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'Hybrid immunity': Why people who had Covid should still get vaccinated

People previously infected with the coronavirus may get a significant boost in immunity if they follow up with vaccination.
Image: A nurse holds a vaccine inside a curtained room in a pop up vaccination site at the American Museum of Natural History in New York City
A nurse holds a vaccine inside a curtained room in a pop-up vaccination site at the American Museum of Natural History in New York City on April 23, 2021.Shannon Stapleton / Reuters

For those who have put off getting vaccinated because they’ve already been infected with the coronavirus, a growing body of evidence suggests vaccination plus natural immunity leads to particularly robust protection, including against variants of the virus. 

So-called hybrid immunity — that is, natural immunity from an infection combined with the immunity provided by the vaccine — appears to result in stronger protection than just infection or vaccination alone.

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“There really is this dramatic increase in immunity in people who’ve previously been infected if they get at least one dose of vaccine,” said Shane Crotty, a professor of immunology at the La Jolla Institute for Immunology in California.

“Against some of the most concerning variants, it’s literally 100 times better levels of antibodies after vaccination compared to before for somebody with natural immunity,” Crotty said. “That’s not a small change.”

Fikadu Tafesse, an assistant professor of molecular microbiology and immunology at Oregon Health and Science University, agreed. Tafesse’s research has found vaccination led to increased levels of neutralizing antibodies against variant forms of the coronavirus in people who had been previously infected. 

“You will get better protection by also getting vaccinated as compared to just an infection,” he said. 

Though a previous case of Covid-19 confers some degree of immunity, the amount of protection can vary, leaving some people vulnerable to reinfection

“Antibody levels are really variable after recovering from infections, and those at the lower end of the spectrum might be more susceptible to reinfections,” said Deepta Bhattacharya, a professor of immunology at the University of Arizona. “But after a single vaccine in people who have recovered from Covid-19, antibodies skyrocket up, including those that neutralize variants of concern.” 

In a study posted to the preprint server BioRxiv, researchers at Rockefeller University in New York City looked at how different types of immunity would protect against potential variants. (Studies posted to preprint servers have not been peer-reviewed.) To do so, they designed a modified version of the coronavirus spike protein with 20 naturally occurring mutations to test how antibodies would work against it. 

These modified spike proteins were tested in lab dishes against antibodies from people who had recovered from Covid-19, from those who had been vaccinated and from those who had hybrid immunity. The spike proteins were able to evade the antibodies from the first two groups, but not antibodies from people with hybrid immunity. 

Another study, from researchers at the Centers for Disease Control and Prevention, found among those who had been previously infected, vaccination reduced the risk of reinfection by more than twofold, compared to natural infection alone. 

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The immunological advantage from hybrid immunity, according to Crotty, stems in part from what are called memory B cells: immune cells that churn out the antibodies that fight off the virus.

“Memory B cells are basically antibody factories with the lights turned off,” Crotty said. “If the virus gets past your first line of defense, which is the circulating antibodies, the memory B cells can turn on and make more antibodies.” 

Memory B cells are basically antibody factories with the lights turned off.

These cells are trained to produce antibodies to specific threats — like the coronavirus — after they are first exposed to the threat. But memory B cells don’t only make antibodies that have worked in previous infections; these cells are also constantly tinkering with the formula, producing antibodies that could target variants of viruses that may not exist yet. 

Both vaccine-induced immunity and natural infection turn on memory B cells’ antibody-generating abilities. But research has found memory B cell levels are, on average, higher in people with hybrid immunity compared with natural infection or vaccination alone.

That could contribute to the wider breadth of antibodies seen in people with hybrid immunity.

Those antibodies “recognize all these things that other people just don’t recognize," Crotty said.

That recognition may go beyond variants of the virus that causes Covid-19: Antibodies from hybrid immunity can also recognize the original SARS virus from 2003, according to a study published in June in the journal Science.

The findings make Crotty hopeful that a vaccine against all coronaviruses is a possibility in the future.

“You really could have a vaccine that could recognize a range of current and future coronaviruses, which is not just a daydream,” he said. “The data support that really is possible.” 

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