As the U.S. rounds out its second year of the pandemic, many people are trying to figure out just how vulnerable they may be to COVID-19 infection, and whether it’s finally safe to fully return to all the activities they miss.

On an individual basis, the degree and durability of the immunity a person gets after vaccination versus an infection is not an easy question to answer. But it’s one that science is hotly pursuing.

“This virus is teaching us a lot about immunology,” says Gregory Poland, MD, who studies how the body responds to vaccines at the Mayo Clinic in Rochester, MN. Poland says this moment in science reminds him of a quote attributed to Ralph Waldo Emerson: “We learn about geology the morning after the earthquake.”

“And that’s the case here. It is and will continue to teach us a lot of immunology,” he says.

It’s vital to understand how a COVID-19 infection reshapes the body’s immune defenses so that researchers can tailor vaccines and therapies to do the same or better.

“Because, of course, it’s much more risky to get infected with the actual virus, than with the vaccine,” says Daniela Weiskopf, PhD, a researcher at the La Jolla Institute for Immunology in California.

What is known so far is that how much protection you get and how long you may have it depends on several factors. Those include your age, whether you’ve had COVID-19 before and how severe your symptoms were, your vaccination status, and how long it has been since you were infected or inoculated. Your underlying health matters, too. Immune protection also depends on the virus and how much it is changing as it evolves to evade all our hard-won defenses.

In a new scientific brief, the CDC digs into the evidence behind the immune protection created by infection compared with immunity after vaccination. Here’s what we know so far:

Durability of Immunity

The agency’s researchers say if you’ve recovered from a COVID-19 infection or are fully vaccinated, you’re probably in good shape for at least 6 months. That’s why this is the recommended interval for people to consider getting a booster dose.

Even though the protection you get after infection and vaccination is generally strong, it’s not perfect.

Getting COVID-19 after you’ve been vaccinated or recovered is still possible. But having some immunity — whether from infection or vaccination — really drops the odds of this happening to you. And if you do happen to catch COVID, if your immune system has already gotten a heads up about the virus, your infection is much less likely to be one that lands you in the hospital or morgue.

According to CDC data, at the height of the Delta surge in August, fully vaccinated people were six times less likely to get a COVID-19 infection compared with unvaccinated people, and 11 times less likely to die if they did get it.

How Strong Is Immunity After a COVID-19 Infection?

About 90% of people develop some number of protective antibodies after a COVID-19 infection, according to the CDC. But how high those levels climb appears to be all over the map. Studies show peak antibody concentrations can vary as much as 200-fold, or 2,000%.

Where you fall within that very large range will depend on your age and how sick you became from your COVID-19 infection. It also depends on whether you have an underlying health condition or take a medication that blunts immune function.

Our immune system slows down with age. This process, called immunosenescence, starts to affect a person’s health around the age of 60. But there’s no bright line for failure. People who exercise and are generally healthy will have better immune function than someone who doesn’t, no matter their age. In general, though, the older you are, the less likely you are to get a robust immune response after an infection or a vaccination. That’s why this group has been prioritized both for first vaccine doses and boosters.

Beyond age, your protection from future infection seems to depend on how ill you were with the first. Several studies have shown that blood levels of immune defenders called antibodies rise faster and reach a higher peak in people with more severe infections.

In general, people with cold-like symptoms who tested positive but recovered at home are better protected than people who didn’t get any symptoms. And people who were hospitalized for their infections are better protected over the long term than people with milder infections. Though they may have paid a steep price for that protection: Many hospitalized patients continue to have debilitating symptoms that last for months after they go home.

On average, though, protection after infection seems to be comparable to vaccination, at least for a while. Six large studies from different countries have looked into this question, and five of them have used the very sensitive real-time polymerase chain reaction test (RT-PCR) — the one that has to be sent off and processed in a lab, usually after an uncomfortably long swab is inserted deep into your sinuses —to count people as truly being previously infected. These studies found that for 6 to 9 months after recovery, a person was 80% to 93% less likely to get COVID-19 again.

There are some caveats to mention, though. Early in the pandemic when supplies were scarce, it was hard to get tested unless you were so sick you landed in the hospital. Studies have shown that the concentration of antibodies a person makes after an infection seems to depend on how sick they got in the first place.

