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.
As a type 2 diabetic, Michael Snyder has long been interested in how blood sugar levels vary from one person to another in response to the same food, and whether a more personalized approach to nutrition could help tackle the rapidly cascading levels of diabetes and obesity in much of the western world.
Eight years ago, Snyder, who directs the Center for Genomics and Personalized Medicine at Stanford University, decided to put his theories to the test. In the 2000s continuous glucose monitoring, or CGM, had begun to revolutionize the lives of diabetics, both type 1 and type 2. Using spherical sensors which sit on the upper arm or abdomen – with tiny wires that pierce the skin – the technology allowed patients to gain real-time updates on their blood sugar levels, transmitted directly to their phone.
It gave Snyder an idea for his research at Stanford. Applying the same technology to a group of apparently healthy people, and looking for ‘spikes’ or sudden surges in blood sugar known as hyperglycemia, could provide a means of observing how their bodies reacted to an array of foods.
“We discovered that different foods spike people differently,” he says. “Some people spike to pasta, others to bread, others to bananas, and so on. It’s very personalized and our feeling was that building programs around these devices could be extremely powerful for better managing people’s glucose.”
Unbeknown to Snyder at the time, thousands of miles away, a group of Israeli scientists at the Weizmann Institute of Science were doing exactly the same experiments. In 2015, they published a landmark paper which used CGM to track the blood sugar levels of 800 people over several days, showing that the biological response to identical foods can vary wildly. Like Snyder, they theorized that giving people a greater understanding of their own glucose responses, so they spend more time in the normal range, may reduce the prevalence of type 2 diabetes.
The commercial potential of such apps is clear, but the underlying science continues to generate intriguing findings.
“At the moment 33 percent of the U.S. population is pre-diabetic, and 70 percent of those pre-diabetics will become diabetic,” says Snyder. “Those numbers are going up, so it’s pretty clear we need to do something about it.”
Fast forward to 2022,and both teams have converted their ideas into subscription-based dietary apps which use artificial intelligence to offer data-informed nutritional and lifestyle recommendations. Snyder’s spinoff, January AI, combines CGM information with heart rate, sleep, and activity data to advise on foods to avoid and the best times to exercise. DayTwo–a start-up which utilizes the findings of Weizmann Institute of Science–obtains microbiome information by sequencing stool samples, and combines this with blood glucose data to rate ‘good’ and ‘bad’ foods for a particular person.
“CGMs can be used to devise personalized diets,” says Eran Elinav, an immunology professor and microbiota researcher at the Weizmann Institute of Science in addition to serving as a scientific consultant for DayTwo. “However, this process can be cumbersome. Therefore, in our lab we created an algorithm, based on data acquired from a big cohort of people, which can accurately predict post-meal glucose responses on a personal basis.”
The commercial potential of such apps is clear. DayTwo, who market their product to corporate employers and health insurers rather than individual consumers, recently raised $37 million in funding. But the underlying science continues to generate intriguing findings.
Last year, Elinav and colleagues published a study on 225 individuals with pre-diabetes which found that they achieved better blood sugar control when they followed a personalized diet based on DayTwo’s recommendations, compared to a Mediterranean diet. The journal Cell just released a new paper from Snyder’s group which shows that different types of fibre benefit people in different ways.
“The idea is you hear different fibres are good for you,” says Snyder. “But if you look at fibres they’re all over the map—it’s like saying all animals are the same. The responses are very individual. For a lot of people [a type of fibre called] arabinoxylan clearly reduced cholesterol while the fibre inulin had no effect. But in some people, it was the complete opposite.”
Eight years ago, Stanford's Michael Snyder began studying how continuous glucose monitors could be used by patients to gain real-time updates on their blood sugar levels, transmitted directly to their phone.
The Snyder Lab, Stanford Medicine
Because of studies like these, interest in precision nutrition approaches has exploded in recent years. In January, the National Institutes of Health announced that they are spending $170 million on a five year, multi-center initiative which aims to develop algorithms based on a whole range of data sources from blood sugar to sleep, exercise, stress, microbiome and even genomic information which can help predict which diets are most suitable for a particular individual.
“There's so many different factors which influence what you put into your mouth but also what happens to different types of nutrients and how that ultimately affects your health, which means you can’t have a one-size-fits-all set of nutritional guidelines for everyone,” says Bruce Y. Lee, professor of health policy and management at the City University of New York Graduate School of Public Health.
With the falling costs of genomic sequencing, other precision nutrition clinical trials are choosing to look at whether our genomes alone can yield key information about what our diets should look like, an emerging field of research known as nutrigenomics.
