testing

Antibody Testing Alone is Not the Key to Re-Opening Society

COVID-19 OPINION ESSAY
Antibody Testing Alone is Not the Key to Re-Opening Society

Immunity tests have too many unknowns right now to make them very useful in determining protective antibody status.

(© tilialucida and Grispb/Adobe)


[Editor's Note: We asked experts from different specialties to weigh in on a timely Big Question: "How should immunity testing play a role in re-opening society?" Below, a virologist offers her perspective.]

With the advent of serology testing and increased emphasis on "re-opening" America, public health officials have begun considering whether or not people who have recovered from COVID-19 can safely re-enter the workplace.
"Immunity certificates cannot certify what is not known."

Conventional wisdom holds that people who have developed antibodies in response to infection with SARS-CoV-2, the coronavirus that causes COVID-19, are likely to be immune to reinfection.

For most acute viral infections, this is generally true. However, SARS-CoV-2 is a new pathogen, and there are currently many unanswered questions about immunity. Can recovered patients be reinfected or transmit the virus? Does symptom severity determine how protective responses will be after recovery? How long will protection last? Understanding these basic features is essential to phased re-opening of the government and economy for people who have recovered from COVID-19.

One mechanism that has been considered is issuing "immunity certificates" to individuals with antibodies against SARS-CoV-2. These certificates would verify that individuals have already recovered from COVID-19, and thus have antibodies in their blood that will protect them against reinfection, enabling them to safely return to work and participate in society. Although this sounds reasonable in theory, there are many practical reasons why this is not a wise policy decision to ease off restrictive stay-home orders and distancing practices.

Too Many Scientific Unknowns

Serology tests measure antibodies in the serum—the liquid component of blood, which is where the antibodies are located. In this case, serology tests measure antibodies that specifically bind to SARS-CoV-2 virus particles. Usually when a person is infected with a virus, they develop antibodies that can "recognize" that virus, so the presence of SARS-CoV-2 antibodies indicates that a person has been previously exposed to the virus. Broad serology testing is critical to knowing how many people have been infected with SARS-CoV-2, since testing capacity for the virus itself has been so low.

Tests for the virus measure amounts of SARS-CoV-2 RNA—the virus's genetic material—directly, and thus will not detect the virus once a person has recovered. Thus, the majority of people who were not severely ill and did not require hospitalization, or did not have direct contact with a confirmed case, will not test positive for the virus weeks after they have recovered and can only determine if they had COVID-19 by testing for antibodies.

In most cases, for most pathogens, antibodies are also neutralizing, meaning they bind to the virus and render it incapable of infecting cells, and this protects against future infections. Immunity certificates are based on the assumption that people with antibodies specific for SARS-CoV-2 will be protected against reinfection. The problem is that we've only known that SARS-CoV-2 existed for a little over four months. Although studies so far indicate that most (but not all) patients with confirmed COVID-19 cases develop antibodies, we don't know the extent to which antibodies are protective against reinfection, or how long that protection will last. Immunity certificates cannot certify what is not known.

The limited data so far is encouraging with regard to protective immunity. Most of the patient sera tested for antibodies show reasonable titers of IgG, the type of antibodies most likely to be neutralizing. Furthermore, studies have shown that these IgG antibodies are capable of neutralizing surrogate viruses as well as infectious SARS-CoV-2 in laboratory tests. In addition, rhesus monkeys that were experimentally infected with SARS-CoV-2 and allowed to recover were protected from reinfection after a subsequent experimental challenge. These data tentatively suggest that most people are likely to develop neutralizing IgG, and protective immunity, after being infected by SARS-CoV-2.

However, not all COVID-19 patients do produce high levels of antibodies specific for SARS-CoV-2. A small number of patients in one study had no detectable neutralizing IgG. There have also been reports of patients in South Korea testing PCR positive after a prior negative test, indicating reinfection or reactivation. These cases may be explained by the sensitivity of the PCR test, and no data have been produced to indicate that these cases are genuine reinfection or recurrence of viral infection.

