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.
Scientists search for a universal coronavirus vaccine
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has made progress with an early stage universal coronavirus vaccine.
The Covid-19 pandemic had barely begun when VBI Vaccines, a biopharmaceutical company based in Cambridge, Massachusetts, initiated their search for a universal coronavirus vaccine.
It was March 2020, and while most pharmaceutical companies were scrambling to initiate vaccine programs which specifically targeted the SARS-CoV-2 virus, VBI’s executives were already keen to look at the broader picture.
Having observed the SARS and MERS coronavirus outbreaks over the last two decades, Jeff Baxter, CEO of VBI Vaccines, was aware that SARS-CoV-2 is unlikely to be the last coronavirus to move from an animal host into humans. “It's absolutely apparent that the future is to create a vaccine which gives more broad protection against not only pre-existing coronaviruses, but those that will potentially make the leap into humans in future,” says Baxter.
It was a prescient decision. Over the last two years, more biotechs and pharma companies have joined the search to find a vaccine which might be able to protect against all coronaviruses, along with dozens of academic research groups. Last September, the US National Institutes of Health dedicated $36 million specifically to pan-coronavirus vaccine research, while the global Coalition for Epidemic Preparedness Innovations (CEPI) has earmarked $200 million towards the effort.
Until October 2021, the very concept of whether it might be
theoretically possible to vaccinate against multiple coronaviruses remained an open question. But then a groundbreaking study renewed optimism.
The emergence of new variants of Covid-19 over the past year, particularly the highly mutated Omicron variant, has added greater impetus to find broader spectrum vaccines. But until October 2021, the very concept of whether it might be theoretically possible to vaccinate against multiple coronaviruses remained an open question. After all, scientists have spent decades trying to develop a similar vaccine for influenza with little success.
But then a groundbreaking study from renowned virologist Linfa Wang, who runs the emerging infectious diseases program at Duke-National University of Singapore Medical School, provided renewed optimism.
Wang found that eight SARS survivors who had been injected with the Pfizer/BioNTech Covid-19 vaccine had neutralising antibodies in their blood against SARS, the Alpha, Beta and Delta variants of SARS-CoV-2, and five other coronaviruses which reside in bats and pangolins. He concluded that the combination of past coronavirus infection, and immunization with a messenger RNA vaccine, had resulted in a wider spectrum of protection than might have been expected.
“This is a significant study because it showed that pre-existing immunity to one coronavirus could help with the elicitation of cross-reactive antibodies when immunizing with a second coronavirus,” says Kevin Saunders, Director of Research at the Duke Human Vaccine Institute in North Carolina, which is developing a universal coronavirus vaccine. “It provides a strategy to perhaps broaden the immune response against coronaviruses.”
In the next few months, some of the first data is set to emerge looking at whether this kind of antibody response could be elicited by a single universal coronavirus vaccine. In April 2021, scientists at the Walter Reed Army Institute of Research in Silver Spring, Maryland, launched a Phase I clinical trial of their vaccine, with a spokesman saying that it was successful, and the full results will be announced soon.
The Walter Reed researchers have already released preclinical data, testing the vaccine in non-human primates where it was found to have immunising capabilities against a range of Covid-19 variants as well as the original SARS virus. If the Phase I trial displays similar efficacy, a larger Phase II trial will begin later this year.
Two different approaches
Broadly speaking, scientists are taking two contrasting approaches to the task of finding a universal coronavirus vaccine. The Walter Reed Army Institute of Research, VBI Vaccines – who plan to launch their own clinical trial in the summer – and the Duke Human Vaccine Institute – who are launching a Phase I trial in early 2023 – are using a soccer-ball shaped ferritin nanoparticle studded with different coronavirus protein fragments.
VBI Vaccines is looking to elicit broader immune responses by combining SARS, SARS-CoV-2 and MERS spike proteins on the same nanoparticle. Dave Anderson, chief scientific officer at VBI Vaccines, explains that the idea is that by showing the immune system these three spike proteins at the same time, it can help train it to identify and respond to subtle differences between coronavirus strains.
