Repeated Vaccinations and Immune Exhaustion: What We Know

Shin Jie Yong

When Covid vaccine booster shots were proposed last year, people debated their practicality and risk-benefit ratio, especially among the younger populations. Every vaccine shot has side effects and risks, which must not outweigh their protective benefits.

In the end, the Food and Drug Administration (FDA) authorized mRNA booster shots for groups at risk of severe Covid in September 2021. A few months later, the World Health Organization (WHO) recommended booster shots for those who are immunocompromised or got inactivated vaccines.

But earlier this year in March, due to the emergence of Omicron, the most immune evasive variant to date, the WHO endorsed booster shots to all, especially for high-risk groups. And now, with the rise of even more immune evasive Omicron subvariants BA.4 and BA.5, the FDA is encouraging another round of booster shots, this time with Omicron-specific vaccines, which the FDA hopes to be tested and authorized by October 2022.

But we still have one enigmatic problem: Will repeated vaccinations lead to immune or T-cell exhaustion?

What’s immune exhaustion?

Immune exhaustion refers to the weakening of T-cells with every stimulation. T-cells are a part of the adaptive immune system that kills abnormal cells like virus-infected cells or cancers. In essence, T-cells become gradually exhausted if they encounter the same threat over and over again.

Such exhausted T-cells are continuously activated, but unable to eliminate the threat. So, exhausted T-cells are typically seen in cancers or chronic infections like human immunodeficiency virus (HIV) or hepatitis viruses, where the immune system fails to deal with the threat for too long.

But T-cell exhaustion may be part of ‘disease tolerance,’ where the immune system thinks it’s better to limit the damage caused by an infection rather than forcefully eliminate the infection, which may come with collateral damage. The cytokine storm, for example, is where the immune system tries to eliminate the threat intensely that it may end up killing the host.

T-cell exhaustion can happen during Covid-19. Studies have found that T-cells of Covid-19 patients — especially those with more severe disease — were reduced in number and had higher levels of PD-1 compared to T-cells of non-Covid controls. PD-1, programmed death-1, is a marker of T-cell exhaustion.

Experts have cautioned about T-cell exhaustion from repeated vaccinations

Since last year, several experts have raised the possibility of T-cell exhaustion from repeated vaccinations of the same or highly similar vaccine.

For example, journalist Apoorva Mandavilli wrote for the New York Times in September 2021, “In younger people, officials must balance the limited benefit of a third dose with the risk of side effects like blood clots or heart problems, researchers said.” And, quoting Marrion Pepper, Ph.D., University of Washington’s immunologist, “repeatedly stimulating the body’s defenses can also lead to a phenomenon called immune exhaustion.”

Similarly, journalist Jef Akst reported in The Scientists, “with each vaccine dose carrying a small risk of side effects and repeated vaccination increasing the chances of immune exhaustion, in which T cells mount a diminished response in the face of chronic antigen exposure, a bump in neutralizing antibodies is not necessarily sufficient to justify booster approval.”

“The idea of vaccinating every four months or even more than that is novel. It’s something that you haven’t seen with other types of viruses,” Reinhard Obst, a professor of immunology at Ludwig Maximilian University, said. “And the idea of T cell exhaustion is the reason why you might pause.”

Sarah Fortune, MD, a professor of immunology and infectious disease at the Harvard TH Chan School of Public Health, also admits that the concern of repeated Covid vaccinations inducing T-cell exhaustion has a scientific basis. But this concern has never been demonstrated experimentally.

So, T-cell exhaustion is a possibility we should look out for, not something we should treat as a definite occurrence, Prof. Dr. Fortune advised.

But there’s a reason to be optimistic

T-cell exhaustion is usually seen in situations of continuous exposure to a foreign threat, such as during chronic HIV infection or cancer.

But the antigen present in Covid vaccines — i.e., the modified spike protein of SARS-CoV-2 — doesn't last long. The mRNA vaccine, for example, instructs the cells to make spike proteins to train the immune system, but only for up to a week or two until the mRNA is degraded. So, the stimulus coming from vaccines doesn’t seem to be long-term enough to induce T-cell exhaustion.

There’s also no concrete evidence of T-cell exhaustion happening from other vaccines. Critics could argue that multiple studies have found that people who took repeated influenza vaccinations within the span of a few years had lower vaccine effectiveness compared to those who took fewer vaccinations. But whether T-cell exhaustion was responsible for this problem was not inspected. Rather, other reasons, such as the original antigenic sin or virus evolution, are likely to be accountable, rather than T-cell exhaustion.

Still, influenza vaccines are given once annually, which is very unlikely to cause T-cell exhaustion. But Covid vaccines are given at a rate twice that — up to 4–5 shots in two years (four shots for people over 50 years, and five shots for immunocompromised people). So, we must be prudent in evaluating the necessity of every booster shot we take, especially when it’s too soon.

But given a choice between another booster shot or an increased risk of catching another Covid, taking the booster shot seems wiser. After all, T-cell exhaustion has been documented during Covid (as discussed above), but not vaccination. And there’s evidence that repeated re-infections or Covid pose destructive short-term clinical and long-term health consequences.

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MSc Biology | 7x first-author academic papers | 250+ articles on coronavirus | Freelance medical writer


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