Complicating matters further, not all serology tests measure antibody titers. Some rapid serology tests are designed to be binary—the test can either detect antibodies or not, but does not give information about the amount of antibodies circulating. Based on our current knowledge, we cannot be certain that merely having any level of detectable antibodies alone guarantees protection from reinfection, or from a subclinical reinfection that might not cause a second case of COVID-19, but could still result in transmission to others. These unknowns remain problematic even with tests that accurately detect the presence of antibodies—which is not a given today, as many of the newly available tests are reportedly unreliable.

A Logistical and Ethical Quagmire

While most people are eager to cast off the isolation of physical distancing and resume their normal lives, mere desire to return to normality is not an indicator of whether those antibodies actually work, and no certificate can confer immune protection. Furthermore, immunity certificates could lead to some complicated logistical and ethical issues. If antibodies do not guarantee protective immunity, certifying that they do could give antibody-positive people a false sense of security, causing them to relax infection control practices such as distancing and hand hygiene.

"We should not, however, place our faith in assumptions and make return to normality contingent on an arbitrary and uninformative piece of paper."

Certificates could be forged, putting susceptible people at higher exposure risk. It's not clear who would issue them, what they would entitle the bearer to do or not do, or how certification would be verified or enforced. There are many ways in which such certificates could be used as a pretext to discriminate against people based on health status, in addition to disability, race, and socioeconomic status. Tracking people based on immune status raises further concerns about privacy and civil rights.

Rather than issuing documents confirming immune status, we should instead "re-open" society cautiously, with widespread virus and serology testing to accurately identify and isolate infected cases rapidly, with immediate contact tracing to safely quarantine and monitor those at exposure risk. Broad serosurveillance must be coupled with functional assays for neutralization activity to begin assessing how protective antibodies might actually be against SARS-CoV-2 infection. To understand how long immunity lasts, we should study antibodies, as well as the functional capabilities of other components of the larger immune system, such as T cells, in recovered COVID-19 patients over time.

We should not, however, place our faith in assumptions and make return to normality contingent on an arbitrary and uninformative piece of paper. Re-opening society, the government, and the economy depends not only on accurately determining how many people have antibodies to SARS-CoV-2, but on a deeper understanding of how those antibodies work to provide protection.

Angela Rasmussen
Dr. Angela Rasmussen uses systems biology techniques to interrogate the host response to viral infection. She has studied a huge range of viral pathogens, from the “common cold” (rhinovirus) to Ebola virus to highly pathogenic avian influenza virus to SARS-CoV-2/COVID-19. By combining current classical approaches to modeling infection and pathogenesis with sequencing technology and machine learning, Dr. Rasmussen and her colleagues and collaborators have identified new host mechanisms by which viruses cause disease.
Leaps of the Past

How thousands of first- and second-graders saved the world from a deadly disease

History Feature Story
How thousands of first- and second-graders saved the world from a deadly disease

Although Jonas Salk has gone down in history for helping rid the world (almost) of polio, his revolutionary vaccine wouldn't have been possible without the world’s largest clinical trial – and the bravery of thousands of kids.

Photo by Charlein Gracia on Unsplash

Exactly 67 years ago, in 1955, a group of scientists and reporters gathered at the University of Michigan and waited with bated breath for Dr. Thomas Francis Jr., director of the school’s Poliomyelitis Vaccine Evaluation Center, to approach the podium. The group had gathered to hear the news that seemingly everyone in the country had been anticipating for the past two years – whether the vaccine for poliomyelitis, developed by Francis’s former student Jonas Salk, was effective in preventing the disease.

Polio, at that point, had become a household name. As the highly contagious virus swept through the United States, cities closed their schools, movie theaters, swimming pools, and even churches to stop the spread. For most, polio presented as a mild illness, and was usually completely asymptomatic – but for an unlucky few, the virus took hold of the central nervous system and caused permanent paralysis of muscles in the legs, arms, and even people’s diaphragms, rendering the person unable to walk and breathe. It wasn’t uncommon to hear reports of people – mostly children – who fell sick with a flu-like virus and then, just days later, were relegated to spend the rest of their lives in an iron lung.

