Why a fourth shot is — or isn't — necessary

At this point, one thing about the pandemic is clear: The COVID-19 vaccines, even when followed by a booster, aren't going to stop the coronavirus — or provide long-term protection from infections.

Right after the third shot — the booster — antibodies rise up quickly. But then about a month later, they begin to decline. As a result, protection against infection drops down to about 50% three months later.

So the question is: Should you get a fourth dose to beef up protection again?

A preliminary study from Israel, published last Tuesday, suggests that for the general population, the answer is likely no. A fourth shot of the same vaccine — in this case Pfizer-BioNTech or Moderna — offered very little extra protection against infection compared with only three shots.

"Not a third dose, not a fourth dose, not a fifth dose will do anything to stop infections [long term]," says Dr. Gili Regev-Yochay, an infectious disease specialist at Sheba Medical Center in Tel HaShomer, Israel, and lead author of the new study.

But that's not to say that an additional dose is pointless in all circumstances. For older people or those at high risk, an extra dose may be needed to help maintain protection against severe disease, Regev-Yochay says. "A fourth dose probably does have a role in protecting against severe disease. I've seen preliminary data looking into that question."

What does a fourth dose do to the immune system?

In the new study, Regev-Yochay and her team gave about 300 health care workers a fourth shot, either Pfizer or Moderna. And then they looked to see if those people were less likely to become infected while working at Sheba Medical Center, compared with about 400 health care workers who had received only three shots.

They also measured antibody levels in the health care workers' blood before and after the fourth dose.

Although the extra shot boosted antibody levels to about the level observed right after the third shot, the rise in antibodies didn't translate into strong protection against infection. The extra dose reduced the risk of an infection by only about 10% to 30%, Regev-Yochay and her team report. During the 30-day study period, about 20% of the people who received the extra shot became infected with the omicron variant of the coronavirus, compared with about 25% of the people who received only three shots. The extra dose also didn't appear to activate T cells, which are critical for clearing out a future infection.

Regev-Yochay and her colleagues conclude that the fourth dose restores some protection lost after the third shot but doesn't boost immunity beyond that.

Although scientists don't know exactly why the fourth dose didn't trigger a strong immune response, some believe the current vaccine might not be the best tool for fighting a variant as infectious as omicron.

The vaccines now being administered were designed to fight variants circulating in 2020, which are very different from omicron.

"I think what's happening is we're just reaching a threshold with this vaccine," says Jenna Guthmiller, an immunologist at the University of Chicago.

"Omicron, in my opinion, has changed everything. This virus is way more likely to cause an infection, and so what worked for previous variants, such as alpha and even delta, is perhaps not the same vaccine that's going to be necessary for omicron."

The current vaccines trigger a strong immune response inside the blood, "which provides great protection against severe disease," Guthmiller says. But the vaccine doesn't produce a strong immune response inside the respiratory tract, where the virus initiates an infection.

"So I'm really excited that people are working on mucosal-based vaccines [such as nasal sprays] that can really train our immune system within our nasopharyngeal [area and] lungs to provide robust protection," she says. "That's probably the step forward we need if we want to get robust protection against infection with a variant, like omicron, which is just so infectious."

Could a fourth dose help extend protection against severe disease?

Despite the disappointing results for a fourth shot, the current crop of vaccines is still remarkably helpful when it comes to saving lives. So far, the vaccines are "doing a good job in preventing hospitalizations and death," Regev-Yochay says.

Indeed, a study published this month found that three doses offer about 90% protection against hospitalization with an omicron infection two months after the last dose. But that protection drops to about 80% after four months, the study reported in the Morbidity and Mortality Weekly Report.

That small drop in protection has some scientists concerned, including Sara Tartof, an epidemiologist at Kaiser Permanente in Pasadena, Calif.

"Overall, protection against severe disease remains higher than against infection, but evidence is emerging that protection against severe disease may decline with time against omicron," says Tartof, who has unpublished data that supports the results in the MMWR study.

For healthy people under age 65 or so, this waning protection may not cause a big problem because they have a relatively low risk of hospitalization to begin with.

"But if you have an overall higher risk of hospitalization," Tartof says, "this waning might cause a bigger impact than for somebody who has an overall very low risk of severe disease to begin with."

So an extra booster will likely help extend protection against severe disease for people over 65, people with health factors that increase their risk or people with compromised immune systems.

"These people will likely be the first group to require another booster," says Akiko Iwasaki, an immunologist at Yale University. "Their immune response is not as robust as a healthy young person."

But, she says, scientists don't know yet when these people will need that extra shot. "It depends on how fast the immunity is waning. So we'll have to wait and see."

Waiting is exactly what the Food and Drug Administration has decided to do before it recommends an extra booster shot to anyone. "We simply don't have enough data to know that it's a good thing to do," Dr. Peter Marks of the FDA told The New York Times on Thursday.

But several countries are already moving forward with a fourth dose. On Tuesday, Sweden began to offer an extra jab to people over age 80 and those living in nursing homes. Chile now offers a fourth dose to anyone over age 55 who had their third dose more than five months ago. And Israel has authorized fourth shots to adults over age 60 and any adult with underlying health conditions.

"So getting a fourth dose is probably important only for those vulnerable populations who need this extra protection," says Regev-Yochay, of Sheba Medical Center. "In general, I would recommend they receive any protection they can."

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