COVID-19 Booster Enhances Protection, Contrary to ‘Immune Fatigue’ Claims

“The booster has a clear benefit in older age groups at keeping them out of the hospital,” Wherry said, “and a clear benefit even in younger individuals at preventing or reducing the incidence of infection, very likely reducing transmission, and duration of illness” if a person is infected.

The latest figures from the Centers for Disease Control and Prevention’s COVID-NET, for example, show that for the month of December, which is when the omicron variant emerged and became predominant, fully unvaccinated adults above the age of 50 were 18 times more likely to have a COVID-19-associated hospitalization than people who were fully vaccinated. When compared with boosted individuals, those figures rise to 46 times for 50-to-64-year-olds and 52 times for the 65-and-older crowd.

For Maher, who just turned 66 years old, being boosted offers much better odds of avoiding a COVID-19 hospitalization.

As we’ve written, multiple other studies have identified similar benefits to boosters, including a Jan. 21 CDC study that found mRNA vaccine effectiveness against hospitalization in adults while omicron was predominant was 90%, at least two weeks after the third dose — up from 57% six months or more after a second dose.

The CDC recommends a booster for everyone 12 years of age and older. Adults may receive either of the mRNA vaccines at least five months after completing the second dose, or the Johnson & Johnson vaccine at least two months after the single dose, although the mRNA vaccines are preferred. Eligible teens are only allowed to receive the Pfizer/BioNTech vaccine.

‘Immune System Fatigue’ Not a Concern

Maher’s second claim that boosters can lead to “immune system fatigue” is also misguided. He’s correct that the concern was mentioned in a Dec. 23 New York Times article. The reporter used the term “a sort of immune system fatigue” and attributed it to “a few members” of the Israeli government’s vaccine advisory panel, per “a written summary” the paper obtained of the panel’s discussion over whether to recommend giving fourth doses to higher-risk populations — a decision the group endorsed.

Dr. Tal Brosh-Nissimov, an advisory board member, however, disputed part of that account. “The experts that raised these concerns were not a part of the discussion in the advisory board on COVID-19 vaccination,” he told us in an email. “They discussed it on the media. A few of them had a meeting with us later on and raised their concerns.”

The concerns, he said, were about T cells and “a possible narrowing of the breadth of the antibody response,” the latter of which, as we’ll explain later, is a potential issue with continued boosting, depending on the design of the vaccine. Brosh-Nissimov said there are “no scientific data supporting” the concerns “right now.”

In any case, scientists told us that exhausting the immune system isn’t something to be worried about with the COVID-19 vaccines.

“There’s no evidence whatsoever for immune system burnout or immune system exhaustion from boosters,” Wherry told us in a phone interview, later adding in an email that he found “no justification … for highlighting the concern of immune system fatigue” and did not agree with the way the New York Times portrayed the issue.

It’s not entirely clear what “immune system fatigue” is, since it’s not a technical term, but in immunology there is a concept known as T cell exhaustion, which is when immune cells known as T cells stop functioning normally after being continuously stimulated by antigens, such as those from a virus or tumor.

Wherry, who studies the phenomenon, said that exhaustion occurs only if there’s no rest or no break in between antigen stimulation — which is not the case with periodic boosters.

“Getting a booster every year or getting a booster even every four months simply will not induce exhaustion,” he said. “It’s a fundamentally different process.”

Instead, exhaustion occurs in chronic infections, such as with hepatitis C or HIV, or in cancer with tumors that the immune system fails to control or eliminate.

And COVID-19 itself — not the vaccines — could possibly trigger exhaustion, Wherry said, as there have been reports that some immunocompromised patients have been infected with SARS-CoV-2, or the coronavirus, for weeks or months. “So, if anything, getting boosters and getting vaccinated would prevent exhaustion,” Wherry said.

Even with daily vaccinations — an extreme hypothetical that no one is proposing — Wherry said T cell exhaustion would be unlikely with the COVID-19 vaccines because the vaccines are good at eliciting effective antibodies.

With the authorized and approved COVID-19 vaccines, the body is instructed to temporarily produce its own spike protein — a protein on the surface of the coronavirus — so that the immune system can mount a protective response. This includes the production of antibodies, or Y-shaped proteins that can glom onto the virus and clear it.

