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September 7, 2021 10:41 AM EDT

Contracting a case of COVID-19 is bad enough. Contracting a case that requires you to be hospitalized is decidedly worse. But according to a new study published in the journal Science, there is one small good hidden in that otherwise unalloyed bad. Recovery from a coronavirus infection severe enough to land you in the hospital appears to provide better protection against later infection with at least three of the viral variants currently in circulation than does recovery from a less severe infection.

The study, conducted by a team of researchers affiliated with the University of Amsterdam, involved a relatively small cohort of 69 COVID-19 patients infected between March 2020 and January 2021. Twenty-eight of those patients were hospitalized and the remainder weren’t. An additional sample group of 50 uninfected health care workers who had received two doses of the Pfizer-BioNTech vaccine were also included. In the period in which the infected subjects became ill, the three SARS-CoV-2 variants causing the most concern were Alpha, which emerged in the U.K.; Beta, which first appeared in South Africa; and Gamma, which emerged in Brazil. Delta, far and away the most concerning variant now, was not first identified until December of 2020.

To conduct their research, the investigators drew blood serum from the 69 patients four to six weeks after their initial infection, and from the vaccinated subjects four weeks after they got their second shots—the point at which the immune response would be highest in both groups. They then exposed the three variants, as well as the original SARS-CoV-2—the so-called “wild-type” virus—to the neutralizing antibodies in the sera.

For the wild type, the response was uniform—and encouraging. Fully 96% of the convalescent patients—regardless of their hospitalization status—and 100% of the vaccinated subjects exhibited a powerful neutralizing response. When it came to the variants, things were more complicated.

For starters, there was almost no uniformity in the degree of immunity conferred by previous infection with the virus, with the strength of the antibody reaction varying 1,200-fold between the strongest and weakest responders in the 69-person patient group. Among the 50 vaccinated subjects, things were more uniform, but there was still a 10-fold difference separating the greatest and weakest immune response.

All subjects showed weaker immunity to the variants compared to the wild type. Among the 69 convalescent subjects, the immune response was reduced 2.4-fold, three-fold and four-fold for the Alpha, Beta and Gamma variants respectively. Among vaccinated subjects the figures were two-fold, 2.6-fold and 3.1-fold. But a weaker immune response is not the same as no immune response, and the critical question is whether the neutralizing power of the blood serum would be enough to prevent disease or minimize the severity of the symptoms in a person exposed to one of the variants.

There’s a way of measuring that in the lab: If the serum is diluted by a ratio of 1 to 100 and is still able to induce an immune response 50% of the time, it would be considered sufficient to provide protection. That standard revealed a lot. All of the 28 hospitalized patients in the study and all but one vaccinated subject retained sufficient immune levels in their blood serum to neutralize the wild type virus and all three variants, the researchers concluded. Among the non-hospitalized patients, immune responses were still strong enough to prevent disease when it came to the wild type virus and the Alpha variant. But 39% of that group lost neutralizing ability against the Beta variant and 34% were similarly helpless against the Gamma variant.

In other words, says microbiologist Rogier Sanders of the University of Amsterdam and Weill Cornell Medical College in New York, a co-author of the paper, “in the context of these variants, the neutralizing antibody levels drop below the threshold [of immunity] among some of the mild cases.”

When it comes to variants, the news isn’t all bad for people who ducked a severe infection the first time around. The very fact that they only got mildly ill with the wild type virus, Sanders says, may, at least in theory, portend good things about their underlying immune system’s ability to battle a variant. “They were able to handle the first infection, so why wouldn’t they be able to handle the second infection?” he asks. It’s also important to consider that this study only looked at antibodies, but those aren’t the only defense the body mounts against invaders like SARS-CoV-2. The immune system also produces B calls, known as memory cells, which, as their name suggests, can recognize an antigen that once excited the immune system, sometimes decades after the first encounter. “Even if you don’t have neutralizing antibodies in your blood, you do have memory B cells,” says Sanders. “So, the memory components of your immune system may kick in and prevent severe disease.”

The researchers have begun, but not completed, similar studies of the Delta variant. Preliminary findings, Sanders says, place it on a par with the Gamma variant in terms of the antibody resistance an earlier infection confers. That is to say, those who have recovered from severe cases of COVID-19 are highly likely to have strong antibody responses to Delta, but those who had a mild infection are likely to still be at risk of catching a case of the variant.

There is a way around all this odds-making and risk-taking, of course: vaccination. Variant or wild type, hospitalized or not, the shots just work. “As our data and experience from about everywhere suggests,” says Sanders, “if you’re fully vaccinated, you don’t have a high chance of getting severe disease even when infected with a new variant.”


Write to Jeffrey Kluger at [email protected].

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