Seattle Children’s Researchers Discover That Functional COVID-19 Antibodies Are Lost Quickly After Mild Cases

Seattle Children’s researchers have published a study that has uncovered a deeper understanding of why people who have had mild cases of the novel coronavirus 2019 (COVID-19) lose functional antibodies within a few months.

Last year, while seeing the bulk of research analysis focused on severe cases of COVID-19, a team of researchers led by Seattle Children’s Research Institute’s Center for Global Infectious Disease Research, the largest pediatric infectious disease research center in the country, sought to evaluate the immune responses that occur after people recover from more mild cases of COVID-19. Mild cases, researchers say, are the most common type of cases. Published in Cell Reports Medicine, a team of researchers found that while antibodies did persist over time, they were not the functional antibodies needed to protect someone from reinfection.

The study evaluated a cohort of 34 adults, ranging in age from 24-74 for up to six months. It characterizes antibody responses to infection and does not investigate T cell or vaccine responses. Antibody responses to vaccination are likely to behave very differently and have different longevity.

At first, researchers found a sustained and maturing presence of an antibody called Immunoglobulin G (IgG) among participants, which should normally mean protection from infection of a virus would improve, says Dr. Noah Sather, a principal investigator at  Seattle Children’s Research Institute and associate professor at the University of Washington.

However, despite a steady presence of IgG antibodies, researchers found that neutralization (the ability of an antibody to prevent infection of a cell) against SARS-CoV-2, the virus that can cause COVID-19, waned quickly. That led researchers to believe that there were other antibody types that were playing a large role in neutralization.

“In our initial analysis, we focused on IgGs, because that’s the prototypical antiviral response you generate after infection,” said Sather. “But because this wasn’t adding up, we started measuring all these other antibody types that you don’t typically associate with neutralizing antibody responses,” he said.

It was then that the team of researchers found that the presence of a different antibody, known as Immunoglobulin M (IgM), waned more quickly than IgG antibodies. This antibody is the first antibody dispatched by a body’s immune response to a mild case of COVID-19. The researchers noticed that IgM antibodies declined in perfect correlation with the loss of neutralizing activity against the virus.

IgMs provide a transient response until more mature antibodies, known as IgGs, arrive to provide a more sustained antiviral response to an infection.

Compared to antibodies such as IgG or Immunoglobulin A, another antibody evaluated in the study, IgM level was the strongest predictor of neutralization against the virus, says Dr. Whitney Harrington, a pediatric infectious disease specialist and researcher at Seattle Children’s Research Institute and assistant professor at the University of Washington.

“It’s as if the first antibody your body starts to pump out in response to this virus is very functional; it can effectively neutralize the virus,” said Harrington of IgM. “But then, as your immune response starts to mature and produce different antibodies, that maturation is actually detrimental in terms of your ability to neutralize the virus,” she said.

This suggests that for people who had mild cases of COVID-19, they may be at risk of reinfection after a relatively short period of time, says Harrington.

“Our research provided a mechanistic link of why we seem to be losing neutralization (functional antibody response) so quickly, despite all these reports that antibodies stick around for a really, really long time,” said Sather.  “Really our identification was that as the IgM goes away, so does the neutralization – and it provides an explanation of why people seem to be at risk of reinfection after three to four months,” he added.

When neutralizing antibody activity is associated with IgG, it can last years, says Sather. IgM, on the other hand, is naturally programmed to decline quickly and be replaced by IgG, he said.

“In this case, because IgM appears to be the major driver of neutralization, the neutralizing activity waned as IgM waned,” said Sather.

Another takeaway for researchers is that current antibody tests people receive when recovering from mild cases of COVID-19 measure only IgG, rather than IgM, which best predicts an ability to neutralize the virus.

While the antibody tests are a valid measure of whether or not someone has antibodies, they are not the antibodies that necessarily help someone after they are infected with the virus, says Sather.

The significance to the public is that people make determinations about public health behavior, such as whether or not to wear a mask or distance, based on an evaluation of whether they are immune to the virus or not, says Sather. For some, they may assume that if they have had a mild infection, they will now be immune to the virus.

“If you’re recovering from infection and you get one of these tests and it says, ‘Bing! You have antibodies.’ Well, based on our study, that doesn’t mean you’re protected from infection,” said Sather. “Our data do strongly suggest that that really is not the answer you need to understand whether you’re immune to the virus or not,” he added.

Harrington and Dr. Lisa Frenkel, co-director of the research institute’s Center for Global Infectious Disease Research, recruited and enrolled the cohort of participants. From there, they engaged in clinical extraction work, which included evaluating the severity of participants’ disease and follow-up data analysis.

Sather and a team of researchers in the Sather Lab performed functional research for the paper, such as blood tests to measure the presence and level of antibodies and sequential benchwork.

The researchers all pivoted from ongoing work to devote themselves to this critical research. Harrington’s previous research has focused on immunology and infection at the maternal-fetal interface, while Frenkel’s has included investigating practical questions related to the prevention of HIV-1 infection in infants and understanding mechanisms leading to the persistence of HIV infection.

Sather’s previous research has looked into deciphering the mechanisms of antibody mediated protective immunity by HIV or malaria vaccination.

Researchers plan to do follow-up studies on other parts of the immune system like innate immune cells and T cells in participants from this cohort compared to people who have been vaccinated.

Learn more about COVID-19 research at Seattle Children’s.