People who had milder infections, or who didn’t have any symptoms at all, may not develop as much protection as those who have more severe symptoms. So these studies may reflect the immunity developed by people who were pretty ill during their first infections.

One study of 25,000 health care workers, who were all tested every 2 weeks — whether they had symptoms or not — may offer a clearer picture. In this study, health care workers who’d previously tested positive for COVID-19 were 84% less likely to test positive for the virus again. They were 93% less likely to get an infection that made them sick, and 52% less likely to get an infection without symptoms, for at least 6 months after they recovered.

How Does Protection After Infection Compare to Vaccination?

Two weeks after your final vaccine dose, protection against a COVID-19 infection is high — around 90% for the Pfizer and Moderna mRNA vaccines and 66% for the one-dose Johnson & Johnson shot. Clinical trials conducted by the manufacturer have shown that a second dose of the Johnson & Johnson vaccine given at least 2 months after vaccination boosts protection against illness in the U.S. , which is why another dose has been recommended for all Johnson & Johnson vaccine recipients 2 months after their first shot.

Vaccination creates a big spike in neutralizing antibodies — Y-shaped proteins that are custom-made by immune system cells to latch onto specific sites of a virus and neutralize it so it can’t infect cells and make more copies of itself.

It’s not yet known how long the COVID-19 vaccines remain protective. There’s some evidence that protection against symptomatic infections wanes a bit over time as antibody levels drop. But protection against severe illness, including hospitalization and death, has remained high so far, even without a booster.

Are Antibodies Different After Infection Compared to Vaccination?

Yes. And researchers don’t yet understand what these differences mean.

It seems to come down to a question of quality versus quantity. Vaccines seem to produce higher peak antibody levels than natural infections do. But these antibodies are highly specialized, able to recognize only the parts of the virus they were designed to target.

“The mRNA vaccine directs all the immune responses to the single spike protein,” says Alice Cho, PhD, who is studying the differences in vaccine and infection-created immunity at The Rockefeller University in New York. “There’s a lot more to respond to with a virus than there is in a vaccine.”

During an infection, the immune system learns to recognize and grab onto many parts of the virus, not just its spike.

The job of remembering the various pieces and parts of a foreign invader, so that it can be quickly recognized and disarmed should it ever return, falls to immune cells called memory B cells.

Memory B cells, in turn, make plasma cells that then crank out antibodies that are custom tailored to attach to their targets.

Antibody levels gradually fall over a few months’ time as the plasma cells that make them die off. But memory B cells live for extended periods. One study that was attempting to measure the lifespan of individual memory B cells in mice, found that these cells probably live as long as the mouse itself. Memory B cells induced by smallpox vaccination may live at least 60 years — virtually an entire lifetime.

“Those stay resident in our lymph nodes and primarily in our bone marrow and are called out whenever the body sees that same pathogen again,” Poland says.

Cho’s research team has found that when memory B cells are trained by the vaccine, they become one-hit wonders, cranking out copious amounts of the same kinds of antibodies over and over again.

Memory B cells trained by viral infection, however, are more versatile. They continue to evolve over several months and produce higher quality antibodies that appear to become more potent over time and can even develop activity against future variants.

Still, the researchers stress that it’s not smart to wait to get a COVID-19 infection in hopes of getting these more versatile antibodies.

“While a natural infection may induce maturation of antibodies with broader activity than a vaccine does — a natural infection can also kill you,” says Michel Nussenzweig, MD, PhD, head of Rockefeller’s Laboratory of Molecular Immunology.

Sure, memory B cells generated by infections may be immunological Swiss Army Knives, but maybe, argues Donna Farber, PhD, an immunologist at Columbia University in New York, we really only need a single blade.

“The thing with the vaccine is that it’s really focused,” she says. “It’s not giving you all these other viral proteins. It’s only giving you the spike.”

“It may be even better than the level of neutralizing spike antibodies you’re going to get from the infection,” she says. “With a viral infection, the immune response really has a lot to do. It’s really being distracted by all these other proteins.”