“The antibodies you generate against spike will actually limit how much exposure your T cells get to that spike protein,” he explained, “because the antibodies will end up clearing the spike more rapidly.”

That’s different from what happens with cancer or certain chronic infections, when the antibodies are ineffective or can’t eliminate the antigen.

Wherry said that in situations in which boosting is too frequent, what typically happens is that you’d just get a very weak boost to the immune system, and the vaccine or its produced antigen would be eliminated so quickly that you wouldn’t get much stimulation.

“So not only will you not get exhaustion when you’re delivering boost, but it would actually be very hard to get exhaustion giving repeated doses of a very good vaccine,” he said.

Frances E. Lund, director of the University of Alabama at Birmingham School of Medicine Immunology Institute, agreed that immune fatigue would not be an issue for additional COVID-19 boosters.

“If the boosters are too close together (every month for example) they may not be very effective because the viral proteins in the boost (mRNA encodes the viral proteins) will get cleared so quickly that the immune system may not make much of a response,” she said in an email. “That’s not fatigue – it’s simply that this boost doesn’t do a lot to further increase the response (the immune system is ‘ignorant’ to the boost).”

Lund suggested people might be mistakenly thinking of another phenomenon known as activation-induced cell death — but said that it, too, isn’t relevant to the COVID-19 vaccines.

“What some people may have confused is if you introduce the antigen again very quickly (a few days apart), that can actually have some effect on the overall quality and size of the memory response induced by the vaccine,” she said. “If you have immunity, then boost and then boost again a few days later, some of the immune cells that were activated after the first boost may get re-activated after the second boost and then die.”

But, she said, this phenomenon isn’t applicable to the COVID-19 vaccines because the doses are staggered and no one is suggesting vaccinating that frequently.

“With the regimen that is happening now (prime, wait three weeks boost, wait 4-6 months boost, wait 4-6 months boost),” Lund said, “there is no reason to think that you would see fatigue, ignorance or activation induced death.”

A Misinterpreted Press Conference

Along with Maher’s claims about “immune system fatigue,” Children’s Health Defense, Robert F. Kennedy Jr.’s anti-vaccination organization, has highlighted misinterpreted comments from a European Medicines Agency official about repeated boosting to undermine confidence in boosters generally.

Citing news reports from Reuters and Bloomberg, one of which was corrected, a Children’s Health Defense article misleadingly said that the official said frequent boosters “could adversely affect the immune system” and “could pose a risk of overloading people’s immune systems and lead to fatigue.”

What the official said shares some of that language, but was misunderstood, the agency told us.

“If we have a strategy in which we give boosters, let’s say, every four months approximately, we will end up potentially having [a] problem with the immune response and the immune response may end up not being as good as we would like it to be, so we should be careful in not overloading the immune system with repeated immunization,” said Marco Cavaleri in response to a question during a Jan. 11 press briefing. “And secondly, of course there is the risk of fatiguing the population with the continuous administration of boosters.”

“Despite what some people have incorrectly reported, Dr Cavaleri has never said or implied that the repeated administration of boosters would weaken the immune system in any way,” an EMA spokesperson told us in an email. “What he said is that repeated administration of boosters might lead to the immune response to the vaccine [booster] being lower, which means the vaccines [boosters] could become less effective.”

Cavaleri clarified his comments in a Jan. 18 briefing, when he said repeated boosters with short intervals “might reduce the level of antibodies that can be produced at each administration, as our immune system needs a certain amount of time to mature the response to the antigens it is presented with. So, potentially making the vaccination a little bit less efficient over time.”

Thus, even though the Children’s Health Defense article is correct that Cavaleri was calling for caution on boosters beyond a third dose of an mRNA vaccine — a sentiment shared by many scientists — he was not suggesting immune fatigue might be a problem or that a theoretical policy of repeated boosters would damage the immune system as a whole.

And he was not urging caution against first boosters. In the Jan. 11 briefing, in fact, Cavaleri emphasized the importance for all eligible E.U. citizens to receive boosters, given evidence from the U.K. that the shots can restore some of the protection lost to waning immunity over time and immune evasion from the omicron variant.

Booster Challenges

While “immune system fatigue” is not something that immunologists are worried about, there are other concerns about boosters as populations consider second boosters and beyond.

Israel has started to roll out fourth doses of the Pfizer/BioNTech vaccine to higher risk groups, but many scientists and governments say it’s too early to know whether those are effective or needed, outside of additional shots for the immunocompromised.