The Duke Human Vaccine Institute is utilising the same method, but rather than including the entire spike proteins from different coronaviruses, they are only including the receptor binding domain (RBD) fragment from each spike protein. “We designed our vaccine to focus the immune system on a site of vulnerability for the virus, which is the receptor binding domain,” says Saunders. “Since the RBD is small, arraying multiple RBDs on a nanoparticle is a straight-forward approach. The goal is to generate immunity to many different subgenuses of viruses so that there will be cross-reactivity with new or unknown coronaviruses.”
But the other strategy is to create a vaccine which contains regions of the viral protein structure which are conserved between all coronavirus strains. This is something which scientists have tried to do for a universal influenza vaccine, but it is thought to be more feasible for coronaviruses because they mutate at a slower rate and are more constrained in the ways that they can evolve.
DIOSynVax, a biotech based in Cambridge, United Kingdom, announced in a press release earlier this month that they are partnering with CEPI to use their computational predictive modelling techniques to identify common structures between all of the SARS coronaviruses which do not mutate, and thus present good vaccine targets.
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has created an early stage vaccine using the fusion peptide region – another part of the coronavirus spike protein that aids the virus’s entry into host cells – which so far appears to be highly conserved between all coronaviruses.
So far Zeichner has trialled this version of the vaccine in pigs, where it provided protection against a different coronavirus called porcine epidemic diarrhea virus, which he described as very promising as this virus is from a different family called alphacoronaviruses, while SARS-CoV-2 is a betacoronavirus.
“If a betacoronavirus fusion peptide vaccine designed from SARS-CoV-2 can protect pigs against clinical disease from an alphacoronavirus, then that suggests that an analogous vaccine would enable broad protection against many, many different coronaviruses,” he says.
The road ahead
But while some of the early stage results are promising, researchers are fully aware of the scale of the challenge ahead of them. Although CEPI have declared an aim of having a licensed universal coronavirus vaccine available by 2024-2025, Zeichner says that such timelines are ambitious in the extreme.
“I was incredibly impressed at the speed at which the mRNA coronavirus vaccines were developed for SARS-CoV-2,” he says. “That was faster than just about anybody anticipated. On the other hand, I think a universal coronavirus vaccine is more equivalent to the challenge of developing an HIV vaccine and we're 35 years into that effort without success. We know a lot more now than before, and maybe it will be easier than we think. But I think the route to a universal vaccine is harder than an individual vaccine, so I wouldn’t want to put money on a timeline prediction.”
The major challenge for scientists is essentially designing a vaccine for a future threat which is not even here yet. As such, there are no guidelines on what safety data would be required to license such a vaccine, and how researchers can demonstrate that it truly provides efficacy against all coronaviruses, even those which have not yet jumped to humans.
The teams working on this problem have already devised some ingenious ways of approaching the challenge. VBI Vaccines have taken the genetic sequences of different coronaviruses found in bats and pangolins, from publicly available databases, and inserted them into what virologists call a pseudotype virus – one which has been engineered so it does not have enough genetic material to replicate.
This has allowed them to test the neutralising antibodies that their vaccine produces against these coronaviruses in test tubes, under safe lab conditions. “We have literally just been ordering the sequences, and making synthetic viruses that we can use to test the antibody responses,” says Anderson.
However, some scientists feel that going straight to a universal coronavirus vaccine is likely to be too complex. Instead they say that we should aim for vaccines which are a little more specific. Pamela Bjorkman, a structural biologist at the California Institute of Technology, suggests that pan-coronavirus vaccines which protect against SARS-like betacoronaviruses such as SARS or SARS-CoV-2, or MERS-like betacoronaviruses, may be more realistic.
“I think a vaccine to protect against all coronaviruses is likely impossible since there are so many varieties,” she says. “Perhaps trying to narrow down the scope is advisable.”
