Early in the pandemic, scientists engaged in a flurry of discussions about the best way to construct COVID-19 vaccines to ensure their efficacy and safety. Some of these discussions centered around antibody-dependent enhancement of immunity (ADE), a potentially deadly immune phenomenon seen with other viral infections and vaccines.
So far, there have been no reports of ADE with COVID-19 vaccines. But the concerns about ADE with COVID-19 vaccines have resurfaced with the emergency of virus variants. What exactly is ADE? What do we know from past experience with it? And why do experts say it's a non-issue with COVID-19 vaccines?
Features of ADE
While can arise by different pathways, perhaps the best known is the so-called "Trojan Horse" pathway. This occurs when non-neutralizing antibodies generated by past infection or vaccination fail to shut down the pathogen upon re-exposure.
Instead, they act as a gateway by allowing the virus to gain entry and replicate in cells that are usually off limits (typically immune cells, like macrophages). That, in turn, can lead to wider dissemination of illness, and over-reactive immune responses that cause more severe illness, Barry Bloom, MD, PhD, of the Harvard T.H. Chan School of Public Health, told 番茄社区.
"The cause of ADE is having antibodies to a virus that don't neutralize it. That enables the virus to be gobbled up by cells that have receptors for antibodies, but not the virus. That's the way of getting virus into cells that it ordinarily would not infect," Bloom said.
ADE can also occur when neutralizing antibodies (which bind the virus and stop it from causing infection) are present at low enough levels that they don't protect against infection. Instead, they can form with viral particles, which in turn leads to worse illness.
What Does Past Experience Tell Us About ADE?
The classic example of Trojan Horse-style ADE comes from . This virus comes in four varieties. They are different enough from each other that past infection with one does not always generate antibodies that match well enough to protect against a different variety.
ADE has also occurred after vaccination for dengue. For example, in 2016 a was developed to protect against all four serotypes and given to 800,000 children in the Philippines. Among children who were vaccinated and later exposed to wild-type dengue, 14 died, presumably from more severe illness. Since then, the vaccine has been recommended only to children 9 years and older who have already been exposed to dengue.
Another classic example comes from the U.S., when ADE occurred during a clinical trial for an inactivated vaccine against respiratory syncytial virus (). In 1967, children who participated in the trial and received the vaccine developed more severe RSV illness when they later encountered the virus in the community. Two toddlers died. The vaccine was associated with immune complex formation that caused lung obstruction and enhanced respiratory disease, pretty much stalling RSV vaccine development.
Similarly, cases of ADE also occurred with an inactivated that was being developed in the U.S. in the 1960s. After vaccinated children developed more severe illness, the vaccine was withdrawn. The live, weakened measles vaccines that are currently in use in the U.S. have not been associated with ADE.
ADE a Non-Issue With COVID Vaccines
Scientists say that ADE is pretty much a non-issue with COVID-19 vaccines, but what are they basing this on?
From the early stages of COVID-19 vaccine development, scientists sought to target a SARS-CoV-2 protein that was least likely to cause ADE. For example, when they found out that targeting the nucleoprotein of SARS-CoV-2 might cause ADE, they quickly abandoned that approach. The safest route seemed to be targeting the S2 subunit of the spike protein, and they ran with that, wrote Derek Lowe, PhD, ."
Scientists designed animal studies to look for ADE. They looked for it in human trials, and they've been looking for it in the real-world data for COVID-19 vaccines with emergency use authorization. So far, they haven't seen signs of it. In fact, the opposite is happening, Lowe noted.
"[W]hat seems to be beyond doubt is that the vaccinated subjects, over and over, show up with no severe coronavirus cases and no hospitalizations. That is the opposite of what you would expect if ADE were happening," he wrote.
Furthermore, ADE is an acute problem, and it can be very dramatic. If it was an issue with these vaccines, we would have spotted it by now, said Brian Lichty, PhD, an associate professor in pathology and molecular medicine at McMaster University in Toronto.
"It'll kill you quickly. In all the places I'm aware of ADE happening, it is an acute, mostly cytokine-driven event," he told 番茄社区.
The one exception may be an inactivated whole-cell, or "killed," vaccine developed by China. That vaccine uses alum, the same adjuvant that was used in the measles and RSV vaccines that caused ADE in the 1960s. The Chinese inactivated whole-cell vaccine could "conceivably" generate ADE like those older vaccines, according to Bloom.
"I don't think that vaccine is ever going to see the light of day in the U.S., and it may not even be worth mentioning. There have been no actual cases of ADE with the Chinese whole-cell killed vaccine, or if so, it hasn't been reported," he said.
What About Variants?
Current COVID-19 vaccines were developed to protect against the original strain of SARS-CoV-2 that became dominant worldwide. As more variants arise, scientists have raised questions about whether one of these could become different enough to cause ADE. So far, that concern seems to be hypothetical, according to Lichty.
"To date, there's really no evidence of ADE with the COVID-19 vaccines. It's all theoretical," he said. "I think all the evidence so far is that ADE is not turning out to be a problem with any existing vaccines or viral variants."
One reason could be that SARS-CoV-2 just may not affect macrophages in a way that can produce ADE, although scientists are still working out the details. ADE has been reported after natural infection with other viruses, such as , , and , as well as other coronaviruses like .
Throughout the pandemic, scientists have been looking for ADE associated with SARS-CoV-2, but so far they haven't found any cases of it, noted Lichty.
"This coronavirus may already be sufficiently adapted to humans, so that if it does get into macrophages via a non-neutralizing antibody interaction, it may not allow the macrophage to produce enough cytokine to cause an obvious pathology," he said.
Newer Vaccines Are Safer
Despite hesitancy about the relative newness of mRNA and adenoviral vector vaccines, these vaccines, in fact, have better safety profiles in terms of ADE than older types of vaccines, according to Bloom.
"The bottom line is that not only is the new technology faster to respond to a new viral pandemic, but so much safer and much more clearly scientifically designed," he said. "The S protein vaccines are so much cleaner, so much more carefully defined, and so much lower risk. All you're seeing is one protein from that virus. So the chances for ADE are much slimmer than with any of the older ways for making virus vaccines."