Part of the challenge, Wherry said, is that the risk-benefit calculation for boosters isn’t the same as for primary vaccination, particularly in healthy young adults, since the benefit is more about preventing infections and keeping workplaces and businesses open, rather than preventing severe disease. Those benefits need to be weighed against the rare chance of a serious adverse event, he said.

In addition, Wherry said there is a possible risk that repeated boosting might hinder a person’s immune response against a future variant if that response gets too focused on a particular coronavirus spike protein. This kind of immune imprinting, which depends on the version of the spike protein that is included in the vaccine, could winnow the range of antibodies that are made, reducing a person’s flexibility to respond to subsequent variants.

Continual boosting with an omicron-specific vaccine, for example, which is not yet available, might “push the antibody response to be, let’s say, more tailored to omicron, which might prevent our ability to respond to a delta-like variant that emerges in the future,” he said.

In other words, it’s possible a booster designed for a particular variant will lock in an immune response that’s less ideal for a future variant, although there is no evidence of this yet.

He said this concern is not well understood and requires further study, but that boosting with vaccines using spike proteins of variants we know now could close off paths to antibodies later.

Wherry is still supportive of a first booster, in part because of the high rate of community transmission — and because the mRNA vaccines might always have been three-dose vaccines, and the Johnson & Johnson vaccine a two-dose vaccine.

Deciding on a second booster, though, he said, will require more research, and should hinge on community transmission levels, which scientists ideally should be able to model to make forecasts; rapid data on any emerging variants of concern; and better, long-term data on a person’s memory T and memory B cells, instead of just focusing on antibodies.

“Fourth doses and beyond need to be thought about for populations at risk and need to be studied more so we understand how they’re tailoring the immune response,” Wherry said. “I’m in favor of the third dose right now, but I’m also very much in favor of studying additional doses in the right contexts.”

Editor’s note: SciCheck’s COVID-19/Vaccination Project is made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over our editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation. The goal of the project is to increase exposure to accurate information about COVID-19 and vaccines, while decreasing the impact of misinformation.

Sources

Dolgin, Elie. “Omicron is supercharging the COVID vaccine booster debate.” Nature. 2 Dec 2021.

Robertson, Lori. “Studies Show Boosted Immunity Against Omicron with Booster Doses.” FactCheck.org 28 Jan 2022.

Patten, Dominic. “Bill Maher On ‘Real Time’s 20th Season, Being ‘Over Covid’ & America’s Upcoming ‘Real Day Of Reckoning.’” Deadline. 21 Jan 2022.

“EMA regular press briefing on COVID-19.” European Medicines Agency. 11 Jan 2022.

COVID Data Tracker. CDC. Accessed 1 Feb 2022.

Thompson, Mark, et al. “Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022.” Morbidity and Mortality Weekly Report. 21 Jan 2022.

Kershner, Isabel. “Israel Considers 4th Vaccine Dose, but Some Experts Say It’s Premature.” New York Times. 23 Dec 2021.

Brosh-Nissimov, Tal. Israeli Ministry of Health vaccine commission member. Emails sent to FactCheck.org. 3 Feb 2022.

Wherry, E. John, and Makoto Kurachi. “Molecular and cellular insights into T cell exhaustion.” Nature Reviews Immunology. 24 Jul 2015.

Wherry, E. John. Chair, Department of Systems Pharmacology & Translational Therapeutics at the University of Pennsylvania’s Perelman School of Medicine. Phone and email interviews with FactCheck.org. 27 Jan 2022 and 2-3 Feb 2022.

Lund, Frances E. Director, University of Alabama at Birmingham School of Medicine Immunology Institute. Emails sent to FactCheck.org. 3 Feb 2022.

“​​EU drug regulator expresses doubt on need for fourth booster dose.” Reuters. 11 Jan 2022.

Anghel, Irina. “Frequent Boosters Spur Warning on Immune Response.” Bloomberg. 11 Jan 2022.

EMA spokesperson. Emails sent to FactCheck.org. 1 and 2 Feb 2022.

“EMA regular press briefing on COVID-19.” European Medicines Agency. 18 Jan 2022.

“Over 250,000 people have received 4 COVID vaccine doses — ministry.” Times of Israel. 9 Jan 2022.