To Boost or Not to Boost After COVID?

With a COVID-19 booster shot available for a segment of the U.S. population, an emerging group may wonder if they really need it -- those with "hybrid immunity."

These are the people who are fully vaccinated but have also recovered from a case of COVID-19. Mounting evidence is clear: a bout with the virus does provide extra immunity, making a booster shot helpful but not necessary, experts say.

If you have hybrid immunity, "I would call yourself a victor," said Paul Offit, MD, the director of the Vaccine Education Center at Children's Hospital of Philadelphia. "Call it a victory and bow out."

Background on Boosters

In September, the CDC issued interim recommendations for a Pfizer vaccine booster. It's a third shot made available through an emergency use authorization from the FDA given at the same dose as the two-shot primary series. All adults 65 and over are eligible for a booster, as are individuals ages 18-64 with a high risk of severe COVID, and those ages 18-64 whose jobs put them at high risk of exposure. This is because of the evidence that vaccine efficacy wanes over time, raising the risk of infection.

Preprint studies, including a nationwide study of Israel's Pfizer vaccine recipients, found waning immunity in all age groups following vaccination after 6 months. Data from the ZOE COVID study, an app that gathers data from a huge swath of people but is not peer-reviewed, found a similar effect.

But Offit noted that in a meeting on September 17, an FDA advisory panel made it clear that for most people, two doses of Pfizer or Moderna, or one dose of Johnson & Johnson, are highly effective on their own. Indeed, Alessandro Sette, Dr.Biol.Sci, an immunologist and professor who runs a lab at the La Jolla Institute for Immunology in California, said that if the goal is to prevent serious infections, "apart from some cases ... nobody needs a booster."

Hybrid Immunity and Evidence

Experts say evidence shows that those who have had a natural infection on top of two shots have had what amounts to a "third" shot -- or the equivalent of a booster. In other words, they don't need the extra boost.

A study out this week in Nature looked at blood samples from 40 healthcare workers vaccinated with either Pfizer of Moderna from before and after vaccination. The study found that those who had been previously infected naturally with COVID had a higher T-cell response and higher neutralization capacity for various strains of COVID than did their counterparts who had not caught the virus.

"People who were infected before they got vaccinated with two doses -- their immune response should be higher than the person who was not infected and getting vaccinated," said Sen Pei, PhD, who studies the transmission dynamics of infectious disease at Columbia University Mailman School of Public Health in New York City.

Other studies have reached similar conclusions. One from Nature in June found that in 63 people who were naturally infected with SARS-CoV-2, antibody responses to the virus in blood tests after mRNA vaccination were stronger than infection-naive people who got the vaccine.

Special Protection

What's more, this "hybrid immunity" appears to be particularly potent. According to a perspective paper in Science this summer, the two types of immunity -- from both "real world" infection and vaccination -- together are greater than either one alone. And, as a preprint paper suggested, having hybrid immunity provides protection against a range of variants compared with uninfected vaccines.

The paper used an analogy of a tree that is bred with another to produce a third, much stronger tree. In this case, memory B cells and CD4+ T cells drive neutralizing antibody levels that are up to 25-100 times higher than infection or vaccination alone.

But it's important to keep in mind, experts said, that the immunity from being infected naturally with COVID-19 is still less protective than getting the vaccine as well. As a CDC study on hundreds of Kentucky COVID cases concluded, people who got COVID naturally and didn't get vaccinated were 2.34 times more likely to be re-infected than those who got vaccinated.

COVID After Vaccination

In the rare instance of breakthrough infections, it's unclear whether or not the same hybrid immunity would occur (although Offit takes issue with the term "breakthrough," which he says implies failure even though these cases are largely asymptomatic or mild). Of the 185 million people who have been vaccinated in the U.S., less than 0.01% had breakthrough cases that led to hospitalization or death.

"Breakthrough infections should not be assumed to be associated with hybrid immunity," Sette cautioned, adding that it could be that those who got a "breakthrough" case were among those with a weaker immune response to the vaccine in the first place, complicating the booster question.

"There is no real good data as yet on breakthrough infection," he said.

A 'Personal Choice'

The bottom line: boosters give extra protection to everyone, but that protection may be really meaningful only to those over 65 and other vulnerable populations.

"Scientific evidence shows that if you get a booster, your antibody level will rise again and you will get better protection," said Pei. "That's the scientific evidence. Whether you want to take [the booster] or not depends on your tolerance of the risks and benefits." He added that people who are worried about side effects from the vaccine might be hesitant about getting a third shot.

Other hesitations to get the booster include vaccine inequity across the globe -- with or without hybrid immunity. "Is it fair to give people in the developed world additional doses when there are places where people haven't even got one vaccination?" Sette asked. "In that respect ... that is a question that is not that simple."

Pei said that "vaccine nationalism" is a problem, with a mindset of, "we want to first protect our country's people, not yours." But "this conversation, we cannot participate in as individuals. We can't make the decision that, you know, 'if I don't take this vaccine, it will go to other places.'"

For Offit, the booster is not the main concern: "The problem in this country is if you really want to get on top of this pandemic, it's not about giving a third dose to people who've already had two," said Offit. "[It's about giving] the first two doses to people who haven't had any. That's the problem -- vaccinating the unvaccinated."

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