ABOVE: Recovered COVID-19 patients can harbor SARS-CoV-2 (green) in the lining of their intestines months after infection. The residual viral traces might shape the immune response to the virus.

Immunity to the virus that causes COVID-19 lasts at least six months and might last much longer, according to a preprint posted November 5 on bioRxiv

Among 87 individuals who had COVID-19, antibodies to SARS-CoV-2 dwindled after six months but were still detectable, the study’s authors found. A closer look at the samples of six of those patients revealed that the antibodies that remained six months after infection were, on average, more potent in neutralizing the virus than were antibodies generated only about a month after infection. And levels of the memory immune cells that make those more-potent antibodies did not drop off with time, the researchers report. 

“This is fantastic news,” says...

The results, which have not yet been peer reviewed, suggest that individuals re-exposed to the virus have a good chance of mounting a quick and effective immune response against it, and they offer a bit of hope for making a long-lasting vaccine, experts say.

In the study, Christian Gaebler, a physician and immunologist at the Rockefeller University in New York City, and colleagues compared the levels and potency of SARS-CoV-2 antibodies in blood samples taken from 87 volunteers one month and then six roughly months after they’d been infected with the virus. The team specifically measured levels of antibodies called immunoglobulin M (IgM), immunoglobulin G (IgG), and immunoglobulin A (IgA), which are created to neutralize a pathogen. IgM is usually the first antibody to develop in response to an infection. IgG is the main type found in the blood, and IgA in the blood helps initiate an inflammatory reaction to infection.

The levels of IgM and IgG antibodies reactive to the SARS-CoV-2 spike protein’s receptor binding domain (RBD) dropped sharply between the two time points, the team found, while IgA levels didn’t decline as steeply. Levels of memory B cells, which generate all of these antibodies when there’s a sign of reinfection, remained steady over the course of the study. The results align with a preprint posted on medRxiv in August that also showed memory B cells to the virus persist after a mild COVID-19 infection.

Gaebler and colleagues next identified the antibodies present both one month and six months after infection, synthesized them in the lab, and tested their reactivity to the RBD. Antibodies from six months after infection bound more tightly to the docking component of the virus than did those from shortly after infection. Those antibodies were also better at neutralizing variants of the SARS-CoV-2 virus.

Those observations indicate that the patients’ bodies were activating a specific immune system program that generates long-lived memory B cells, which then produce potent antibodies against subsequent exposures to the virus, the researchers write. A lack of structures called germinal centers where this production of memory B cells takes place has been tied to severe COVID-19 infection and death. 

See “Some COVID-19 Patients Lack Key Structures for Antibody Creation

Curious if the B cells produced the same antibodies a month after infection as six months after infection, Gaebler and colleagues compared the memory B cell receptors’ genetic sequences and found significant shifts over time. This observation, combined with the improved potency of antibodies produced by these B cells, indicates the B cells and antibodies evolved in response to infection.

Gaebler says he was surprised to see the antibodies had evolved. That typically happens when a pathogen hides out somewhere in the body or specifically in cells’ DNA even after symptoms of infections cease—for instance, with HIV. Saurabh Mehandru, a gastroenterologist at Mount Sinai Hospital, and colleagues had been looking for the SARS-CoV-2 virus in recovered COVID-19 patients’ intestines and had identified traces of it in the gut. His group and Gaebler’s decided to team up to see if those viral stowaways in the gut could be spurring memory B cells’ evolution.

Mehandru’s team took a close look at biopsies from 14 recovered patients infected roughly four months earlier, on average. At the time of the tissue collection, none of them had a positive PCR result for the virus, yet SARS-CoV-2 RNA was detected in the small intestine of three of the 14 patients, and biopsies from five of the patients contained SARS-CoV-2 N protein. Electron tomography on one patient’s biopsy also revealed SARS-CoV-2 viral particles.

“If you have the virus persisting in the intestines, it has the potential to continue to inform the immune system,” Mehandru, a coauthor of the study, tells The Scientist.

Shiv Pillai, an immunologist at the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard who was not involved in the study, agrees, saying that the study makes a strong case for virus in the gut continuing to prime memory B cells for infection. The result also suggests that a latent gut infection may explain MIS-C, or multisystem inflammatory syndrome, a rare condition in which children who contracted SARS-CoV-2 suffer from symptoms, such vomiting, diarrhea, and severe abdominal pain, weeks after recovery. “This fits with that and says, look, there is a reservoir in the gut for the virus to stay,” Pillai says. 

See “Kids’ Severe COVID-19 Reaction Bears Unique Immune Signature

Mehandru says it is important to emphasize that even though the team found traces of the virus in the gut, there is no evidence that SARS-CoV-2 can be transmitted via stool. 

Gaebler says the team is not yet entirely sure if it is the virus in the intestine that is causing the evolution in immunity, or if the virus also persists elsewhere in the body and continues to affect the immune system from there.

How long this memory B cell immune response will last past the six-month mark is not yet clear either. Individuals who were infected with the original SARS virus in 2003 still have memory B cells for that pathogen, so the pattern could be the same for SARS-CoV-2, Gaebler says. “Usually when you see such a memory response, it is quite long lasting.”

A next step, he says, is to screen the blood of individuals who receive a vaccine against the virus for the presence of memory B cells. “The immunity data that we see from those vaccines is very encouraging, and seems to resemble the natural infection very closely, which is good news,” Gaebler says. “That might suggest that [the vaccines] also lead to the same memory response. But this would obviously be very, very important to see.”

C. Gaebler et al. “Evolution 1 of Antibody Immunity to SARS-CoV-2,” bioRxiv, doi.org/10.1101/2020.11.03.367391, 2020.

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