Fourth doses of the COVID-19 vaccine don’t appear to offer significant protection against catching omicron according to a preliminary study conducted in Israel, the first country to authorize a second booster for its general population. Researchers announced the resultsMonday, around three weeks after fourth shots became widely available across the country. 

These findings appear to confirm doubts expressed by the European Union’s top drug regulator last week. Marco Cavaleri, the European Medicines Agency's head of vaccines strategy, said at a news briefingthere’s no data supporting the broad effectiveness of fourth boosters.

Some countries – like Denmark, Hungary and Chile – have already authorized second boosters despite concern from regulators. Near the end of December, the World Health OrganizationDirector-General said blanket booster policies are more likely to prolong the pandemic than end it. 

Along with citing a lack of data on the effectiveness of multiple booster doses, Cavaleri said that frequent boosting could potentially have a negative impact on immune response to COVID-19, causing "fatigue in the population" that's received multiple shots.

Researchers say that although it's true that there's no clinical data proving the effectiveness of multiple boosters, there's also no science to back up the idea that frequent boosters could cause "fatigue” in the population. That's because the research has never been attempted.

T cell exhaustion

Cavaleri was likely referencing a concern that seeing antigens (like those provided by vaccines) over and over again can lead to T cell anergy or "exhaustion”, said Sarah Fortune, a professor at the Harvard TH Chan School of Public Health Department of Immunology and Infectious Diseases, in an email to DW.

T cells play a key role in fighting COVID-19 once it's entered the body.

Fortune said that although there is a scientific foundation for Cavaleri's concern, it should be interpreted as a question that researchers will be watching out for, rather than something they know about COVID-19 vaccines that should inform policy.

In the case of COVID-19, the science on T cell exhaustion is more complicated than merely seeing antigens repeatedly, Fortune said.

"T cells become dysfunctional when they repeatedly see antigen in certain contexts  — and the best studied of that biology are settings like HIV or cancer where the antigen is there all the time, not just repeated vaccination," she wrote.

Vaccinating every couple of months is a novel concept

When someone gets a vaccine, the antigen is there for maybe two weeks, then it goes away, said Reinhard Obst, a professor at Ludwig Maximilian University's Institute of Immunology who has facilitated research on T cell exhaustion in mice.

While T cell exhaustion can be observed in cancer or HIV patients in response to some immune-based treatments, it's never been observed in humans in response to frequent COVID-19 vaccination.

Obst said that although there's little clinical data behind it, Cavaleri's concern makes sense.

"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. And the idea of T cell exhaustion is the reason why you might pause," said Obst.

"If someone would ask me, ‘Hey, would you get vaccinated every four months' or let's even say every two months, four times in a row…yeah, I would raise my hand and say ‘Better careful…give them a rest,'" he said.

'Occasional boosts will be helpful'

Stanford professor of immunology research Holden Maecker said in an email to DW he also hasn’t come across any science behind the idea that multiple boosters overwhelm the immune system, but mentioned data from the UK showing that delaying a second dose or boost until around six months is effective.

Many other studies have shown that the immune system needs time to build memory, indicating that booster shots are not very useful at short intervals, he added.  

With that said, "we get yearly flu shots without detriment, and all indications so far suggest that occasional boosts for COVID-19 vaccines will be helpful," he wrote.

Vaccines held to an impossible standard

Paul Offit, Director of the Vaccine Education Center and an attending physician in the Division of Infectious Diseases at Children's Hospital of Philadelphia, has spoken critically against COVID-19 booster policies for the general population, calling the strategy misguided. Offit is also a member of the US Food and Drug Administration's vaccine advisory committee.

Offit's concern isn't focused on the possibility of potential T-cell exhaustion, but rather the unsustainability of a health strategy centered around trying to prevent mild illness.

The COVID-19 vaccines have been held to an impossible standard, he said. When the phase three studies on the quality of the Moderna and Pfizer vaccines were presented in the US in December 2020, they showed a 95% efficacy against mild illness.

"There's no way that was going to last," said Offit, adding that neutralizing antibodies fade over time.

In response, some vaccinated people will develop mild cases of COVID-19.

"That's okay,” said Offit, adding that the vaccines are working like they're supposed to. "You just want it to keep you out of the hospital, out of the intensive care unit and out of the morgue, and it was doing that. But we labeled those cases breakthroughs, which was, I think, a communications error, and then held this vaccine to a standard that we hold no other mucosal vaccine to."

Typical flu and rotavirus vaccines often don't protect against mild illness, but they do protect against moderate to severe sickness, which is what Offit says is the point. 

US health officials authorized booster doses in order to prevent mild illness, Offit said. But the focus should instead be on administering first and second vaccine doses to people who are unvaccinated, rather than continuing to boost people who have already gotten their first two shots, he told DW.

"It's a worldwide pandemic," said Offit. "We are all going to be suffering this virus until we have control of it in the world."

Better global vaccine access a priority

"As long as the virus is circulating around the world, you're going to need to have a highly immune population," said Offit. "The best way to do that is to make sure that those countries that have limited access to vaccines have access to vaccines in the same manner we do. I think that the third dose, fourth dose, fifth dose is largely a waste, or a detour, from what you really need, which is to make sure people have gotten their primary series because that is likely to protect them against severe disease for a long time, for years, even.”

The US approved boosters for all Americans in November, despite pushback from vaccine committee advisors from the Centers for Disease Control and Prevention (CDC) and the FDA, like Offit.

"It just doesn't make sense to me," Offit said. "I don't know how it came to be. I mean, when President Biden stood up on August 18 and said ‘we're going to have booster doses available for everybody over 16', I just don't know where that came from."

The CDC says that although two doses of the vaccine work to prevent severe illness in most people, boosters can help protect severe illness in people in risk groups, and against reinfection from new variants like omicron.

Recent trials in Israel and the US have also shown that boosters can help protect older people. Offit says they make sense for people who need them due to risk factors, but that protection from omicron alone isn't enough of a reason to boost everyone.

"The people who get hospitalized, people who have multiple comorbidities, who are older or immunosuppressed – boost them. I'm all for that," Offit said. "But I just don't understand the story of this war against mild disease in healthy young people."