Are the gains from gain-of-function research worth the risks?
Gain-of-function research can make pathogens more infectious and deadly. It also enables scientists to prepare remedies in advance.
Scientists have long argued that gain-of-function research, which can make viruses and other infectious agents more contagious or more deadly, was necessary to develop therapies and vaccines to counter the pathogens in case they were used for biological warfare. As the SARS-CoV-2 origins are being investigated, one prominent theory suggests it had leaked from a biolab that conducted gain-of-function research, causing a global pandemic that claimed nearly 6.9 million lives. Now some question the wisdom of engaging in this type of research, stating that the risks may far outweigh the benefits.
“Gain-of-function research means genetically changing a genome in a way that might enhance the biological function of its genes, such as its transmissibility or the range of hosts it can infect,” says George Church, professor of genetics at Harvard Medical School. This can occur through direct genetic manipulation as well as by encouraging mutations while growing successive generations of micro-organism in culture. “Some of these changes may impact pathogenesis in a way that is hard to anticipate in advance,” Church says.
In the wake of the global pandemic, the pros and cons of gain-of-function research are being fiercely debated. Some scientists say this type of research is vital for preventing future pandemics or for preparing for bioweapon attacks. Others consider it another disaster waiting to happen. The Government Accounting Office issued a report charging that a framework developed by the U.S. Department of Health & Human Services (HHS) provided inadequate oversight of this potentially deadly research. There’s a movement to stop it altogether. In January, the Viral Gain-of-Function Research Moratorium Act (S. 81) was introduced into the Senate to cease awarding federal research funding to institutions doing gain-of-function studies.
While testifying before the House COVID Origins Select Committee on March 8th, Robert Redfield, former director of the U.S. Centers for Disease Control and Prevention, said that COVID-19 may have resulted from an accidental lab leak involving gain-of-function research. Redfield said his conclusion is based upon the “rapid and high infectivity for human-to-human transmission, which then predicts the rapid evolution of new variants.”
“It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen,” said Gerald Parker, associate dean for Global One Health at Texas A&M University.
“In my opinion,” Redfield continues, “the COVID-19 pandemic presents a case study on the potential dangers of such research. While many believe that gain-of-function research is critical to get ahead of viruses by developing vaccines, in this case, I believe that was the exact opposite.” Consequently, Redfield called for a moratorium on gain-of-function research until there is consensus about the value of such risky science.
What constitutes risky?
The Federal Select Agent Program lists 68 specific infectious agents as risky because they are either very contagious or very deadly. In order to work with these 68 agents, scientists must register with the federal government. Meanwhile, research on deadly pathogens that aren’t easily transmitted, or pathogens that are quite contagious but not deadly, can be conducted without such oversight. “If you’re not working with select agents, you’re not required to register the research with the federal government,” says Gerald Parker, associate dean for Global One Health at Texas A&M University. But the 68-item list may not have everything that could possibly become dangerous or be engineered to be dangerous, thus escaping the government’s scrutiny—an issue that new regulations aim to address.
In January 2017, the White House Office of Science and Technology Policy (OSTP) issued additional guidance. It required federal departments and agencies to follow a series of steps when reviewing proposed research that could create, transfer, or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility or virulence in humans.
In defining risky pathogens, OSTP included viruses that were likely to be highly transmissible and highly virulent, and thus very deadly. The Proposed Biosecurity Oversight Framework for the Future of Science, outlined in 2023, broadened the scope to require federal review of research “that is reasonably anticipated to enhance the transmissibility and/or virulence of any pathogen” likely to pose a threat to public health, health systems or national security. Those types of experiments also include the pathogens’ ability to evade vaccines or therapeutics, or diagnostic detection.
However, Parker says that dangers of generating a pandemic-level germ are tiny. “It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen.” Since gain-of-function guidelines were first issued in 2017, only three such research projects have met those requirements for HHS review. They aimed to study influenza and bird flu. Only two of those projects were funded, according to the NIH Office of Science Policy. For context, NIH funded approximately 11,000 of the 54,000 grant applications it received in 2022.
Guidelines governing gain-of-function research are being strengthened, but Church points out they aren’t ideal yet. “They need to be much clearer about penalties and avoiding positive uses before they would be enforceable.”
What do we gain from gain-of-function research?
The most commonly cited reason to conduct gain-of-function research is for biodefense—the government’s ability to deal with organisms that may pose threats to public health.
