ABOVE: Coronavirus OC43

There are four common cold coronaviruses that we all catch at some stage. We generate antibodies to them, but our immune memory of them fades over time, and we get re-infected.  

Their names are all too easily forgotten—OC43, HKU1, 229E, and NL63—but our immune systems may nevertheless remember them for a time. There have been hints that exposure to these common coronaviruses might offer some protection from COVID-19, mostly by looking at signs of immune memory in blood samples taken from before the pandemic. A study in the Journal of Clinical Investigation reports the first clinical evidence linking recent endemic coronavirus infections to less severe COVID-19 and even a reduced death rate in patients. 

“The COVID-19 disease is actually much less severe in those patients who had documented endemic coronavirus infections.”

—Manish Sagar, Boston Medical Center

The authors at Boston...

In total, 15,928 patients had at least one such PCR test. Of them, 875 tested positive for an endemic coronavirus (this group was called eCoV+), while the remaining 15,053 people never had a documented coronavirus infection (termed eCoV-).

Of the entire cohort, a total of 1,812 (11.4 percent) later returned for a SARS-CoV-2 test during the initial COVID-19 surge in Boston between March 12 and June 12. 

“Our study is the first to examine people with known endemic coronavirus infections, and compare them to people who, as far as we know, don’t have any recent documented coronavirus infections,” says Manish Sagar, the lead author of the study and a virologist at Boston Medical Center.  

The infection rate for SARS-CoV-2 was no different between those who had a recently recorded endemic coronavirus infection (eCoV+) and those who did not have a positive test (eCoV-). This led the authors to conclude that a recent infection with endemic coronaviruses did not keep SARS-CoV-2 at bay—both groups were just as likely to become infected with the pandemic virus.

When the researchers peered closer at the data, they observed an important difference between the two groups. “The COVID-19 disease is actually much less severe in those patients who had documented endemic coronavirus infections,” says Sagar. The odds of intensive care unit (ICU) admission were significantly lower in eCoV+ than in eCoV- patients, and there was “a trend towards lower odds of mechanical ventilation,” the authors write in their report.

The data also show that among hospitalized patients who had previous positive test results for endemic coronavirus, 4.8 percent of them died compared with 17.7 percent among those in the group without such a test result.

Local immune memory may help explain these results. Such “heterotypic immunity,” says immunologist Joseph Mizgerd, director of the pulmonary center at Boston University School of Medicine, occurs when immune memory is etched into the lungs and/or nose. It’s common after other types of respiratory infections and might offer protection against SARS-CoV-2 if elicited by endemic coronaviruses. Although the Boston group did not measure this type of immunity in patients, they now hypothesize that local immunity gained from endemic coronaviruses helps limit lung injury during COVID-19. “We are testing that in ongoing experiments,” Mizgerd says by email. He adds that such cross-reactive immunity is often mediated by memory T cells, which can localize in the lung, and he notes that lung-localized heterotypic T cells can prevent severe lung infection during pneumonias caused by other types of respiratory pathogens.

If indeed prior infection does ramp up protection against SARS-CoV-2, the study could not answer how long it takes for any such benefit to taper off. Nor did the work shed light on which of the four endemic coronaviruses in particular might be offering protection against the pandemic virus. The scientists are seeking funding to expand their research and include data from other institutions.

Mizgerd and his team did not look into which immune components may be responsible for an endemic coronavirus influencing a person’s immune response to SARS-CoV-2. This is something that immunologist Dennis Burton at the Scripps Research Institute in La Jolla, California, and his colleagues have investigated.  

Since the start of the pandemic, they have been interested in whether pre-existing immune responses to seasonal coronaviruses could influence antibody responses to SARS-CoV-2. In a study published in September as a preprint on bioRxiv, Burton and colleagues compared serum antibodies and antibody-producing B cells from 36 donors sampled prior to the pandemic to see whether those antibodies reacted with the spike protein from the new pandemic virus. Very few antibodies from before the pandemic reacted to SARS-CoV-2, the team found. The vast majority did not bind strongly to the new virus, although they did identify one antibody that could neutralize SARS-CoV-2. 

The group also detected memory B cells in blood samples from before the pandemic that were turned on by the presence of SARS-CoV-2. This activation triggered them to make antibodies that reacted against some proteins made by SARS-CoV-2. “That would suggest that there is some cross reactivity there,” says Burton.  

“A cross-protective vaccine that protects against SARS-CoV-2 plus the endemic coronaviruses would be a really great boon.”

—Manish Sagar, Boston Medical Center

A recent Science study reported that 5 percent of 302 adults and 43 percent of 48 children had antibodies that reacted against certain proteins produced by SARS-CoV-2. Children are more prone to common cold coronavirus infections, perhaps explaining why they might harbor such antibodies, and why they suffer less severe COVID-19 symptoms.

“We do not know yet if the presence of such antibodies modifies the risk of becoming infected or the severity of disease,” senior author George Kassiotis at the Francis Crick Institute in London explains by email. There are conserved parts of the S2 peptide of the spike protein, such as the fusion peptide, in most coronaviruses “that are targeted by such cross-reactive and potentially cross-protective antibodies,” Kassiotis notes. This “may hold promise for a universal vaccine protecting against current, as well as future CoVs,” the authors write in their Science paper.  

Kassiotis says that concerns that “antibody immunity might be short-lived have now been allayed” by recent studies and adds that even if antibodies fell below detectable levels, “the cells that made them will still be there and will respond faster and better to re-infection.”

Antibodies and B cells are part of only one aspect of our immune memory to viruses. Multiple investigations since the beginning of the pandemic have suggested that between 20 percent and 50 percent of people who had never encountered SARS-CoV-2 had T cells that nevertheless seemed to react against peptides from this virus, as noted recently in a Science paper.

In another study in Nature, researchers in Singapore identified memory T cells in patients who had recovered from SARS back in 2003. These were reactive to proteins from SARS-CoV-2, supporting the idea that T cell memory from infections with human coronaviruses may play a role in the response to an infection with the new pandemic virus.  

An additional study recently published in Science used human blood samples from before the pandemic to locate parts of SARS-CoV-2 that stimulated existing T cells. The study found a range of memory T cells that could react to both the new virus and to the four common cold coronaviruses, again suggesting that existing T cells against common coronaviruses could play a role in the immune response to SARS-CoV-2 in some patients. 

Immunologist Stanley Perlman of the University of Iowa who was not involved in any of these studies says that “everybody should have memory B cells against common cold coronaviruses.” We may also have memory T cells that remember these viruses and perhaps help with fighting SAR-CoV-2. However, Perlman emphasized that the implication of this for COVID-19 “is still a work in progress.” 

Burton says he hopes to dig into a molecular understanding of the cross-reactivity of antibodies, which might help design a vaccine against not just SARS-CoV-2, but common cold coronaviruses too. These viruses usually cause mild symptoms, but not always. 

“A cross-protective vaccine that protects against SARS-CoV-2 plus the endemic coronaviruses would be a really great boon,” says Sagar. “These coronaviruses are causes of the common cold, but they are also really important causes of pneumonia, pneumonia hospitalizations, and pneumonia deaths.”

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