The ASPIRE-DNA clinical trial at Imperial College London is aiming to see whether particular genetic variants can be used to classify individuals into two groups, those who are more glucose sensitive to fat and those who are more sensitive to carbohydrates. By following a tailored diet based on these sensitivities, the trial aims to see whether it can prevent people with pre-diabetes from developing the disease.
But while much hope is riding on these trials, even precision nutrition advocates caution that the field remains in the very earliest of stages. Lars-Oliver Klotz, professor of nutrigenomics at Friedrich-Schiller-University in Jena, Germany, says that while the overall goal is to identify means of avoiding nutrition-related diseases, genomic data alone is unlikely to be sufficient to prevent obesity and type 2 diabetes.
“Genome data is rather simple to acquire these days as sequencing techniques have dramatically advanced in recent years,” he says. “However, the predictive value of just genome sequencing is too low in the case of obesity and prediabetes.”
Others say that while genomic data can yield useful information in terms of how different people metabolize different types of fat and specific nutrients such as B vitamins, there is a need for more research before it can be utilized in an algorithm for making dietary recommendations.
“I think it’s a little early,” says Eileen Gibney, a professor at University College Dublin. “We’ve identified a limited number of gene-nutrient interactions so far, but we need more randomized control trials of people with different genetic profiles on the same diet, to see whether they respond differently, and if that can be explained by their genetic differences.”
Some start-ups have already come unstuck for promising too much, or pushing recommendations which are not based on scientifically rigorous trials. The world of precision nutrition apps was dubbed a ‘Wild West’ by some commentators after the founders of uBiome – a start-up which offered nutritional recommendations based on information obtained from sequencing stool samples –were charged with fraud last year. The weight-loss app Noom, which was valued at $3.7 billion in May 2021, has been criticized on Twitter by a number of users who claimed that its recommendations have led to them developed eating disorders.
With precision nutrition apps marketing their technology at healthy individuals, question marks have also been raised about the value which can be gained through non-diabetics monitoring their blood sugar through CGM. While some small studies have found that wearing a CGM can make overweight or obese individuals more motivated to exercise, there is still a lack of conclusive evidence showing that this translates to improved health.
However, independent researchers remain intrigued by the technology, and say that the wealth of data generated through such apps could be used to help further stratify the different types of people who become at risk of developing type 2 diabetes.
“CGM not only enables a longer sampling time for capturing glucose levels, but will also capture lifestyle factors,” says Robert Wagner, a diabetes researcher at University Hospital Düsseldorf. “It is probable that it can be used to identify many clusters of prediabetic metabolism and predict the risk of diabetes and its complications, but maybe also specific cardiometabolic risk constellations. However, we still don’t know which forms of diabetes can be prevented by such approaches and how feasible and long-lasting such self-feedback dietary modifications are.”
Snyder himself has now been wearing a CGM for eight years, and he credits the insights it provides with helping him to manage his own diabetes. “My CGM still gives me novel insights into what foods and behaviors affect my glucose levels,” he says.
He is now looking to run clinical trials with his group at Stanford to see whether following a precision nutrition approach based on CGM and microbiome data, combined with other health information, can be used to reverse signs of pre-diabetes. If it proves successful, January AI may look to incorporate microbiome data in future.
“Ultimately, what I want to do is be able take people’s poop samples, maybe a blood draw, and say, ‘Alright, based on these parameters, this is what I think is going to spike you,’ and then have a CGM to test that out,” he says. “Getting very predictive about this, so right from the get go, you can have people better manage their health and then use the glucose monitor to help follow that.”
Luckily, two college freshmen at the Rotterdam School of Management, Erasmus University, were naïve enough to take their bicycles to the scrapyard. In a previous stroke of fortune, the freshmen, Adrian Goosses and Michael Widmann, had been assigned as roommates and had quickly hit it off. Now they were looking for a cool recycling project for their first semester “strategic entrepreneurship” course—maybe they could turn old tires into comfortable lounge chairs, they thought.
“Everybody gets around by bike in Rotterdam,” says Goosses, now 32, from his home in Cologne, Germany. “The tires were way too heavy and cumbersome to transport by bike,” Widmann chimes in via Zoom from Bolzano, Italy, where he lives.
Sifting through the car trash for something handier led the two students to an idea that has since flourished: Could the airbag and seatbelts from a banged up compact car be salvaged and turned into a sustainable backpack? The size of the airbag was already a natural fit. The seatbelts made perfect shoulder straps. After returning from the scrapyard, “We stitched the prototype together by hand with a needle and yarn,” says Goosses. “Yet we didn’t even know how to sew!”
Much to their surprise, their classmates responded with so much enthusiasm to their “trash bag” concept that it convinced the two innovators to keep going. Every semester, they improved the prototype further. With the help of YouTube videos, they taught themselves how to sew. Because modern electric sewing machines had a difficult time breaking through the tough nylon of the airbags, Goosses and Widmann went to a second-hand shop and purchased an ancient Singer from 1880 for 10 Euros. They dyed the first airbags in a saucepan in the garden outside of the apartment they shared.