In the era of mRNA vaccines, the advance preparedness argument may be even less relevant.
“The need to work with potentially dangerous viruses is central to our preparedness,” Parker says. “It’s essential that we know and understand the basic biology, microbiology, etc. of some of these dangerous pathogens.” That includes increasing our knowledge of the molecular mechanisms by which a virus could become a sustained threat to humans. “Knowing that could help us detect [risks] earlier,” Parker says—and could make it possible to have medical countermeasures, like vaccines and therapeutics, ready.
Most vaccines, however, aren’t affected by this type of research. Essentially, scientists hope they will never need to use it. Moreover, Paul Mango, HSS former deputy chief of staff for policy, and author of the 2022 book Warp Speed, says he believes that in the era of mRNA vaccines, the advance preparedness argument may be even less relevant. “That’s because these vaccines can be developed and produced in less than 12 months, unlike traditional vaccines that require years of development,” he says.
Can better oversight guarantee safety?
Another situation, which Parker calls unnecessarily dangerous, is when regulatory bodies cannot verify that the appropriate biosafety and biosecurity controls are in place.
Gain-of-function studies, Parker points out, are conducted at the basic research level, and they’re performed in high-containment labs. “As long as all the processes, procedures and protocols are followed and there’s appropriate oversight at the institutional and scientific level, it can be conducted safely.”
Globally, there are 69 Biosafety Level 4 (BSL4) labs operating, under construction or being planned, according to recent research from King’s College London and George Mason University for Global BioLabs. Eleven of these 18 high-containment facilities that are planned or under construction are in Asia. Overall, three-quarters of the BSL4 labs are in cities, increasing public health risks if leaks occur.
Researchers say they are confident in the oversight system for BSL4 labs within the U.S. They are less confident in international labs. Global BioLabs’ report concurs. It gives the highest scores for biosafety to industrialized nations, led by France, Australia, Canada, the U.S. and Japan, and the lowest scores to Saudi Arabia, India and some developing African nations. Scores for biosecurity followed similar patterns.
“There are no harmonized international biosafety and biosecurity standards,” Parker notes. That issue has been discussed for at least a decade. Now, in the wake of SARS and the COVID-19 pandemic, scientists and regulators are likely to push for unified oversight standards. “It’s time we got serious about international harmonization of biosafety and biosecurity standards and guidelines,” Parker says. New guidelines are being worked on. The National Science Advisory Board for Biosecurity (NSABB) outlined its proposed recommendations in the document titled Proposed Biosecurity Oversight Framework for the Future of Science.
The debates about whether gain-of-function research is useful or poses unnecessary risks to humanity are likely to rage on for a while. The public too has a voice in this debate and should weigh in by communicating with their representatives in government, or by partaking in educational forums or initiatives offered by universities and other institutions. In the meantime, scientists should focus on improving the research regulations, Parker notes. “We need to continue to look for lessons learned and for gaps in our oversight system,” he says. “That’s what we need to do right now.”
Vaccine passports, if required by businesses and universities, may give people a false sense of security, one expert cautions.
Vaccines are one of the greatest public health accomplishments of all time. For centuries, public health has relied on vaccinations to prevent and control disease outbreaks for a plethora of infectious scourges, with our crowning achievement being the successful eradication of smallpox.
The purpose of vaccine documentation is to provide proof of an individual's protection from either becoming infected or transmitting a vaccine-preventable disease. Vouching for these protections requires a firm knowledge about the epidemiology of the disease, as well as scientific knowledge concerning the efficacy of the vaccine. The vaccines we currently require be documented have met these tests; the vaccine for COVID-19 has not yet been proven to do so.
Let's acknowledge that the term "vaccine passport" is a poor choice of words. Passports are a legal travel document created by nations and governed by law for identification of the bearer to control entry and exit from nation states. They often serve as legal forms of identification and as a record of international travel. They are generally very sophisticated documents that have been created in a secure manner and may include a range of electronic and, in some cases, biometric measures such as fingerprints to ensure the holder is indeed who they say they are. Vaccine passports are medical documents used to document the vaccination status of an individual. They do not undergo the same level of administrative scrutiny and cannot be used to verify that the presenter is indeed the vaccinated individual. Some companies do have electronic methods to address concerns about verification; however, most people currently have paper records that can be easily falsified.
"Vaccine passports" as currently proposed risk giving people a false sense of security.
