Monkeys Develop Protective Antibodies to SARS-CoV-2
Monkeys Develop Protective Antibodies to SARS-CoV-2

Monkeys Develop Protective Antibodies to SARS-CoV-2

A small study of macaques finds they don’t develop a coronavirus infection the second time they are exposed, supporting the idea of using plasma from recovered patients as a treatment for COVID-19.

Katarina Zimmer
Katarina Zimmer
Mar 17, 2020

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Whether people develop immunity to SARS-CoV-2 after being infected once is a pressing question for policymakers, public health professionals, and everyone affected by the spreading COVID-19 pandemic. It’s of particular interest to several research groups and companies currently developing plasma therapies, whereby antibody-containing blood plasma is extracted from recovered patients and administered to patients with severe cases to help them fight off the infection.

Now, a study in monkeys provides some clues. Three rhesus macaques did not develop a second infection after recovering from a first exposure to the coronavirus and being reexposed to SARS-CoV-2, suggesting that primates are capable of developing at least some short-term immunity to the pathogen. The research, posted as a preprint to bioRxiv March 14has yet to undergo peer review. To the authors, the results indicate that reports of some COVID-19 survivors being “re-infected” a second time can be explained by issues with testing rather than a failure to develop immunity.

“This is a really critical preliminary study,” says Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill who wasn’t involved in the study. Although many questions remain as to how the human immune system responds to the virus, “it’s the start of an answer that’s going to be really important to all of us.”

Based on these results, the team questions the reports of COVID-19 survivors recovering and being discharged upon testing negative for the virus, only to then develop another infection.

The team’s research began while the outbreak was mostly restricted to China. Around early February, reports surfaced that recovered COVID-19 patients who were discharged from hospitals later tested positive again, explains Chuan Qin, an experimental pathologist at the Institute of Laboratory Animal Sciences at the Chinese Academy of Medical Sciences. Qin and his colleagues, some of whom have previously studied monkey responses to MERS, wanted to investigate whether it was possible to become re-infected with the new coronavirus.

The team applied a dose of SARS-CoV-2 into the windpipes of four adult rhesus macaques. The researchers detected high concentrations of the virus in the animals’ noses and throats, which peaked three days after the initial infection. This was accompanied by reduced appetite, weight loss, and an increased breathing rate. After sacrificing one of the monkeys and performing a necropsy a week after the initial exposure, the team found the animal had traces of the virus across many body tissues and had developed interstitial pneumonia—characterized by an inflammation of the lungs’ alveoli, which is one of the key symptoms of COVID-19 that can occur in people.

The team collected the blood sera of the three other animals to track whether they were developing antibodies to the virus. Using a specialized assay, they found the monkeys’ blood contained antibodies that targeted the spike protein of SARS-CoV-2, a surface protein the virus uses to enter human cells. Antibody levels were relatively low during the first week after infection, but surged at three and four weeks. “Our study found that neutralizing antibodies are produced in the process of recovery after SARS-CoV-2 infection,” Qin writes in an email to The Scientist.

Roughly a month days after the initial exposure to SARS-CoV-2, the researchers verified that the animals had cleared the infection. They couldn’t detect the virus from swabbing the nose, throat, or anus, and there were no strikingly unusual features in the lungs based on a chest X-ray.

The team then exposed two of the remaining monkeys to a second dose of the coronavirus. Although the animals developed a slight fever, neither showed weight loss. In addition, the researchers couldn’t detect the virus based on nose, throat, or anal swabs. One of the two animals was euthanized and necropsied, which confirmed that there was no viral replication across body tissues.

Support for plasma therapy for COVID-19

The researchers conclude that “neutralizing antibodies produced by SARS-CoV-2–infected monkeys can protect animals from reinfection,” Qin explains. Based on these results, the team questions the reports of COVID-19 survivors recovering and being discharged upon testing negative for the virus, only to then develop another infection. They suspect that this is probably the result of false-negative PCR tests in the hospital that missed lingering virus, and they note in the study that diagnostic techniques need to be further refined.

Columbia University virologist Angela Rasmussen agrees with this interpretation. “This study suggests that reinfection is likely not occurring frequently, if at all. It indicates that infection results in protective immunity against SARS-CoV, at least in the short term,” she writes in an email to The Scientist. Virologists on Twitter concur that reinfection with SARS-CoV-2 is unlikely, citing other recent preprints that describe a production of antibodies in people infected with SARS-CoV-2019.

It’s unclear how long this protective immunity lasts. Sheena Cruickshank, an immunologist at the University of Manchester, points out that the study is very short in duration. It’s too soon to say whether the researchers’ observations are due to the immediate, initial antibody response to the virus or to a long-lasting immune memory.

Typically, viral infection triggers plasma B cells to produce antibodies, but, eventually, memory B cells, which survive for long periods of time, are also stimulated to differentiate into plasma B-cells that generate more-targeted and more-effective antibodies upon re-encountering the same pathogen. It’s not clear whether the antibody surge the team observed is part of the “stage when [initial] antibody levels are still dropping off, rather than a true memory response,” Cruickshank writes to The Scientist in an email. In addition, the study only followed the immune responses of two macaques. “These are really tiny numbers to infer anything,” she adds.

Lengthier studies that follow animals or people at least three months after infection are critical to understanding long-term immune responses to SARS-CoV-2, she explains. Research on other coronaviruses suggest different long-term immune responses. For instance, studies in SARS patients find that antibody levels fade after a few years. Some cold-causing coronaviruses “tend to induce immunity that is very short-lived, at around three months,” notes Peter Openshaw, a professor of experimental medicine at Imperial College London, in a recent statement in response to recent discussions on herd immunity in the UK. (Last week, British officials seemingly presented a plan to combat the outbreak that was communicated as allowing the deadly virus to spread to build immunity among the general population and thereby slow transmission—an approach decried by many scientists. UK Health Secretary Matt Hancock later insisted to the BBC, “herd immunity is not our policy. It’s not our goal.”)

Despite the small numbers of animals observed in the study, “in these circumstances, this study is still informative and useful,” Rasmussen says. To her, the results underscore the possibility that plasma therapy approaches could be a useful treatment option. Administering antibodies from other people is thought to be one way to provide patients with immediate immunity. Some studies suggest this approach reduced the risk of death for flu patients during the 1918 influenza pandemic and improved the prognosis for certain SARS patients in the 2003 outbreak in Hong Kong. Several studies testing such therapies for COVID-19 are currently underway. “Convalescent plasma in particular is a therapy that could be undertaken fairly rapidly and might be a good therapeutic intervention until we can develop an effective vaccine,” Rasmussen says.

To Gralinski, the study underscores that non-human primates could be a useful animal model to study COVID-19, because their symptoms are similar to—but not exactly the same as—those in humans. “These animals certainly aren’t progressing to acute respiratory distress syndrome or anything like that, [which] you see in some people,” she says. Nevertheless, the animals may prove useful in studying whether vaccines, drugs, antivirals, and other therapies may be promising in people, she says.

“We’ve only known about this virus for ten, eleven weeks right now,” Gralinski says. “It’s great to see any type of data this quickly.”

L. Bao et al., “Reinfection could not occur in SARS-CoV-2 infected rhesus macaques,” bioRxiv, doi:10.1101/2020.03.13.990226, 2020. 

Katarina Zimmer is a New York–based freelance journalist. Find her on Twitter @katarinazimmer.

Correction (March 18): A previous version of this article incorrectly stated that upon viral infection, plasma B cells produce antibodies on the spot. The article has been updated to reflect the fact that they take longer to generate.