But if the mission to develop a universal coronavirus vaccine does succeed, it will be one of the most remarkable feats in the annals of medical science. In January, US chief medical advisor Anthony Fauci urged for greater efforts to be devoted towards this goal, one which scientists feel would be the biological equivalent of the race to develop the first atomic bomb
“The development of an effective universal coronavirus vaccine would be equally groundbreaking, as it would have global applicability and utility,” says Saunders. “Coronaviruses have caused multiple deadly outbreaks, and it is likely that another outbreak will occur. Having a vaccine that prevents death from a future outbreak would be a tremendous achievement in global health.”
He agrees that it will require creativity on a remarkable scale: “The universal coronavirus vaccine will also require ingenuity and perseverance comparable to that needed for the Manhattan project.”
This month, Matt Fuchs becomes the new Editor-in-Chief of Leaps.org.
This month, Kira Peikoff passes the torch to me as editor-in-chief of Leaps.org. I’m excited to assume leadership of this important platform.
Leaps.org caught my eye back in 2018. I was in my late 30s and just starting to wake up to the reality that the people I care most about were getting older and more vulnerable to health problems. At the same time, three critical shifts were becoming impossible to ignore. First, the average age in the U.S. is getting older, a trend known as the “gray tsunami.” Second, healthcare expenses are escalating and becoming unsustainable. And third, our sedentary, stress-filled lifestyles are leading to devastating consequences.
These trends pointed to a future filled with disease, suffering and economic collapse. But whenever I visited Leaps.org, my outlook turned from gloomy to solution-oriented. I became just as fascinated in a fourth trend, one that stands to revolutionize our world: rapid, mind-bending innovations in health and medicine.
Brain atlases, genome sequencing and editing, AI, protein mapping, synthetic biology, 3-D printing—these technologies are yielding new opportunities for health, longevity and human thriving. COVID-19 has caused many setbacks, but it has accelerated scientific breakthroughs. History suggests we will see even more innovation—in digital health and virtual first care, for example—after the pandemic.
In 2020, I began covering these developments with articles for Leaps.org about clocks that measure biological aging, gene therapies for cystic fibrosis, and other seemingly futuristic concepts that are transforming the present. I wrote about them partly because I think most people aren’t aware of them—and meaningful progress can’t happen without public engagement. A broader set of stakeholders and society at large, not just the experts, must inform these changes to ensure that they reflect our values and ethics. Everyone should get the chance to participate in the conversation—and they must have the opportunity to benefit equally from the innovations we decide to move forward with. By highlighting cutting-edge advances, Leaps.org is helping to realize this important goal.
Meanwhile, as I wrote freelance pieces on health and wellness for outlets such as the Washington Post and Time Magazine, I kept seeing an intersect between the breakthroughs in research labs and our expanding knowledge about the science of well-being. Take, for example, emerging technologies designed to stop illnesses in their tracks and new research on the benefits of taking in natural daylight. These two areas, lab innovations and healthy lifestyles, both shift the focus from disease treatment to disease prevention and optimal health. It’s the only sensible, financially feasible way forward.
When Kira suggested that I consider a leadership role with Leaps.org, it struck me how much the platform’s ideals have informed my own perspectives. The frontpage gore of mainstream media outlets can feel like a daily dose of pessimism, with cynicism sometimes dressed up as wisdom. Leaps.org’s world view is rooted in something very different: rational optimism about the present moment and the possibility of human flourishing.
That’s why I’m proud to lead this platform, including our podcast, Making Sense of Science, and hope you’ll keep coming to Leaps.org to learn and join the conversation about scientific gamechangers through our sponsored events, our popular Instagram account and other social channels. Think critically about the breakthroughs and their ethical challenges. Help usher in the health and prosperity that could be ours if we stay open-minded to it.
Yours truly,
Matt Fuchs
Editor-in-Chief