Successful disease control from vaccination programs relies on the ability to vaccinate at a level that prevents large-scale disease spread and the ability to rapidly identify the presence of disease outbreaks. It requires reliable, safe, and effective vaccines that are easily delivered in clinical and nonclinical settings. Keeping vaccination information as a part of the medical record, and even having a separate specialized vaccine record for personal use, is a time-honored tradition.
Keeping a vaccination record provides a method to keep track of the many shots one receives and serves as a visual reminder to help ensure the appropriate vaccine shot schedule is maintained for vaccines requiring multiple doses. The vaccine record, when combined with vaccine safety monitoring systems, serves as a mechanism to track adverse events to monitor and ensure the safety of vaccines as a consumer product. The record also serves as the official record of vaccination when required for administrative or legally prescribed purposes.
"Vaccine passports" as currently proposed risk giving people a false sense of security. In the case of the COVID-19 vaccines currently approved for use, many of the essential questions remain unanswered. While we do know the current three vaccines are highly protective against severe disease and death, and there is some evidence that these vaccinations do reduce infections and virus transmission of SARS-CoV-2, we do not yet know the full degree to which this occurs.
For example, we know there have been some cases of people that have been infected in close proximity to getting their full vaccination and rare cases of breakthrough reinfections. A breakthrough infection in a restaurant is a challenge for contact tracing, but an outbreak from a movie theater exposure or a baseball game could spark a major outbreak at our current level of vaccination. Current CDC guidance recommends continued mask wearing in order to address these concerns.
We also do not yet know how long the protections will last and if or when a booster or revaccination is required. In effect, it is too soon to know. Should an annual booster shot be required, then a vaccine passport would require annual updating, a process more frequent than renewal of a driver's license.
We also know that the current SARS-CoV-2 virus is mutating briskly. While the current approved vaccines have remained effective overall, there is evidence of some degree of degradation in vaccine effectiveness against some of the circulating strains. We also have sparse data on many of the other emerging strains of concern because we have not had the surveillance capacity in the U.S. to gain an adequate sense of how the virus is changing to fully align vaccine effectiveness with viral capabilities.
The risk of people misusing these "passports" is troubling. The potential for using these documents for hiring, firing or job limitation is a serious concern. Unvaccinated workers are at risk of this form of discrimination even from well-meaning employers or supervisors. Health insurers are prohibited by the Affordable Care Act from discriminating based on preexisting conditions, but they could probably charge a higher premium for unvaccinated individuals. There also is a risk of stigmatizing individuals who are not vaccinated or have left their vaccine documentation at home. Another concern: the opportunity to discriminate based on race, gender, sexual orientation, or religion, using one's vaccination status as an excuse.
These "passports" are being discussed as a "ticket verification" for entry to many activities, including dining at restaurants, flying domestically and/or internationally, going to movie theaters and sporting events, etc. These are all activities we already are doing at reduced levels and for which wearing a mask, hand hygiene and physical distancing are effective disease control practices. COVID-19 vaccines are indeed the measure that will make the ability to totally reopen our society complete, but we are not there yet. Documentation of one's COVID-19 vaccine status may be useful in selected situations in the future. That remains to be seen.
Finally, inadequate vaccine supply and disparities in vaccine delivery have created enormous challenges in providing equal access to vaccination. Also, the amount of misinformation, disinformation, and lingering vaccine hesitancy continue to limit the speed at which we will reach the level of vaccination of the population that would make this documentation meaningful. The requirement for "vaccine passports" is already alienating people who are opposed to vaccinations for a variety of reasons, paradoxically risking reduced vaccine uptake. This politicization of the vaccination effort is of concern. There are indeed people who, due to medical contraindications or legal exemptions, will not be vaccinated, and we do not yet have a national framework on how to address this.
Vaccine passports are not the solution for reopening our society — a robust vaccination program is. The requirement to document one's vaccination status for COVID-19 may one day have its place. For now, it is an idea whose time has not yet come.
Editor's Note: This op/ed is part of a "Big Question" series on the ethics of vaccine passports. Read the flip side argument here.
A digital health passport required by businesses and universities could help us get back to normal more quickly, one expert argues.
"Vaccine passports" are a system that requires proof of a COVID-19 vaccination as a condition of engaging in activities that pose a risk of transmitted SARS-CoV-2. Digital Health Passes (DHPs) are typically a smartphone application with a code that verifies whether someone has been vaccinated.
