How Scientists Test for COVID-19

Demystifying Coronavirus Tests

Coronavirus tests are making headlines, but confusion remains. Different tests detect different things and have different uses. We walk through the three main types of tests related to SARS-CoV-2, the virus that causes COVID-19: what each test detects, how it detects it and what the test can tell us about current and prior infection.

Think you need to get tested for COVID-19? Read the CDC’s guidance on who should get a test. Please use tests only as directed by your healthcare provider.

Also, read the FDA’s answers to frequently asked questions relating to the development and performance of tests for SARS-CoV-2.

Photo by Rohan Thomson / Getty Images

Testing for Infection: Detecting the Virus’ Genetic Material


This test detects bits of the virus itself and can tell you if you’re currently infected. Swabs are used to collect samples from the mucus membranes in the nose and throat where the virus may be growing or have been coughed up from the lungs. There are two types of tests that detect SARS-CoV-2’s genetic material, or RNA: PCR tests and isothermal amplification, or IA, tests. Because RNA is made up of nucleic acids, both PCR and IA tests are also called nucleic acid amplification technology, or NAAT, tests. PCR tests are considered the gold-standard of NAAT testing.

 

Graphic: A swab is taken from a person’s nose or throat, then sent to a lab for testing.
1. A swab is taken from a person’s nose or throat. Depending on the test, the swab may be sent to a lab for analysis, or analyzed where it was collected.
Graphic: DNA and RNA illustration
2. The virus’ genetic material, RNA, is extracted and purified. The RNA is converted to DNA, a more stable version of its genetic sequence, which preserves characteristic parts of the coronavirus’ genetics.
Graphic: DNA mixed with dyes
3. The DNA is mixed with primers, bits of DNA that bind to those characteristic sections of the virus DNA. In PCR, repeated cycles of heating and cooling these primers with viral DNA and a DNA-building enzyme creates millions of copies of virus DNA. IA tests occur at a steady temperature. Fluorescent dye molecules bind the virus DNA as it is copied, making the sample glow.
Graphic: Glowing test tube
4. If the sample contains viral DNA, the millions of fluorescent bits of viral DNA allows the sample to reach a threshold of fluorescence, leading to a positive result. If there’s no viral DNA to replicate, the sample stays dim — a negative result.
Health worker administering a nasal swab test
A patient is tested for coronavirus in late April, 2020. Photo by Al Bello / Getty Images

Nasal Swab Test

This test is an important tool to determine who should quarantine to help stop the novel coronavirus’ spread. As of early August 2021, the U.S. Food and Drug Administration has granted emergency use authorization to more than 250 molecular SARS-CoV-2 tests. Most have been designed for use in a hospital or medical setting, but a few have been authorized for use in certain patient care settings. Several offer at-home nasal swab collection for lab-based PCR analysis, and just two kits have received emergency authorization to test for SARS-CoV-2 infection at home.

Testing for Infection: Rapid Antigen Test



These tests detect viral proteins, or antigens, in a sample taken using a nasal swab. This type of test can detect an active infection much faster than the PCR test and doesn’t need a specialized lab to run. However, it’s more likely to return an inaccurate result. Inaccurate results come in two types: Either the test wrongly suggests that someone who is infected with SARS-CoV-2 is virus-free (known as a false negative), or the test wrongly suggests that someone who is actually uninfected is carrying the virus (known as a false positive).

 

Graphic: drawing blood
1. A swab is taken from a person’s nose or throat, the placed in an extraction buffer.
Graphic: drawing blood
2. The sample is placed on a paper strip on which there are three lines of antibodies, specialized immune proteins that bind other proteins, also known as antigens. The first line is made up of antibodies that bind a certain SARS-CoV-2 protein (the antigen in question) and are attached to a detector molecule. The second line is made up of similar antibodies that are firmly attached to the paper strip. The third line, also attached to the paper, is made up of unrelated control antibodies that don’t bind the virus.
Graphic: drawing blood
3. As the viral proteins flow down the strip, they are bound by the detector antibodies, and this complex flows into the first antibody line — the anti-SARS-CoV-2 antibodies. Some of the viral protein-antibody complexes stop here, snagged by the line of anti-SARS-CoV-2 antibodies. Some of the complexes continue flowing down the strip until they’re snagged by the control antibodies. A positive test, suggesting the presence of viral proteins, shows up as two colored lines because the detector molecule is present in both lines of antibodies.
Graphic: drawing blood
4. If there are no viral proteins, then no complexes get snagged by the first line of antibodies, and the detector antibodies all continue flowing down to the line of control antibodies. A negative result shows up as one line.
A medical worker demonstrates the administration of a rapid antigen test for air passengers in Munich, Germany.
A medical worker demonstrates the administration of a rapid antigen test for air passengers in Munich, Germany. Photo by Alexander Hassenstein/Getty Images

Rapid Antigen Test

The proteins that the rapid antigen detects are only expressed by the virus if it’s replicating, so the test is best used to detect an early infection. The test is faster, cheaper and easier to run than the gold-standard PCR test. Most of the at-home coronavirus testing kits given emergency use authorization by the FDA are rapid antigen tests.

However, results from rapid antigen tests are less reliable. If the antibodies flow all the way down even in the presence of viral proteins, or get snagged in both lines even when there are no viral proteins to bind, the test can return an inaccurate result. If this test returns a negative result for someone with symptoms of COVID-19, a health care provider may order a more accurate molecular test. According to the World Health Organization, as many as half of people infected with SARS-CoV-2 will receive a false negative result. Experts worry that these tests may give infected people who test negative a false sense of security, or cause unneeded worry in people who aren’t infected but test positive for SARS-CoV-2.

