Unlike polymerase chain reaction (PCR) tests, antibody tests are not intended to identify active SARS-CoV-2 infections. Instead of detecting viral genetic material in throat or nasal swabs, antibody tests reveal markers of immune response , the IgM and IgG antibodies that for most people appear in the blood more than a week after they start. feeling sick, when symptoms may already be decreasing.
Serological antibody testing can not only confirm suspected cases, but can also reveal who was infected and did not know it.
Up to a quarter of people with SARS-CoV-2 infection may spread the virus without realizing it because they have mild or no symptoms.
The implications for health care workers could be substantial, microbiologist Florian Krammer said in an interview. from the Icahn School of Medicine at Mount Sinai: "If we find that you are immune, it is very unlikely that you can be reinfected, which means that you cannot transmit the virus to your colleagues or other patients. And I think it also gives peace of mind if you have "You have to work with COVID-19 patients to know that you are probably immune to the infection ," he explained.
Antibody testing is increasing rapidly, with a growing list of commercial kits and testing protocols from researchers like Krammer’s team and a Dutch team. Scientists said the tests will be critical in the coming weeks and months, when they can be used for disease surveillance, therapies, return-to-work screenings and more. But testing must be implemented correctly , they added, acknowledging that there are still unanswered questions.
Convert antibodies into therapies
In its first therapeutic application, serological tests are used to detect donor antibodies in SARS-CoV-2. Plasma containing antibodies from recovered patients is transfused to seriously ill patients in an experimental treatment known as convalescent plasma. Early results from a small number of Chinese patients, published in JAMA in late March, were promising.
The FDA is coordinating a nationwide effort to develop antibody-based therapies for COVID-19 that include convalescent plasma and the hyperimmune globulin derived from it, which will ideally provide passive immunity to people who have been exposed to the virus.
In an interview, Carlos Cordon-Cardo, who chairs the pathology department at Mount Sinai in New York City, said doctors there have begun transfusing convalescent plasma to critically ill patients as part of an FDA program. Krammer’s research team developed the test that is being used to screen donor blood.
The test detected antibodies in plasma from blood drawn 3 days after patients first developed symptoms. These did not react with other human coronaviruses, demonstrating that it is specific to SARS-CoV-2. "There is no pre-existing immunity. And that makes it very easy to distinguish between people who have been infected and who have not been infected."
Antibody testing could also help address a possible unintended consequence of receiving convalescent plasma or hyperimmune globulin. Some COVID-19 survivors who undergo these treatments may not develop their own immunity, putting them at risk of reinfection , said Lee Wetzler, a professor at Boston University.
Serological tests could be used to check the status of immunity after recovery.
Those with low or no immunity would be prime candidates for a vaccine when one becomes available. "The titers we measured with ELISA appear to correlate with neutralizing antibodies ," Krammer said. "So basically the idea is that the higher these titles are, the better you are protected."
However, a substantial number of the new commercial COVID-19 antibody tests are not ELISA-based. They are lateral flow assays, which provide a simple positive or negative result, without quantitative information. These kits are cheap and easy to use and, depending on how they are used, can be useful for disease surveillance, said Elitza Theel, director of the Infectious Diseases Serology Laboratory at the Mayo Clinic.
Diazyme Laboratories in Poway, California, has developed chemiluminescence immunoassays that are closer in concept to ELISA than lateral flow assays. The tests generate a light signal proportional to the SARS-CoV-2 IgM antibodies.
The right test at the right time
On April 1, the FDA granted Emergency Use Authorization (EUA) to a rapid SARS-CoV-2 IgG and IgM lateral flow assay. The agency in early April had also allowed more than 70 companies to sell COVID-19 antibody tests without this authorization, although with some stipulations; Manufacturers operating without EUA must indicate that they have clinically validated their tests using samples from patients with PCR-confirmed PCR infections.