Vaccine passports could very much be in our future. Many businesses are implementing or planning to require proof of vaccination as a condition of returning to the workplace. Colleges and universities have announced vaccine requirements for students, staff, and faculty. It may not be long before the private sector requires a vaccination card or image to attend an entertainment or sporting event, to travel, or even to dine or shop indoors, at least in some venues.
But it's unlikely the federal government or the states will launch DHPs, at least not in the near-term. President Biden announced the White House has no intention of requiring proof of vaccination. While no state has mandated DHPs, New York is piloting its Excelsior Pass on a voluntary basis, partnering with IBM. Other nations are not so hesitant. Israel's "Green Pass" has gotten the nation back to normal in record time. And various countries and regions are planning DHPs, including the European Union and the United Kingdom. Foreign airlines are likely to require proof of vaccination as a condition of flying internationally.
DHPs could emerge as a way to get us back to normal more quickly, but are they ethical? Let's start with the law. The US Equal Opportunity Commission (EEOC) has specifically said that employers have the legal right to require proof of vaccination as a condition of returning to work. Colleges and universities already require several vaccines for students living in dorms. Hospitals and nursing homes often mandate influenza vaccinations. And, of course, all states require childhood vaccinations for school attendance. Vaccine passports are lawful but are they ethical? The short answer is "yes" but only if we ensure no one is left behind.
Vaccine passports "don't force anyone to be vaccinated against his or her will. They simply say to individuals that if you choose not to be vaccinated, you can't work or recreate in public spaces that risk transmission of the virus."
Why are vaccine passports ethical? Vaccines are a miracle of modern science, but they have become a political symbol, and a significant part of the population doesn't want to get a jab. The rare cases of blood clots associated with the Johnson & Johnson and AstraZeneca vaccines have only created more distrust.
Most opposition to vaccine passports hinges on the claim that they infringe personal autonomy and liberty. But this argument misses the point. Of course, every competent adult has the right to make decisions that affect his or her own health and safety. But no one has a right to infringe on the rights of others, such as by exposing them to a potentially serious or deadly infectious disease. An individual can't claim the right to attend a crowded event mask-less and unvaccinated. This was once accepted across the political spectrum. Conservative economists called it an "externality," that is a person has no right to harm others. The U.S. has lost the tradition of the common good. We have become so focused on our own individual rights that we forget about our ethical obligations to our neighbors and to our community.
In fact, DHPs actually don't force anyone to be vaccinated against his or her will. They simply say to individuals that if you choose not to be vaccinated, you can't work or recreate in public spaces that risk transmission of the virus.
DHPs also don't infringe on privacy. Again, everyone has the choice whether to show proof of vaccination. It isn't required. Moreover, DHPs may actually protect privacy because all they do is show whether or not you have been vaccinated. They don't disclose any other personal medical information. All of us actually have already had to show proof of vaccination as a condition of going to school. Thus, DHPs are well established in the United States.
But there is one ethical argument against DHPs that I find to be powerful, and that is equity. If we require proof of vaccination while doses are scarce, we will give the already privileged even more privilege. And that would be unconscionable. Thus, DHPs should not be implemented until everyone who wants a vaccine is able to get a vaccine. Equity isn't a side issue. It needs to be front and center.
As of today, all adults in the U.S. are eligible to get vaccinated, and President Biden has pledged that by the end of May there will be enough doses to vaccinate the entire U.S. population. It is a realistic promise. Once vaccines become plentiful, everyone should get their shot. All Food and Drug Administration authorized vaccines are highly safe and effective, even the Johnson & Johnson vaccine that the FDA has just put on pause.
Businesses have an economic incentive to require proof of vaccination. Very few of us would feel comfortable returning to our jobs, shops, theaters, or restaurants unless we feel safe. Businesses understand the duty to create safer places for work, recreation, and commerce.
One question has dominated national conversation since the pandemic began. "When will we get back to normal?" There is a deep human yearning to hug family and friends, see our work colleagues, recreate, and be entertained. One day we will have defeated this wily virus and get back to normal. But vaccine passports can help us get back to the things we love faster and more safely. As long as we don't leave anyone behind, using this miracle of modern science to make our lives better is both lawful and ethical.
Editor's Note: This op/ed is part of a "Big Question" series on the ethics of vaccine passports. Read the flip-side argument here.