The coronavirus pandemic has provided the world with a quick study in the intricacies of immunology. “Herd immunity” and “serological tests” have become household terms. Front and center among these concepts are antibodies. These immune proteins typically emerge during the second or third week after an infection, glomming onto invaders and preventing them from sneaking into human cells. If antibodies targeting a particular virus turn up in a blood sample, their appearance provides confirmation of an immune response that may protect against reinfection.
Eliciting the right antibodies to disarm SARS-CoV-2, the virus responsible for the current pandemic, is the goal of dozens of vaccine developers, several of which have already launched human trials in record time. But public health officials and scientists caution against moving too quickly. In rare instances, these immune defenders can exacerbate disease rather than guard against it.
That concern has not yet materialized in the early stages of making a COVID-19 vaccine. Yet based on research related to past coronavirus outbreaks, vaccine manufacturers do not view the hurdle as purely theoretical.
Typically SARS-CoV-2 and the earlier related coronavirus SARS-CoV make their way into cells through a docking site: a cell-surface receptor called ACE2. Vaccines that provide the sought-after immunization make “neutralizing” antibodies against viral proteins, blocking the pathogen’s entrance through the ACE2 portal.
But just because an antibody can keep a virus from entering cells in a lab dish does not necessarily mean it will behave that way in the body, says Akiko Iwasaki, an immunologist at Yale University. In scenarios she describes in a recent Nature Reviews Immunology commentary, antibodies may occasionally help a virus invade and thwart immune cells that would normally engulf and help clear the pathogen.
If some of the antibodies produced do not bind to the virus well enough—or are not present in the right concentration—they can latch onto it and exacerbate disease through a process known as antibody-dependent enhancement (ADE). In ADE, antibody-coated viruses gain a “backdoor” entry through antibody receptors on macrophages and other members of the cellular cleanup crew—in essence, disabling the very cells that would have chopped up those viruses and chemically disposed of them. In some cases, this process can trigger a harmful inflammatory response.
Indeed, it seems that some pathogens, including coronaviruses, have “found a way to use the antibody as a Trojan horse” to infect disease-fighting cells,” Iwasaki says. Her lab is working to understand the types of immune responses that help people recover from COVID-19 versus those that contribute to disease.
Through ADE, Iwasaki suggests, the virus can initiate an overproduction of inflammatory signaling proteins called cytokines, leading to “cytokine storms” that can promote acute respiratory distress syndrome and damage lung tissue. Similar problems can also be unleashed in some COVID-19 patients by other immune cells called neutrophils.
Scientists are not yet sure if ADE actually promotes cytokine storms or immune-related tissue damage in COVID-19. They are connecting hypothetical dots based on past studies of experimental vaccines for previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), in which some immunized animals developed more severe disease. Plus, earlier work by Iwasaki and others suggests that pathogens entering cells through the back door get shunted to different cellular compartments that are rich in receptors that sense microbial threats and release molecules linked to cytokine storms. “That’s a well-known fact,” Iwasaki says. “Why wouldn’t SARS-CoV-2 also be recognized this way?”
Some research from earlier coronavirus outbreaks does, in fact, lend support to the idea that antibodies could trigger inflammatory pathology by co-opting macrophages. In an analysis of monkeys published last year in JCI Insight, researchers in China showed that SARS-CoV antibodies from serum in vaccinated animals were sufficient to trigger lung damage in a set of unvaccinated ones. The transferred antibodies worsened disease and seemed to switch lung macrophages from a protective to a pathogenic state, as judged by an examination of the immune cells’ genetic activity.
ADE has cropped up as a suspected problem for other vaccines. Certain dengue and respiratory syncytial virus vaccines have provoked severe immune reactions. Antibodies could be one of the initiators, but vaccine scientists say immune-related tissue damage is a bigger potential concern. Liver and lung damage caused by an inflammatory reaction has occurred in animals infected with the SARS virus after vaccination. But ADE as a mechanism was documented in lab dish experiments, so the phenomenon “is a bit more theoretical,” says Peter Hotez, co-director of the Texas Children’s Hospital Center for Vaccine Development, which is building on its SARS vaccine work to create a COVID-19 vaccine.
While it is possible that suboptimal antibodies could lead to inflammation and tissue damage, he says these problems could also result from the aberrant activity of T cells, which serve as another virus fighter in the immune system’s arsenal. A study published on May 14 in Cell suggests SARS-CoV-2-specific T cells, when functioning normally, may help people combat COVID-19.
Scientists are well aware of the potential danger of ADE. It is “something which may happen,” says Paul Henri Lambert, a vaccine scientist at the University of Geneva and a consultant at the Coalition for Epidemic Preparedness Innovations (CEPI). “But at this stage, we do not have any evidence that this is a problem for vaccines against SARS-CoV-2.”
Moderna, a Massachusetts biotech company that announced preliminary findings from an early-stage clinical trial of its RNA-based COVID-19 vaccine last week, has found no serious health problems in study participants. Another COVID-19 vaccine that was tested in an early-stage trial in China appeared to be safe and produced neutralizing antibodies in some of the study’s 108 participants, according to a May 22 study in the Lancet.
Several additional COVID-19 vaccines have been tested in nonhuman primates. One was made from an inactivated virus by researchers in China, who reported on May 6 that the highest dose gave protection. The team found no evidence for disease enhancement in four monkeys analyzed seven days after they were infected with SARS-CoV-2. A non-peer-reviewed paper on a second vaccine, developed using the SARS-CoV-2 protein responsible for viral entry into host cells, was posted on the preprint server bioRxiv on May 13. It also showed no signs of enhanced disease. And in a May 20 study of macaques immunized with another type of candidate (a DNA vaccine), scientists reported that they “did not observe enhanced clinical disease even with the suboptimal vaccine constructs that failed to protect.”
Stanley Perlman, a physician and viral immunologist at the University of Iowa, has participated in COVID-19 vaccine committees set up by both the National Institutes of Health and the World Health Organization. These committees have thoroughly discussed possible risks posed by ADE, he says. But given the urgency of the pandemic, Perlman adds, “people say, we’ve got to get a vaccine yesterday. And on the other hand, you have people saying, ‘Oh no, we have to be really careful.’ How to balance this? We can’t open up the country until we have a vaccine, until we have herd immunity. So it becomes a difficult question: What’s the most correct course of action?”
The real question is whether COVID-19 vaccines will cause ADE when they are given to hundreds of thousands of people. This concern is shared by researchers testing if blood plasma from recovered patients can safely treat people hospitalized with the disease. ADE has not been reported thus far in a study of 5,000 patients given this convalescent plasma nationwide, which was posted on May 14 on the preprint server medRxiv.
Analyses of immune responses in early-stage clinical trial volunteers and nonhuman primates studied before moving on to the next phase of a given investigation should be able to identify vaccines at potential risk for immune enhancement, Lambert says. Hotez thinks it will be important to watch for ADE and damaging inflammatory reactions when immunizing study participants in areas where the virus is spreading. “If you’re going to see a problem, that’s where you would see it,” he says. “In individuals who are vaccinated and then exposed to the virus, you would want to monitor for liver and lung function to make sure there’s no worsening.”
Beyond vaccines, ADE could influence other aspects of the immune response to SARS-CoV-2. Jorge Caballero, a Stanford University anesthesiologist who organizes data and engineering support for COVID-19 surveillance testing, wonders if the process could underlie other disease manifestations, including “COVID toes,” respiratory distress linked to lung pathology and a mysterious inflammatory condition striking some kids with the disease. Emerging data “suggest that the common link—Occam’s razor, if you will—may be a little understood phenomenon known as antibody-dependent enhancement,” he says.