Keep Reading Keep Reading
Sarah Watts

Sarah Watts is a health and science writer based in Chicago.

tech

Why you should (virtually) care

OPINION ESSAY Health
Why you should (virtually) care

Virtual-first care, or V1C, could increase the quality of healthcare and make it more patient-centric by letting patients combine in-person visits with virtual options such as video for seeing their care providers.

(© Elnur/Fotolia)

As the pandemic turns endemic, healthcare providers have been eagerly urging patients to return to their offices to enjoy the benefits of in-person care.

But wait.

The last two years have forced all sorts of organizations to be nimble, adaptable and creative in how they work, and this includes healthcare providers’ efforts to maintain continuity of care under the most challenging of conditions. So before we go back to “business as usual,” don’t we owe it to those providers and ourselves to admit that business as usual did not work for most of the people the industry exists to help? If we’re going to embrace yet another period of change – periods that don’t happen often in our complex industry – shouldn’t we first stop and ask ourselves what we’re trying to achieve?

Certainly, COVID has shown that telehealth can be an invaluable tool, particularly for patients in rural and underserved communities that lack access to specialty care. It’s also become clear that many – though not all – healthcare encounters can be effectively conducted from afar. That said, the telehealth tactics that filled the gap during the pandemic were largely stitched together substitutes for existing visit-based workflows: with offices closed, patients scheduled video visits for help managing the side effects of their blood pressure medications or to see their endocrinologist for a quarterly check-in. Anyone whose children slogged through the last year or two of remote learning can tell you that simply virtualizing existing processes doesn’t necessarily improve the experience or the outcomes!

But what if our approach to post-pandemic healthcare came from a patient-driven perspective? We have a fleeting opportunity to advance a care model centered on convenient and equitable access that first prioritizes good outcomes, then selects approaches to care – and locations – tailored to each patient. Using the example of education, imagine how effective it would be if each student, regardless of their school district and aptitude, received such individualized attention.

Keep Reading Keep Reading
Jennifer C. Goldsack & Linette Demers
Jennifer C. Goldsack co-founded and serves as the CEO of the Digital Medicine Society (DiMe), a 501(c)(3) non-profit organization dedicated to advancing digital medicine to optimize human health. Jennifer’s research focuses on applied approaches to the safe, effective, and equitable use of digital technologies to improve health, healthcare, and health research. She is a member of the Roundtable on Genomics and Precision Health at the National Academies of Science, Engineering and Medicine and serves on the World Economic Forum Global Leadership Council on mental health. Previously, Jennifer spent several years at the Clinical Trials Transformation Initiative (CTTI), a public-private partnership co-founded by Duke University and the FDA. There, she led development and implementation of several projects within CTTI’s Digital Program and was the operational co-lead on the first randomized clinical trial using FDA’s Sentinel System. Jennifer spent five years working in research at the Hospital of the University of Pennsylvania, first in Outcomes Research in the Department of Surgery and later in the Department of Medicine. More recently, she helped launch the Value Institute, a pragmatic research and innovation center embedded in a large academic medical center in Delaware. Jennifer earned her master’s degree in chemistry from the University of Oxford, England, her masters in the history and sociology of medicine from the University of Pennsylvania, and her MBA from the George Washington University. Additionally, she is a certified Lean Six Sigma Green Belt and a Certified Professional in Healthcare Quality. Jennifer is a retired athlete, formerly a Pan American Games Champion, Olympian, and World Championship silver medalist. ___________________________________________________________________________ Linette Demers leads IMPACT, a DiMe initiative dedicated to advancing high value, evidence-based virtual first care for patients, healthcare providers, and payers. Previously, Linette was responsible for commercialization, entrepreneurship and capital formation programs at Life Science Washington and WINGS Angels. Her 20 year career in healthcare spans strategy, business development, and population health management in oncology care at Fred Hutch, and management consulting at Sg2. Linette holds a PhD in Chemistry and a BS in Health Economics and Outcomes Research.