“By the time we graduated, we had a presentable prototype and a business plan,” Goosses says.
Despite their progress, Goosses and Widmann are up against a problem that’s immense: Cars are notoriously difficult to recycle because many parts are considered toxic waste.
It’s an example of “upcycling,” when you spot a potential new use in something that’s been trashed, shelved or otherwise retired. The approach has received increasing attention and support from the U.S. Environmental Protection Agency and others to boost sustainability in all kinds of areas, from fashion (where even luxury brands like Balenciaga or Coach repurpose vintage clothing and bags) to architecture, where reusing wood, steel and bricks significantly reduces a building’s carbon footprint.
In addition to helping the planet, those who do it well can make a living from it. These days, Goosses and Widmann own a flourishing company: Airpaq. A crowdfunding campaign in 2017 yielded 70,000 Euros to get them started. Since then, they have upcycled 80,000 airbags, 100,000 seatbelts and 28,000 belt buckles – the equivalent of 60 tons of car trash.
For the successful upcycling, they received the 2021 German Design Award and, earlier this year, the renowned German Sustainability Award. The jurors evaluating the product commented that the startup “convinced us not only because of their uncompromising quality and functionality but also because of their ecological and ethical values….How well the startup translates upcycling and green fashion into an urban lifestyle brand is impressive.”
Despite their progress, Goosses and Widmann are up against a problem that’s immense: Cars are notoriously difficult to recycle because many parts are considered toxic waste. Therefore, up to 25% of vehicle scraps get shredded every year in Germany alone, the equivalent of over 501,000 tons. Because airbags and seatbelts are nearly indestructible, they are costly to recycle and almost always end up in landfills. Given that airbags and seatbelts save lives, they are subject to stringent security regulations, and manufacturers have a sky-high reject rate. “If a tiny filament protrudes somewhere, the manufacturer will throw out the entire output,” Widmann explains.
The nearly indestructible qualities that make this material very difficult to recycle render it an excellent resource for backpacks. “The material is so durable, you almost cannot tear it,” Goosses adds and demonstrates with a hard tug that even when the material already has a hole, it won’t rip it further. The material is also water repellent and extremely light.
The antique Singer is still in their Cologne headquarters but only as decoration. Their company with 12 employees is producing 500 backpacks and fanny packs every week in Romania, where the parts are professionally cut by laser, dyed and sewed. Airpaq still procures the belt buckles at scrapyards but they get most of the airbags directly from the reject pile of a nearby airbag producer. “We process the materials where they are produced,” Goosses explains. Only about 15 miles lie between one of Europe’s biggest airbag manufacturers and the Airpaq seamsters in Romania.
Co-founders Adrian Goosses and Michael Widmann demonstrate their company's equation: airbag plus seatbelt equals a backpack that's durable and eco-friendly.
Airpaq
The founders are aware that with price tags ranging from 100 to 160 Euro - a cost that reflects their intensive production process - Airpaq’s bags are hardly competitive. After all, anybody can buy a discount backpack for a fraction of the cost. So they recently added fanny packs for 30 Euro to their product line. Goosses and Widmann know they will need to lower their prices in the long run if they want to expand. Among other things, they didn’t pay themselves salaries during the first two years after founding the company.
Money-making isn’t their only objective. “Of course, it would be cheaper if we did what almost all textile producers do and move production to Asia,” Goosses says. That wasn’t an option for him. “Ship trash to Vietnam and let seamsters sew it together for cheap? No way, that would be anything but sustainable,” he says.
Michael Widmann’s family was already operating a textile production in Romania, mainly producing thin, elastic sports fashion. The family allowed Widmann and Goosses to produce their first professional prototypes there, but then the two youngsters had to buy their own machines, acquire the necessary knowhow, and hire their staff. They both moved to Romania for six months “to get to know the people behind the machines.” The founders emphasize that they pay fair wages, use eco-certified dyes and clean their own wastewater. “Normal production uses five to six liters of water per kilo material,” Widmann explains. “We only need a fraction because we massage the dye into the material by hand: 100 ml water for washing and dying per kilo.”
However, every time they return to the scrapyard, the abundance of trash sparks new ideas. “When you see how much material ends up there…” Widmann says, shaking his head without finishing the sentence. Goosses picks up the train of thought: “We want to make upcycling the new standard. You just have to be creative to get upcycling into the mainstream.”
And maybe they’ll return to their roots and finally find an idea for the tires after all. “One could turn the rubber into soles for comfortable shoes,” Widmann thinks out loud.