Many thousands of Americans have been infected with the omicron strain of COVID-19 in the last month, including many who were vaccinated.

That’s no knock against the vaccines. They remain very effective at preventing severe disease and death, especially for those who have received three doses: an initial two plus a booster.

But most people — including hundreds of thousands in the Philadelphia area — have not gotten a booster. If they’ve recovered from an infection with omicron, can they skip the third shot? Now that cases are once again on the decline, are they good to go?

In the short term, probably yes, according to researchers who study the immune system. But as with so much else during the last two years, the answer is complicated and still emerging. And another variant will likely arrive.

For the latest on what some are calling “hybrid immunity,” we spoke to Brianne Barker, a Drew University biologist who studies the immune system’s response to viruses; Jeremy Kamil, a microbiologist at Louisiana State University Health Shreveport; and E. John Wherry, director of the Institute for Immunology at the University of Pennsylvania’s Perelman School of Medicine.

But first, a reminder: No one should ever contemplate getting infected on purpose.

Why you should never get infected on purpose

This misguided idea has been floating around since the start of the pandemic — an echo of those “pox parties” of long ago, when parents would deliberately expose children to chickenpox to “get it over with.”

Here’s why that’s still a bad approach with COVID, even if you’ve already had two doses of a vaccine:

  • COVID can have serious consequences, even death. Yes, that’s unlikely for someone who is vaccinated, but why take a chance? “You literally played Russian roulette,” Kamil says. (And think about the flawed logic there for a second: A person would deliberately get infected in order to boost immunity, so as to … not get infected again?)

  • If infected, you can spread the disease to others.

  • Every infection is another chance for the virus to develop troublesome new mutations. The vast majority of mutations are not a problem, but again, why roll the dice?

  • The “dose” of virus from an infection is unpredictable. In a mild case, for example, the person may be exposed to small amounts of virus — meaning the immune system has less opportunity to learn from the exposure and prepare for next time. The effect of vaccination, on the other hand, is consistent and well-known, said Penn’s Wherry. With each dose, the immune system is exposed to similar amounts of coronavirus protein fragments, providing a harmless sneak preview of the real thing.

But if you got omicron anyway …

It’s no secret that plenty of vaccinated people have gotten breakthrough infections.

That’s likely the result of two phenomena, says Barker, an associate professor at Drew, in Madison, N.J. Their levels of protective antibodies may have waned since vaccination, so the virus was able to gain a foothold. And because the virus has mutated, it is better able to evade the vaccine-induced immune response.

But for those who recovered, good news: Evidence suggests that the combination of vaccination plus infection — regardless of which came first — enhances the antibody response much like a booster shot.

“Hybrid” immunity is more of a layperson’s term, not found in scientific textbooks. The key is the number of exposures, whether it’s through three doses of the vaccine or two doses plus infection, Barker says.

“Basically if you’ve seen the virus three times, you have similar antibody levels,” she said. “But we don’t know about the longevity of those antibody responses.”

In addition to becoming more abundant with each exposure, the antibody response becomes more “mature,” said Kamil, an associate professor at LSU Shreveport.

“It sharpens itself with exposure,” he said. “It’s almost like the bull chasing the bullfighter’s red cape. The bull eventually realizes it should aim for the bullfighter.”

Antibodies vs. T-cells

Given the pressures of an ongoing pandemic, scientists keep conducting research at a fast clip. That means we hear a lot about antibodies, as those are easy to measure. Less is known about how the combination of vaccination and infection affects a different arm of the immune system, called T-cells, as that type of analysis takes longer.

That’s where the response to the vaccine might differ from the response to an infection. The vaccines prompt the person’s cells to make a fragment of the coronavirus — the familiar “spike” proteins that protrude from the surface of each virus particle. The immune system learns to make both antibodies and T-cells that recognize the spike.

But in an infection, the immune system is exposed to the whole virus. In that case, the immune system also makes T-cells that recognize the rest of the virus, not just the spike. It’s not yet clear how the T-cell response might be different after a breakthrough infection, compared with what happens with the vaccines, Barker said.

As with antibodies, the T-cell response is likely to be more consistent in response to vaccines, compared with what happens after an infection, Kamil said.

And don’t get him started on the term natural immunity. Natural, in this case, is a wild card. Given a choice, stick with the proven science of the vaccines.

“Why do we need to have a fair fight with the virus?” he said. “Why not give your body a head start in making antibodies and T-cells? Nature can be quite cruel. Cheetahs eat gazelles.”

How long to wait before a booster

Even if you’ve had two doses of a vaccine plus an infection, it can’t hurt to supplement that protection with a booster shot, Wherry said.

The question is when.

The CDC advises people to wait at least a few weeks after infection before getting vaccinated. That’s partly to prevent spreading disease to others at the clinic, and also because the immune system’s amped-up response may “sop up” the vaccine before it has a chance to stimulate additional protection, Wherry said.

“If you get the booster dose too early, it’s not going to do any harm,” he said. “You may just not get all the benefits.”

So how long should you wait? Omicron is a recent phenomenon, so there are not much data yet to determine the best timing for a booster.

But based on the rate at which antibody levels have waned after vaccination and infection with other strains, it likely makes sense to wait several months before getting a booster, Wherry said.

Are three shots plus infection too much?

At his Penn lab, Wherry studies how T-cells can become “exhausted” while battling cancer and chronic infections such as HIV and hepatitis B.

But that’s generally not an issue with COVID and most other infectious diseases, he said. Three or four exposures to the vaccine or the coronavirus are not going to wear out your immune system.

“If you have rest between the exposures,” he said, “you’re not going to get exhaustion.”

After all, plenty of other vaccines are administered on a three-dose schedule. And in some countries, physicians are now administering fourth doses of a COVID vaccine to those with compromised immune systems.

For most people, it’s not clear that a fourth dose would provide much additional protection, at least in the near future.

But someday, COVID will be endemic — still circulating, yet not out of control — like the seasonal flu. And public health officials recommend vaccination against that disease every single year.