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.
[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.
Will religious people reject organ transplants from pigs?
Scientists are getting better at transplanting pig organs into humans. But religious followers of prohibitions on consuming pork may reject these organs, even if their bodies could accept them.
The first successful recipient of a human heart transplant lived 18 days. The first artificial heart recipient lived just over 100.
Their brief post-transplant lives paved the way toward vastly greater successes. Former Vice President Dick Cheney relied on an artificial heart for nearly two years before receiving a human heart transplant. It still beats in his chest more than a decade later.
Organ transplantation recently reached its next phase with David Bennett. He survived for two months after becoming the first recipient of a pig’s heart genetically modified to function in a human body in February. Known as a xenotransplant, the procedure could pave the way for greatly expanding the use of transplanted vital organs to extend human lives.
Clinical trials would have to be held in the U.S. before xenotransplants become widespread; Bennett’s surgery was authorized under a special Food and Drug Administration program that addresses patients with life-threatening medical conditions.
German researchers plan to perform eight pig-to-human heart transplants as part of a clinical trial beginning in 2024. According to an email sent to Leaps.org by three scholars working on the German project, these procedures will focus on one of the reasons David Bennett did not survive longer: A porcine infection from his new heart.
The transplant team will conduct more sensitive testing of the donor organs, “which in all likelihood will be able to detect even low levels of virus in the xenograft,” note the scientists, Katharina Ebner, Jochen Ostheimer and Jochen Sautermeister. They are confident that the risk of infection with a porcine virus in the future will be significantly lower.
Moreover, hearts are not the only genetically modified organs that are being xenotransplanted. A team of surgeons at the University of Alabama at Birmingham successfully transplanted genetically modified pig kidneys into a brain-dead human recipient in September. The kidneys functioned normally for more than three days before the experiment ended. The UAB team is now moving forward with clinical trials focusing on transplanting pig kidneys into human patients.
Some experts believe the momentum for xenotransplantation is building, particularly given the recent successes. “I think there is a strong likelihood this will go mainstream,” says Brendan Parent of NYU Langone Health.
Douglas Anderson, a surgeon who is part of that kidney xenotransplant team, observes that, “organ shortages have been the major issue facing transplantation since its inception” and that xenotransplantation is a potential solution to that quandary. “It can’t be understated the number of people waiting for a kidney on dialysis, which has a significant mortality rate,” he says. According to the advocacy group Donate Life America, more than 100,000 people in the U.S. alone are waiting for a donated organ, and 85 percent of them need a kidney.
Other experts believe the momentum for xenotransplantation is building, particularly given the recent successes. “I think there is a strong likelihood this will go mainstream,” says Brendan Parent, director of transplant ethics and policy at NYU Langone Health, a New York City-based hospital system. Like the UAB team, surgeons at NYU Langone have had success coaxing modified pig kidneys to work in deceased humans.
“There is a genuinely good chance that within a generation, (xenotransplantation) might become very common in reasonably wealthy countries,” says Michael Reiss, professor of science education at University College in London. In addition to his academic position, Reiss sits on the Nuffield Council on Bioethics, a nonprofit that is one of Britain’s most prominent watchdogs regarding medical and scientific issues. Reiss is also an Anglican priest and has studied xenotransplantation from both a scientific and religious point of view.
Moreover, genetic modifications could one day lead to organs being specifically optimized for their recipients. That could ensure issues like donor rejection and the calculated risk of artificially suppressing recipient immune systems become concerns of the past.
Major bioethical, religious concerns
Despite the promise of xenotransplantation, numerous bioethical issues swirl around the procedure. They could be magnified if xenotransplantation evolves from one-off experiments to a routine medical procedure.
One of the biggest is the millennia-long prohibitions Islam and Judaism have had regarding the consumption of pork. Will followers of these religions assume such rules extend to those taboo materials being inserted into a human body?
“Initially, one’s instinctual reaction is that, oh, crumbs! – how are Jews and Muslims going to react to that?” Reiss says. But in a world where science and secularism are accepted on an everyday basis, he notes it is not a significant issue. Reiss points out that valves from pig hearts have been used in human patients for decades without any issues. He adds that both Islam and Judaism waive religious dietary restrictions if a human life is at risk.