Testing for Exposure: Blood, Antibody or Serology Test


If you’ve gotten a blood test, antibody test, or serology test, you’ve been tested for an immune response to SARS-CoV-2. This type of test uses a blood sample to detect specific immune proteins known as antibodies. These are found in the serum, the clear liquid that remains when clotting proteins and cells have been removed from blood. Our bodies make antibodies in response to infections, including coronaviruses. The ELISA assay is the most common method used to detect these antibodies.

 

Graphic: drawing blood
1. A blood sample is taken, then sent to the testing lab.
Graphic: vials of blood and serum
2. Red blood cells and clotting factors are removed from the blood, leaving behind a clear serum that contains the antibodies produced in response to coronavirus infection.
Graphic: SARS-CoV-2 protein
3. As part of the ELISA test for these antibodies, dishes are coated with bits of lab-grown SARS-CoV-2 proteins.
Graphic: Serum and detector antibody
4. The serum sample and a detector antibody are added to the dish.
Graphic: SARS-CoV-2 protein and SARS-CoV-2 antibody
5. If a patient’s serum contains antibodies to SARS-CoV-2, they will bind to these proteins coating the dish.
Graphic: SARS-CoV-2 protein, SARS-CoV-2 antibody and detector antibody
6. The detector antibody will bind to the patient’s antibody and reveal the interaction between their antibodies and the coronavirus proteins.
Graphic: green and blue vials
7. If the patient’s antibodies bind the coronavirus proteins, the liquid in the well turns blue. This means that the patient mounted an immune response to SARS-CoV-2.
A Research Technician in the McElrath lab at Fred Hutch
Hayley Glantz, a research technician in Dr. Julie McElrath's lab, works with COVID-19 samples. Photo by Jake Siegel / Fred Hutch

Blood Test

While we produce antibodies to coronavirus during infection, antibodies to viruses also linger long after the infection has passed, which makes serology tests poor indicators of active infection. Additionally, most serology tests are designed detect a type of antibody that arises later during an infection, making them better at showing prior exposure.

What these type of antibody tests cannot do is show whether someone is protected from reinfection by SARS-CoV-2. A different type of test, which measures how well a person’s antibodies block infection by the novel coronavirus, gets closer to showing whether they’re protected or not. (These tests are not yet available in clinical settings.) Scientists are currently studying the question of how well antibody levels — whether after infection or vaccination — correlate with protection against infection (or reinfection) by SARS-CoV-2.

And while the ELISA is a major type of serology test, it’s not the only one available. Several kinds of tests, including those that use technology similar to pregnancy tests, have hit the market become available, though not all give reliable results.

How Scientists Use These Tests

 

Research scientist in the Bloom Lab at Fred Hutch
Research scientist Adam Dingens performs ELISAs with serum samples in the Bloom Lab at Fred Hutch. Photo by Robert Hood / Fred Hutch

Tests for both active infection and prior exposure are being used as health officials and scientists grapple with the scope of the SARS-CoV-2 epidemic. Both will help us understand how far the virus has spread, who it affects and how much. The serology test is also used in studies looking at the potential therapeutic use of antibodies from those who have had COVID-19 and recovered.

The serology test will also help them determine whether most people mount a detectable immune response the novel coronavirus, as well as how long it lasts, key information needed to develop a protective vaccine. Studies of correlates of protection — biological indicators that a vaccine protects against coronavirus infection — draw on information provided by serology tests.

But as the U.S. moves to reopen the economy and companies speed vaccine development, other tests must also come into play. A critical piece of information, which neither the swab test nor the basic serology test provide, is how well an immune response to SARS-CoV-2 protects against reinfection. Not all antibodies will neutralize, or block infection, by the novel coronavirus. Other tests that measure neutralization, like one being used by Moderna in their vaccine trial, will be to critical understanding whether a vaccine looks promising. They will also give us a better sense of how much we can rely on herd immunity to protect against later waves coronavirus infection. Currently there are no tests for neutralizing immunity available outside of a research setting.

Enrolling Participants: COVID-19 Clinical Trials

photo of COVID-19 Clinical Research Center

COVID-19 Clinical Research Center

Located on Fred Hutch's South Lake Union campus in Seattle, the COVID-19 Clinical Research Center conducts Phase 1-3 clinical trials to find effective treatments for people who are positive for SARS-CoV-2.

graphic of COVID-19 virus

COVID-19 Prevention Network

Formed by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, CoVPN conducts Phase 3 efficacy trials of COVID-19 vaccines and monoclonal antibodies to prevent COVID-19.

graphic of COVID-19 virus

CovidWatch

This Fred Hutch research project is enrolling volunteers who are at high risk of being exposed to the coronavirus including health care workers, employees of long-term care facilities and hospitals, first responders, grocery store employees and bus drivers. 

graphic Icon of COVID-19 virus

COVID-19 and Cancer Consortium

More than 30 U.S. cancer centers and organizations, including Fred Hutch and its clinical care partner Seattle Cancer Care Alliance, have come together to collect and disseminate data to better understand the scope and severity of COVID-19 in patients with cancer.

Photo of a Doctor reviewing test results with a patient

Seattle COVID Cohort

The Seattle Vaccine Trials Unit, part of Fred Hutch, is looking for people who are at risk for COVID-19 or have tested positive for the virus that causes COVID-19 to take part in a research study. Individuals are needed to help us learn more about how the virus affects the immune system.

woman wearing a protective mask

COVID-19 Immune Protection Study

Fred Hutch researchers are seeking healthy adults without current or past history of COVID-19 to take part in a research study about COVID-19 immunity. Volunteers will be paid to perform weekly home testing for COVID-19 and complete symptom questionnaires.

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