺LAG-3⁺TIM-3⁻ spike-specific CD8⁺ T-cells relative to the second dose. The functional significance of this increase is unclear, as any reduction in T-cell function did not accompany it.

Repeated SARS-CoV-2 vaccination did not lead to a loss of diversity in expressed cytokine combinations. Sensitivity analyses revealed no reduction in the most highly polyfunctional T-cell subsets in the three cohorts after multiple vaccinations within a short interval.

Research has shown that chronic infections can induce T-cells to adopt a terminally differentiated phenotype, characterized by the loss of CD28 expression and the expression of CD57, particularly within the EMRA compartment. No such changes were noted in the LTC, HA, and RA cohorts following repeated SARS-CoV-2 vaccinations.

The study observed that LTC participants had higher frequencies of effector memory CD4+ T cells and lower levels of naïve CD4+ T cells across all time points. This change is likely due to aging and fragility rather than the vaccination itself.

The authors also compared different dosing intervals between vaccine doses in healthy adults. They found no evidence that shorter or longer intervals affected the likelihood of T-cell exhaustion or reduced functionality.

Alterations in exhaustion marker expression on spike-specific CD4⁺ and CD8⁺ T-cells varied by vaccine dose between the cohorts. For CD4, the HA cohort showed significantly higher levels than the LTC cohort after administering the second dose.

There were subtle differences in T-cell responses to vaccination across cohorts, which persisted following the fourth vaccine dose for CD4⁺ but not CD8⁺ T-cells. However, these differences did not result in decreased functional capacity of T-cells in any group.

The small sample size for the RA group, loss of follow-up in the healthy adult cohort, and the inclusion of only individuals without prior COVID-19 infection who received mRNA vaccines limit the findings of this study. The results may not apply to other vaccine types, populations, or individuals with a history of previous SARS-CoV-2 infection.

Conclusions

Following repeated SARS-CoV-2 vaccination, no decline was noted in spike-specific CD4⁺ and CD8⁺ T-cell levels. The expression of exhaustion markers on spike-specific or total T-cells also remained stable. T-cell polyfunctionality did not decline in any cohort following repeated vaccination, and they did not show greater quantities of terminally differentiated T-cells.

The study concludes that repeated SARS-CoV-2 vaccinations, as recommended for vulnerable people and healthy populations, do not induce T-cell exhaustion or compromise T-cell function.

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