Antibody Testing Alone is Not the Key to Re-Opening Society
[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.
Genes that protect health with Dr. Nir Barzilai
In today’s podcast episode, I talk with Nir Barzilai, a geroscientist, which means he studies the biology of aging. Barzilai directs the Institute for Aging Research at the Albert Einstein College of Medicine.
My first question for Dr. Barzilai was: why do we age? And is there anything to be done about it? His answers were encouraging. We can’t live forever, but we have some control over the process, as he argues in his book, Age Later.
Dr. Barzilai told me that centenarians differ from the rest of us because they have unique gene mutations that help them stay healthy longer. For most of us, the words “gene mutations” spell trouble - we associate these words with cancer or neurodegenerative diseases, but apparently not all mutations are bad.
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Centenarians may have essentially won the genetic lottery, but that doesn’t mean the rest of us are predestined to have a specific lifespan and health span, or the amount of time spent living productively and enjoyably. “Aging is a mother of all diseases,” Dr. Barzilai told me. And as a disease, it can be targeted by therapeutics. Dr. Barzilai’s team is already running clinical trials on such therapeutics — and the results are promising.
More about Dr. Barzilai: He is scientific director of AFAR, American Federation for Aging Research. As part of his work, Dr. Barzilai studies families of centenarians and their genetics to learn how the rest of us can learn and benefit from their super-aging. He also organizing a clinical trial to test a specific drug that may slow aging.
Show Links
Age Later: Health Span, Life Span, and the New Science of Longevity https://www.amazon.com/Age-Later-Healthiest-Sharpest-Centenarians/dp/1250230853
American Federation for Aging Research https://www.afar.org
https://www.afar.org/nir-barzilai
https://www.einsteinmed.edu/faculty/484/nir-barzilai/
Metformin as a Tool to Target Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
Benefits of Metformin in Attenuating the Hallmarks of Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/
The Longevity Genes Project https://www.einsteinmed.edu/centers/aging/longevity-genes-project/
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Awash in a fluid finely calibrated to keep it alive, a human eye rests inside a transparent cubic device. This ECaBox, or Eyes in a Care Box, is a one-of-a-kind system built by scientists at Barcelona’s Centre for Genomic Regulation (CRG). Their goal is to preserve human eyes for transplantation and related research.
In recent years, scientists have learned to transplant delicate organs such as the liver, lungs or pancreas, but eyes are another story. Even when preserved at the average transplant temperature of 4 Centigrade, they last for 48 hours max. That's one explanation for why transplanting the whole eye isn’t possible—only the cornea, the dome-shaped, outer layer of the eye, can withstand the procedure. The retina, the layer at the back of the eyeball that turns light into electrical signals, which the brain converts into images, is extremely difficult to transplant because it's packed with nerve tissue and blood vessels.
These challenges also make it tough to research transplantation. “This greatly limits their use for experiments, particularly when it comes to the effectiveness of new drugs and treatments,” said Maria Pia Cosma, a biologist at Barcelona’s Centre for Genomic Regulation (CRG), whose team is working on the ECaBox.
Eye transplants are desperately needed, but they're nowhere in sight. About 12.7 million people worldwide need a corneal transplant, which means that only one in 70 people who require them, get them. The gaps are international. Eye banks in the United Kingdom are around 20 percent below the level needed to supply hospitals, while Indian eye banks, which need at least 250,000 corneas per year, collect only around 45 to 50 thousand donor corneas (and of those 60 to 70 percent are successfully transplanted).
As for retinas, it's impossible currently to put one into the eye of another person. Artificial devices can be implanted to restore the sight of patients suffering from severe retinal diseases, but the number of people around the world with such “bionic eyes” is less than 600, while in America alone 11 million people have some type of retinal disease leading to severe vision loss. Add to this an increasingly aging population, commonly facing various vision impairments, and you have a recipe for heavy burdens on individuals, the economy and society. In the U.S. alone, the total annual economic impact of vision problems was $51.4 billion in 2017.
Even if you try growing tissues in the petri dish route into organoids mimicking the function of the human eye, you will not get the physiological complexity of the structure and metabolism of the real thing, according to Cosma. She is a member of a scientific consortium that includes researchers from major institutions from Spain, the U.K., Portugal, Italy and Israel. The consortium has received about $3.8 million from the European Union to pursue innovative eye research. Her team’s goal is to give hope to at least 2.2 billion people across the world afflicted with a vision impairment and 33 million who go through life with avoidable blindness.
Their method? Resuscitating cadaveric eyes for at least a month.
If we succeed, it will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo. -- Maria Pia Cosma.
“We proposed to resuscitate eyes, that is to restore the global physiology and function of human explanted tissues,” Cosma said, referring to living tissues extracted from the eye and placed in a medium for culture. Their ECaBox is an ex vivo biological system, in which eyes taken from dead donors are placed in an artificial environment, designed to preserve the eye’s temperature and pH levels, deter blood clots, and remove the metabolic waste and toxins that would otherwise spell their demise.
Scientists work on resuscitating eyes in the lab of Maria Pia Cosma.
Courtesy of Maria Pia Cosma.
