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Searching for Clues to COVID-19 Immunity

covid 19 virus

Oct. 23, 2020 -- People who have recovered from COVID-19 may worry about lingering health effects, but some may also focus on what they see as the good news: Now they are immune.

Or are they?

It's true that the number of reinfections has been small -- about two dozen reported from more than 41 million cases globally. While scientists are learning more about how the immune system responds to the novel coronavirus, SARS-CoV-2, that causes COVID-19, many questions remain.

Getting more specific answers about how the immune system responds to the virus, including whether recovery is likely permanent, is crucial not only to those who have recovered. These answers can help inform vaccine makers to make the most effective vaccines as well.

To get the answers, scientists are studying immune responses of infected people. They are also looking back at other serious viral diseases, such as Ebola, to see if they can apply the knowledge about immunity from those conditions to COVID.

Immune System: The Basics

Scientists talk about the innate immune system and the adaptive immune system. Both play a crucial role in helping to fight off viruses and other invaders. "The innate immune system is the evolutionary, older part of your immune response," says Santosha Vardhana, MD, PhD, assistant professor of medicine and attending physician at Memorial Sloan Kettering Cancer Center in New York. "It's what we describe as the 'first wave of defense.''' This reaction is often what drives the initial symptoms of fever seen with COVID-19, he says.

"That is followed by what is called the adaptive immune response," he says. "Your adaptive immune response is much more specific." When your adaptive immune system kicks in, certain types of white blood cells, or lymphocytes, mount a defense. This includes B and T lymphocyte cells.

B lymphocyte cells make antibodies, which attach to a specific invading antigen or protein and help the immune cells destroy it.

T lymphocyte cells come in two forms: helper cells and killer cells. The killer cells attack the antigens directly and help control the immune system, releasing chemicals known as cytokines.

The helper cells assist the B cells in making protective antibodies.

Immunity to COVID: What Is Known

"Most people infected, 90% of people, develop antibodies," says Joel Ernst, MD, an immunology expert who is professor of medicine and chief of the division of experimental medicine at UCSF School of Medicine.

People who are infected with COVID-19 but don't have symptoms have less robust antibodies, perhaps undetectable, Ernst says. However, ''most with proven infection do develop an immune response, including neutralizing antibodies."

Neutralizing antibodies, as the name implies, defend a cell by neutralizing the harmful effect the virus (or other pathogen) has on it.

"These so-called neutralizing antibodies are associated with protective immunity," Ernst says. "If you get a sufficient level, you are protected against infection at least from that strain. From the very beginning, it seemed pretty likely that a goal of vaccine development and a goal of natural immunity after infection would involve neutralizing antibodies."

Researchers have found that how someone’s T cells respond to a COVID-19 infection varies greatly, Ernst says. Factors include the severity of the illness and the person’s gender -- women have higher responses than men.

In a recent study, researchers from the La Jolla Institute for Immunology and other institutions found that the immune system must launch a ''multi-layered" and virus-specific approach to control how severe the infection becomes. In the study, they collected blood samples from 50 COVID-19 patients and analyzed the antibodies specific to the coronavirus, the helper T cells and the killer T cells.

They found that people who had a strong specific T cell response to the infection tended to have milder disease. People who had a less-coordinated response or weak T cell response did poorly.

The findings may explain why people over age 65, who were more likely to have a poor T cell response, are at higher risk of severe infection or death, the researchers say. Immunity weakens as we age.

What else is known? "The virus generally does not mutate very quickly," Vardhana says, so that's good news for a vaccine being effective. If a virus changes quickly, a vaccine may no longer work against it.

Immunity to COVID-19: Unanswered Questions

One of the biggest unknowns about COVID-19 immunity is how long it lasts.

Canadian researchers analyzed blood samples from 31 people who were recovering from COVID-19. They measured antibodies at 1-month intervals, finding they dropped about 6-10 weeks after symptoms began. Another recent study found that people who had severe cases of COVID-19 produced antibodies for up to 4 months after they had symptoms.

Researchers also aren’t sure about what level of antibodies you need in your blood to protect you, Ernst says.

Nicolas Vabret, PhD, assistant professor of medicine at the Icahn School of Medicine at Mt. Sinai, agrees. "One thing we don't know yet is the minimal immune response that is necessary to prevent infection." That's important for vaccine development.

Ernst says data from ongoing vaccine trials may provide insight into that question. It will be important to monitor immune responses to the vaccine, especially in older people and others more vulnerable to severe infection, Ernst says.

Another unknown: How often reinfection will occur and why it occurs. Researchers recently took a closer look at four reinfection cases. According to their report in The Lancet Infectious Diseases, none had known immune deficiencies. Two had worse infections the second time than the first.

Researchers also found one person in the study was infected by a different strain from the first case to the second. This suggests being infected might not guarantee total immunity.

Looking back at other coronavirus outbreaks, such as the MERS-CoV, the Middle East respiratory syndrome outbreak first reported in 2012, ''have provided a foundation for our understanding" of COVID-19 in general, Vabret says.

Researchers studied 117 survivors of the Ebola virus, a deadly viral disease that caused international alarm in 2013-2016. They compared the survivors' blood samples to those of their 66 contacts and 23 negative control subjects, finding that many of the survivors had the capacity to fight off reinfection due to their ability to produce T cells, even without antibodies.

But experts don’t agree yet on which is more important: antibody or T-cell response. In general, the vaccines now in development have produced a response in neutralizing antibodies, although some have been reported to have T cell responses, Ernst said.

According to the La Jolla investigators, it may be that T cells are more important in fighting a ''natural" infection with SARS-CoV-2, while antibodies may be more important in a vaccine. Or the researchers say, the T-cell response may be important in both for the vaccine and for someone who gets infected naturally.

Finding out the minimal immune response needed that allows people infected naturally to fight off the infection will be valuable information to vaccine developers, Vabret says. That can then be a target to aim for in the vaccine development and trials.

WebMD Health News Reviewed by Hansa D. Bhargava, MD on October 23, 2020


Joel Ernst, MD, professor of medicine and chief of the division of experimental medicine, UCSF School of Medicine, San Francisco.

Santosha Vardhana, MD, PhD, assistant professor of medicine and attending physician, Memorial Sloan Kettering Cancer Center, New York.

Nicolas Vabret, PhD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York.

Medline Plus: "Immune response." 

Journal of Experimental Medicine: "The many faces of the anti-COVID immune response."

UCSF: "Ask the Expert: Seeking Immunity Against COVID-19."

La Jolla Institute for Immunology: "T Cells Take the Lead in Controlling SARS-COV-2 and Reducing Covid-19 Severity."

Cell: "Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity."

Immunity: "Immunology of COVID-19: Current State of the Science."

The Lancet Infectious Diseases: "Genomic evidence for reinfection with SARS-CoV-2: a case study," and "What reinfections mean for COVI-19."

Johns Hopkins Coronavirus Resource Center.

The Lancet Infectious Disease: "Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study."

mBio: "Decline of Humoral Responses against SARS-CoV-2 Spike in Convalescent Individuals."

Science Immunology: “Persistence and decay of human antibody response to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients.”

BRO News: “COVID-19 reinfection tracker.”

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