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UF researchers scour coronavirus studies for clues to a future shared with COVID-19

Sept. 17, 2020: UF researchers sifted through several thousand studies on human coronaviruses related to the novel SARS-CoV-2 which causes COVID-19, with the goal of learning from the past to help shape the future.

UF researchers scour coronavirus studies for clues to a future shared with COVID-19

This scanning electron microscope image shows SARS-CoV-2 (round magenta objects) emerging from the surface of cells cultured in a laboratory. SARS-CoV-2 is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S. Image captured and colorized at NIAID's Rocky Mountain Laboratories in Hamilton, Montana. Credit: National Institute of Allergy and Infectious Diseases

A team of UF biology researchers sifted through a few thousand published scientific studies on immunity and human coronaviruses to seek out trends and patterns that might illuminate how immunity to SARS-CoV-2 will affect the trajectory of the COVID-19 pandemic. Their work was published today in Nature Communications.

UF preeminence professor Derek Cummings said his team sought to augment prevailing knowledge about how human coronaviruses interact with our immune system to better understand what the future might have in store regarding SARS-CoV-2.

“The viruses we included in this study are genetically similar to SARS-CoV-2,” says Cummings, a professor in UF’s College of Liberal Arts and Sciences Department of Biology. “And a fundamental principle in biology is that if organisms are genetically close, then they may hold some similarities. We were interested to know how immunity may work for these genetically related viruses, and whether that will tell us how immunity may work for SARS-2.”

The research team comprised members of Cummings’ Infectious Disease Dynamics lab. They focused their search on studies of human coronaviruses, including four strains that cause common colds, plus two that are comparatively more severe: Middle East respiratory syndrome, also called MERS-Cov, and severe acute respiratory syndrome, or SARS-CoV. Systematically reviewing 2,452 abstracts and 491 full manuscripts that were published before March 21, 2020, the team set out to answer a few key questions:

  • Are people reinfected with the same coronavirus multiple times, and how much time needs to pass before someone can be reinfected?
  • Does immune cross-reactivity between similar coronaviruses confer cross-protection?
  • Do people who have more severe disease have stronger antibody responses after infection?
  • What are antibody-based measurable signs that a person is immune?

Reinfection

One concern many lock-down fatigued people have is how SARS-CoV-2 will shape our lives over the next few years as it becomes entrenched in the population, what scientists term endemic. A key part of this question is how long people will be immune after an infection, and the possibility of becoming reinfected. Given the genetic relatedness between SARS-CoV-2 and other less deadly coronaviruses, it is also important to ask what effect past infections with either common coronaviruses or SARS-CoV-2 might have upon subsequent reinfections.

To dig into this line of inquiry, Cummings’ group looked at studies reporting antibody and blood serum markers to endemic coronaviruses (strains 229E, OC43, HKUI and NL63) to learn how often people experience reinfection over their lifetimes. They found that with common colds, most children are infected with their first coronavirus at around 5 years old, and that most people have been infected by the four most common coronavirus strains by age 20. Additional studies showed that people were reinfected with all four strains throughout adulthood.

“This suggests that through whatever mechanism, these coronaviruses are unlike viruses such as measles where you are infected once and then have solid immunity for the rest of your life,” says Cummings, who is also affiliated with UF’s Emerging Pathogens Institute.

In the time since this study ended, media and clinical reports have surfaced of people becoming reinfected with COVID-19.

“In some of the early reports it wasn’t clear that patients were having a second infection or just not fully clearing the original infection,” Cummings says. “But at least one recent study sequenced virus from the same person, from two episodes, and showed the two were genetically distinct enough to suggest they are reinfections. It’s still a rare phenomenon — but possible. It’s also very consistent with what we see in the endemic human coronaviruses.”

Length of immune protective response, and cross-protection

The research team reviewed studies where people were experimentally infected with common coronaviruses to investigate the length of time needed before people could be successfully reinfected again. In other words, how long did their immune response protect them before waning?

Two studies were not able to reinfect participants after one year; and while one study was able to induce a second infection, they reported it produced mild symptoms compared to the first. 

In general, it appears that immunity from the coronavirus strains that cause colds last for roughly one year. In contrast, other studies of SARS-CoV indicate that people’s immune response to these coronaviruses can last closer to several years, even upwards of three. But a lack of information about reinfections with SARS-CoV prevents researchers from knowing whether this immune response is protective.

One of the study’s co-first authors, doctoral candidate Angkana (Hat) Huang, cautions however that these studies were only analyzing the immune response of people with symptoms and did not account for responses from people who were infected but never developed symptoms.