“One of the great challenges is the passage of the blood in the capillary branches of the eye, what we call long-term perfusion,” Cosma said. Capillaries are an intricate network of very thin blood vessels that transport blood, nutrients and oxygen to cells in the body’s organs and systems. To maintain the garland-shaped structure of this network, sufficient amounts of oxygen and nutrients must be provided through the eye circulation and microcirculation. “Our ambition is to combine perfusion of the vessels with artificial blood," along with using a synthetic form of vitreous, or the gel-like fluid that lets in light and supports the the eye's round shape, Cosma said.
The scientists use this novel setup with the eye submersed in its medium to keep the organ viable, so they can test retinal function. “If we succeed, we will ensure full functionality of a human organ ex vivo. It will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo,” Cosma added.
A rapidly developing field of regenerative medicine aims to stimulate the body's natural healing processes and restore or replace damaged tissues and organs. But for people with retinal diseases, regenerative medicine progress has been painfully slow. “Experiments on rodents show progress, but the risks for humans are unacceptable,” Cosma said.
The ECaBox could boost progress with regenerative medicine for people with retinal diseases, which has been painfully slow because human experiments involving their eyes are too risky. “We will test emerging treatments while reducing animal research, and greatly accelerate the discovery and preclinical research phase of new possible treatments for vision loss at significantly reduced costs,” Cosma explained. Much less time and money would be wasted during the drug discovery process. Their work may even make it possible to transplant the entire eyeball for those who need it.
“It is a very exciting project,” said Sanjay Sharma, a professor of ophthalmology and epidemiology at Queen's University, in Kingston, Canada. “The ability to explore and monitor regenerative interventions will increasingly be of importance as we develop therapies that can regenerate ocular tissues, including the retina.”
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation.
But is the world ready for eye transplants? “People are a bit weird or very emotional about donating their eyes as compared to other organs,” Cosma said. And much can be said about the problem of eye donor shortage. Concerns include disfigurement and healthcare professionals’ fear that the conversation about eye donation will upset the departed person’s relatives because of cultural or religious considerations. As just one example, Sharma noted the paucity of eye donations in his home country, Canada.
Yet, experts like Sharma stress the importance of these donations for both the recipients and their family members. “It allows them some psychological benefit in a very difficult time,” he said. So why are global eye banks suffering? Is it because the eyes are the windows to the soul?
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation. In fact, most major religions of the world permit and support organ transplantation and donation, and by extension eye donation, because they unequivocally see it as an “act of neighborly love and charity.” In Hinduism, the concept of eye donation aligns with the Hindu principle of daan or selfless giving, where individuals donate their organs or body after death to benefit others and contribute to society. In Islam, eye donation is a form of sadaqah jariyah, a perpetual charity, as it can continue to benefit others even after the donor's death.
Meanwhile, Buddhist masters teach that donating an organ gives another person the chance to live longer and practice dharma, the universal law and order, more meaningfully; they also dismiss misunderstandings of the type “if you donate an eye, you’ll be born without an eye in the next birth.” And Christian teachings emphasize the values of love, compassion, and selflessness, all compatible with organ donation, eye donation notwithstanding; besides, those that will have a house in heaven, will get a whole new body without imperfections and limitations.
The explanation for people’s resistance may lie in what Deepak Sarma, a professor of Indian religions and philosophy at Case Western Reserve University in Cleveland, calls “street interpretation” of religious or spiritual dogmas. Consider the mechanism of karma, which is about the causal relation between previous and current actions. “Maybe some Hindus believe there is karma in the eyes and, if the eye gets transplanted into another person, they will have to have that karmic card from now on,” Sarma said. “Even if there is peculiar karma due to an untimely death–which might be interpreted by some as bad karma–then you have the karma of the recipient, which is tremendously good karma, because they have access to these body parts, a tremendous gift,” Sarma said. The overall accumulation is that of good karma: “It’s a beautiful kind of balance,” Sarma said.
For the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the already existing body is sacred since it will be the basis of a new refashioned body in an afterlife.---Omar Sultan Haque.
With that said, Sarma believes it is a fallacy to personify or anthropomorphize the eye, which doesn’t have a soul, and stresses that the karma attaches itself to the soul and not the body parts. But for scholars like Omar Sultan Haque—a psychiatrist and social scientist at Harvard Medical School, investigating questions across global health, anthropology, social psychology, and bioethics—the hierarchy of sacredness of body parts is entrenched in human psychology. You cannot equate the pinky toe with the face, he explained.
“The eyes are the window to the soul,” Haque said. “People have a hierarchy of body parts that are considered more sacred or essential to the self or soul, such as the eyes, face, and brain.” In his view, the techno-utopian transhumanist communities (especially those in Silicon Valley) have reduced the totality of a person to a mere material object, a “wet robot” that knows no sacredness or hierarchy of human body parts. “But for the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the [already existing] body is sacred since it will be the basis of a new refashioned body in an afterlife,” Haque said. “You cannot treat the body like any old material artifact, or old chair or ragged cloth, just because materialistic, secular ideologies want so,” he continued.
For Cosma and her peers, however, the very definition of what is alive or not is a bit semantic. “As soon as we die, the electrophysiological activity in the eye stops,” she said. “The goal of the project is to restore this activity as soon as possible before the highly complex tissue of the eye starts degrading.” Cosma’s group doesn’t yet know when they will be able to keep the eyes alive and well in the ECaBox, but the consensus is that the sooner the better. Hopefully, the taboos and fears around the eye donations will dissipate around the same time.