“While nobody's saying an individual patient is to be forced to have these, the very high proportion of people who identify as Jews or Muslims when given this option are content with it,” he says.
Concurring with Reiss is Michael Gusamano, professor of health policy at Lehigh University and director of its Center for Ethics. He is currently performing research on the ethics of xenotransplantation for the National Institutes of Health.
“Leaders from all major religions have commented on this and have indicated that this is not inconsistent with religious doctrine,” Gusamano says in written remarks to Leaps.org. “Having said that, it is plausible to believe that some people will assume that this is inconsistent with the teaching of their religion and may object to…receiving a xenotransplant as part of routine medical care.”
A history of clashes
Despite those assurances, science has long clashed with theology. Although Galileo proved the planets revolved around the sun, the Catholic Church found him guilty of heresy and rewarded his discovery with house arrest for the last decade of his life. A revolt occurred in mid-19th century India after native-born soldiers believed the ammunition supplied by their British occupiers had been lubricated with pork and beef tallow. Given they had to use their mouths to tear open ammunition pouches, this violated both the tenets of Islam and Hinduism. And one of the conspiracy theories hatched as a result of COVID-19 was that the vaccines developed to fight the disease were the “mark of the beast” – a sign of impending Armageddon under evangelical Christian theology.
The German xenotransplant research team has encountered such potential concerns when the procedure is regarded through a religious lens. “The pastors in our research suspected that many recipients might feel disgust and revulsion,” they write. “Even beyond these special religious reservations, cultural scripts about pigs as inferior living beings are also generally widespread and effective in the western world, so that here too possible disgust reactions cannot be ruled out.”
The German researchers add that “Jewish and Muslim hospital pastoral workers believe possible considerable problems in this respect, which must be dealt with psychosocially, religiously, and pastorally prior to a possible transplantation in order to strengthen the acceptance of the received organ by the patients and their relatives.”
Parent, the director at NYU Langone, shares a concern that xenotransplantation could move “too fast,” although much of his worry is focused on zoonotic disease transmission – pig viruses jumping into humans as a result of such procedures.
Another ethical issue
Moreover, the way pigs and other animals are raised for transplants could pose future ethical dilemmas.
Reiss notes that pigs raised for medical procedures have to be grown and kept in what are known as a designated pathogen-free facility, or DPF. Such facilities are kept painstakingly antiseptic so as to minimize the risk of zoonotic transmissions. But given pigs are fond of outdoor activities such as wallowing in mud and sleeping on hay, they lead “stunningly boring lives” that they probably do not enjoy, Reiss observes.
Ethical concerns with using pigs may push transplantation medicine into its next logical phase: Growing functional organs for transplant in a laboratory setting.
“There’s no doubt that these research pigs have gotten much better veterinary care, et cetera, (compared to farmed pigs). But it’s not a great life,” Reiss says. “And although it hasn’t so far dominated the discussion, I think as the years go by, rather as we’ve seen with the use of apes and now monkeys in medical research, more and more theologians will get uncomfortable about us just assuming we can do this with…pigs.”
The German research team raises the same concerns, but has taken a fairly sanguine view on the topic. “The impairments of the species-typical behavior will certainly provoke criticism and perhaps also public protest. But the number of animals affected is very small in relation to slaughter cattle,” the German researchers note. “Moreover, the conditions there and also in several animal experiments are far worse.”
Observers say that may push transplantation medicine into its next logical phase: Growing functional organs for transplant in a laboratory setting. Anderson, the UAB transplant surgeon, believes such an accomplishment remains decades away.
But other experts believe there is a moral imperative that xenotransplantation remain a temporary solution. “I think we have a duty to go in that direction,” Parent says. “We have to go that way, with the xenotransplantation process (as) a steppingstone and research path that will be useful for bioengineered organs.”
The Friday Five: Scientists treated this girl's disease before she was born
In this week's Friday Five, scientists treated this girl's rare diseases in utero. Plus, how to lift weights in half the time, electric shocks help people regain the ability to walk, meditation is found to work as well as medication, and much more.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Kids treated for diseases before they're born
- How to lift weights in half the time
- Electric shocks help people regain the ability to walk
- Meditation just as good as medication?
- These foods could pump up your motivation