Test reports should note that the FDA has not reviewed the assays and should not be used as the sole basis for diagnosing or excluding SARS-CoV-2 infection or for informing patients of infection status.
According to media reports, the newly available rapid and point-of-care PCR tests will not substantially increase diagnostic testing capacity in the near term. Faced with a shortage of PCR tests amid incredible demand, health systems may consider using serological tests .
However, experts strongly stressed that antibody tests should not be used to diagnose active cases.
Krammer said resorting to antibody testing to diagnose active infections is a "complete misuse . " Not only are antibody tests likely to report false negatives early on, but they will also fail to detect infections in people who are immunocompromised and do not produce antibodies.
"Molecular testing will continue to be the preferred method for diagnosing COVID-19 in symptomatic patients ," Theel said. In his opinion, the only appropriate use of antibody testing for active infection might be for people who have had symptoms for more than a week but are PCR negative .
"I think it’s very important that we understand the limitations of serological tests, recognizing that it takes time to mount a detectable immune response and using them for the right reasons," Theel said. "A false negative serological result in an acutely symptomatic patient with virus replicating and shedding has serious public health consequences" .
Back to work
Government officials and health systems need accurate infection counts to understand the spread of COVID-19, conduct contact tracing, develop public health recommendations, and prepare for surges in demand for health care. When the dust has settled, epidemiologists will use the data to more accurately estimate how many people who contracted the virus became seriously ill or died.
To that end, an “antibody survey” funded by the National Institutes of Health is enrolling 10,000 volunteers across the U.S. and, according to media reports, is scheduled to begin later this year. Meanwhile, WHO is providing countries with early protocol and technical support for sero-epidemiological studies and is launching a multi-country antibody testing study called SOLIDARITY II.
Many believe antibody tests can also be used to return immunized people to work or keep them there, starting with health care professionals and emergency personnel.
Krammer suggested that staffing nursing homes with immune workers could reduce their high case fatality rates, for example.
"I think it makes sense that if immunity is building and we have, say, 50% of people immune to this, then we have much less chance of the virus spreading," said Melanie Ott, a senior researcher at the Gladstone Institute of Virology. and Immunology in San Francisco.
Along these lines, media outlets have reported that researchers in Germany and Italy will conduct and study large-scale antibody testing, with Germany planning to issue "immunity certificates" to transition its citizens toward the end of the virus. isolation.
Allowing people to re-enter society based on their antibody status assumes that prior infection protects against reinfection, something researchers said was likely but not yet well defined. "How broad, long-lasting and effective this immune response is is still unclear ," Ott said.
Scientists around the world will work to understand what type of protection it provides, both in the laboratory and by following recovered patients to see if reinfections occur. So far, the new coronavirus does not appear to mutate quickly. This, along with experience with other viral infections, suggests that people with SARS-CoV-2 antibodies may be protected at least for some time.
However, there is another potential problem. Individuals can be PCR positive even after antibodies develop.
"The question is, is it the live virus that we’re detecting? Is it replicating? And is it transmissible? And I think that’s still an unknown ," Theel said. Coupling a positive antibody test with a negative PCR result could reduce the chance of people who are still contagious re-entering society.
Ultimately, a positive antibody test could be a kind of get-out-of-isolation card.
"In the long term, I think it would be good to provide this to the entire population because whoever is immune could basically go back to normal life because they can’t infect anyone else ," Krammer said.
For now, he warned that new coronavirus infections are probably not yet widespread among the general population of the United States, which is right at the "beginning of a major epidemic." But as more people become infected and immunized, they could help boost the economy by returning to work. They could also potentially provide practical support to people vulnerable to severe infection, until a vaccine arrives.
In early April, Cordon-Cardo said Mount Sinai would likely expand the use of its trial beyond experimental therapies to test on health care workers. And at the Mayo Clinic, clinical antibody testing began in mid-April.
| If these applications are followed by a rollout of widespread antibody testing for the general public, they could lead to a gradual reopening of society to a world changed by COVID-19. |