“Whereas with the vaccine, it’s just saying to the immune response, ‘This is the immunity we need,’ ” Farber says. ” ‘Just generate this immunity.’ So it’s focusing the immune response in a way that’s going to guarantee that you’re going to get that protective response.”

What if You Had COVID and Later Got Vaccinated?

This is called hybrid immunity, and it’s the best of both worlds.

“You have the benefit of very deep, but narrow, immunity produced by vaccine, and very broad, but not very deep, immunity produced by infection,” Poland says. He says you’ve effectively cross-trained your immune system.

In studies of people who recovered from COVID-19 and then went on to get an mRNA vaccine, after one dose, their antibodies were as high as someone who had been fully vaccinated. After two doses, their antibody levels were about double the average levels seen in someone who’d only been vaccinated.

Studies have shown this kind of immunity has real benefits, too. A recent study by researchers at the University of Kentucky and the CDC found that people who’d gotten COVID-19 in 2020, but not been vaccinated, were about twice as likely to be reinfected in May and June compared with those who recovered and went on to get their vaccines.

What Antibody Level Is Protective?

Scientists aren’t exactly sure how high antibody levels need to be for protection, or even which kinds of antibodies or other immune components matter most yet.

But vaccines appear to generate higher antibody levels than infections do. In a recent study published in the journal Science, Weiskopf and her colleagues at the La Jolla Institute of Immunology detail the findings of a de-escalation study, where they gave people one-quarter of the normal dose of the Moderna mRNA vaccine and then collected blood samples over time to study their immune responses.

Their immune responses were scaled down with the dose.

“We saw that this has the exact same levels as natural infection,” Weiskopf says. “People who are vaccinated have much higher immune memory than people who are naturally infected,” she says.

Antibody levels are not easy to determine in the real world. Can you take a test to find out how protected you are? The answer is no, because we don’t yet know what antibody level, or even which kind of antibodies, correlate with protection.

Also, there are many different kinds of antibody tests and they all use a slightly different scale, so there’s no broadly agreed upon way to measure them yet. It’s difficult to compare levels test to test.

Weeks or Months Between Doses? Which Is Best?

Both the Pfizer and Moderna vaccines were tested to be given 3 and 4 weeks apart, respectively. But when the vaccines were first rolling out, shortages prompted some countries to stretch the interval between doses to 4 or more months.

Researchers who have studied the immune responses of people who were inoculated on an extended dosing schedule noticed something interesting: When the interval was stretched, people had better antibody responses. In fact, their antibody responses looked like the sky-high levels people got with hybrid immunity.

Susanna Dunachie, PhD, a global research professor at the University of Oxford in the United Kingdom, wondered why. She’s leading a team of researchers who are doing detailed studies of the immune responses of health care workers after their vaccinations.

“We found that B cells, which are the cells that make antibodies to the viral spike protein after vaccination, carry on increasing in number between 4 and 10 weeks after vaccination,” she says.

Waiting to give the second vaccine 6 to 14 weeks seems to stimulate the immune system when all of its antibody-making factories are finally up and running.

For this reason, giving the second dose at 3 weeks, she says, might be premature.

But there’s a tradeoff involved in waiting. If there are high levels of the virus circulating in a community, you want to get people fully vaccinated as quickly as possible to maximize their protection in the shortest window of time, which is what we decided to do in the U.S.

Researchers say it might be a good idea to revisit the dosing interval when it’s less risky to try it.

Sources:

Susanna Dunachie, PhD, global research professor, University of Oxford, United Kingdom.

Gregory Poland, MD, consultant, Vaccine Research Group, Mayo Clinic, Rochester, MN.

Daniela Weiskopf, PhD, Research Assistant Professor, La Jolla Institute for Immunology, La Jolla, CA.

Alice Cho, PhD, Postdoctoral Fellow, The Rockefeller University, New York, NY.

Donna Farber, PhD, professor, Microbiology and Immunology, Columbia University, New York, NY.

CDC, Science Brief: SARS-CoV2 Infection Induced and Vaccine Induced Immunity, Oct. 29, 2021.

MMWR, Aug. 13, 2021.

Nature, June 14, 2021.

MedRxiv, Sept. 21, 2021.

Cell, Oct. 16, 2021.

Science, Sept. 14, 2021.

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