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.
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman