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At this point in the COVID-19 pandemic, two years in, people have reached varying levels of immunity to SARS-CoV-2. And, they have taken different paths to get there. Whether the path includes vaccination, a natural infection, an infection after vaccination, or vice versa, many people are left wondering what their level of immunity is. Now, a new study finds that there are two routes to enhanced immune protection—breakthrough infections following vaccination or vaccination after natural infection—both of which provide roughly equal levels of enhanced immune protection.

This study is published in Science Immunology in the paper, “Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants.

The research follows a study published in December that described extremely high levels of immune response following breakthrough infections—so-called “super immunity.” That study was the first to use multiple live SARS-CoV-2 variants to measure cross-neutralization of blood serum from breakthrough cases.

The new study found that it doesn’t matter whether someone gets a breakthrough infection or gets vaccinated after a natural infection. In both cases, the immune response measured in blood serum revealed antibodies that were equally more abundant and more potent—at least 10 times more potent—than immunity generated by vaccination alone.

“It makes no difference whether you get infected-and-then-vaccinated, or if you get vaccinated-and-then-a-breakthrough infection,” said Fikadu Tafesse, PhD, assistant professor of molecular microbiology and immunology in the Oregon Health & Science University (OHSU) School of Medicine. “In either case, you will get a really, really robust immune response—amazingly high.”

Researchers divided 104 people, all vaccinated by the Pfizer vaccine, into three groups: 42 who were vaccinated with no infection, 31 who were vaccinated after an infection, and 31 who had breakthrough infections following vaccination. Controlling for age, sex, and time from vaccination and infection, the researchers drew blood samples from each participant and exposed the samples to three variants of the live SARS-CoV-2 virus.

They found both of the groups with “hybrid immunity” generated greater levels of immunity compared with the group that was vaccinated with no infection.

The study was done before the emergence of the Omicron variant, but researchers expect the hybrid immune responses would be similar with the new highly transmissible variant. “The likelihood of getting breakthrough infections is high because there is so much virus around us right now,” Tafesse said. “But we position ourselves better by getting vaccinated. And if the virus comes, we’ll get a milder case and end up with this super immunity.”

“I would expect at this point many vaccinated people are going to wind up with breakthrough infections—and hence a form of hybrid immunity,” said Bill Messer, MD, PhD, assistant professor of molecular microbiology and immunology and medicine (infectious diseases) in the OHSU School of Medicine.

The scientists say they haven’t tested multiple rounds of natural infection, although many people will likely find themselves in that category given that millions of people in the United States and around the world remain entirely unvaccinated.

Given the spread of the Omicron variant, many unvaccinated people who were previously infected are likely to confront the virus again. For that group, previous research reveals a more variable level of immune response than vaccination, Messer said. “I can guarantee that such immunity will be variable, with some people getting equivalent immunity to vaccination, but most will not,” he said. “And there is no way, short of laboratory testing, to know who gets what immunity. Vaccination makes it much more likely to be assured of a good immune response.”

“These results,” said Marcel Curlin, MD, associate professor of medicine (infectious diseases) in the OHSU School of Medicine, “together with our previous work, point to a time when SARS-CoV-2 may become a mostly mild endemic infection like a seasonal respiratory tract infection instead of a worldwide pandemic.”

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