“There could be differences in how long immunity lasts, and how strong immune responses are, based on the severity of your symptoms, and many studies we reviewed don’t capture that,” Huang says.

Given that people can become infected with coronaviruses multiple times throughout their lives, it’s fair to ask how past exposures to endemic coronaviruses may inform our immune system’s response to the new SARS-CoV-2 virus. The study found evidence that while current coronavirus infections can boost immunity against coronaviruses someone was previously exposed to, it doesn’t work the other way around.

“I think of it like reading a book,” Huang says. “You read the chapters and by the time you get to chapter 7, you can say, ‘Oh this reminds me of Chapter 5,’ because you have read that already. But you can't say chapter 7 reminds you of chapter 10, because you have not gotten to chapter 10 yet.”

In other words, there is little evidence that past exposures to the coronaviruses that cause common colds will inform antibody responses that provide protection against the novel coronavirus.

But Cummings cautioned that a lack of detectable antibody responses does not necessarily mean that people are not protected from future infections, because our immune system has a different trick up its sleeve. Long after antibodies fade from circulating in our serum, our immune system can still be triggered to make cells and biological molecules that seek out and destroy coronavirus invaders.

“There may be more interaction than we previously understood between these endemic coronaviruses that our bodies already know and SARS-2,” Cummings says. “And these interactions might not be entirely mediated by just antibodies. This is definitely a research area that needs to be explored.”

Another area in need of research is the role that immune responses might play in contributing to disease. Huang says the team found a small number of papers suggesting that cross-reactions between coronaviruses might contribute to more severe symptoms or disease, a phenomenon known as immune enhancement — which, counterintuitively produces enhanced disease. The team summarized this evidence but decided it was not strong enough to say that enhancement occurs.

“The strength of this paper is that we are leveraging relevant information to identify gaps in knowledge and help shape future research,” Huang says. “For example, if someone is running a clinical trial with a candidate vaccine, our paper will help inform them of the importance of collecting data that can ensure that vaccines are not contributing to immune enhancement of disease in any way.”

Measuring immune responses

In the studies reviewed, the team found that antibody responses to coronavirus infection was rarely reported during the acute illness phase. Most studies reported a robust immune response after the second or third week of illness.

The team also looked at how long coronavirus antibodies could be measured in people’s blood serum. They found that overall, people who had less severe bouts of human coronavirus infections tended to have reduced antibody responses.

The team also found that measures of a common antibody associated with immune-mediated responses, IgG, declined in some people who had been infected with SARS-CoV and MERS-CoV from detectable levels by one to three years after infection. This waning effect can lead to situations where people who had infections later test negative for the antibodies, giving a false impression that they were never infected.

A matrix graph showing immune cross reactions from various human coronaviruses

Matrix showing evolutionary relatedness of different human coronaviruses, and the strength of antibody responses against different viruses. Image courtesy of the authors.

What’s next

Knowing the length of time people experience durable immunity against SARS-CoV-2, and how past coronavirus infections may influence our immune responses to the novel coronavirus, will help researchers predict the pandemic's trajectory and what happens next when peak infections begin to fall.

Matt Hitchings, a co-first author to the study and member of Cummings’ lab, says it seems inevitable that SARS-CoV-2 will be with us for a while.

“Early in the pandemic, many hoped it would be eliminated but it now looks like it will become endemic,” Hitchings says. “If that’s the case, what we’ve learned from endemic coronaviruses suggests that children could become infected early in life. This adds urgency to understanding the rare but serious outcomes we have seen in infants, and to track potential long-term outcomes in children that have been infected with SARS-CoV-2.”

Having a better understanding of how the human immune system responds to the new coronavirus at all stages of life will be key.

“I’ve come to view the immune system as being poised on a knife’s edge between doing too little and doing too much when faced with a new pathogen,” Cummings says. “Pathogens replicate so quickly; the immune response needs to respond just as fast. Our immune systems are amazing and in the overwhelming majority of people infected, it responded to this new enemy really effectively.”

One of the challenges posed by this virus, however, is that people are encountering it for the first time at a life stage when they don’t usually see completely new viruses.

“We get exposed to the coronaviruses that cause common colds from an early age and the memory of those viruses that we retain can help protect us over the course of our life,” Cummings says. “Clearly coronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the coronaviruses that cause common colds vary a lot in severity. SARS-CoV-2 is new, and it may be that some of the severity is due to the fact that people are encountering it at a time in their lives when they don’t usually encounter new pathogens. It may be that once we see it once, even if our immunity doesn’t prevent re-infection, it may protect us from severe disease.”


Creator Credits

Written by DeLene Beeland

Read more

Read Cummings’ EPI profile.