What is “Antibody-Dependent Enhancement”? What does it have to do with viral infections? Is there an actual danger of ADE from vaccines against COVID-19?
As of today, more than 147 million people worldwide have been vaccinated against the coronavirus, SARS-CoV-2. That is almost 2 people for every 100 people on the planet. The race for the vaccine has brought with it an immense feeling of hope, and along with it some concerns, cautious questioning and a lot of disinformation.
Recently, posts on social media express concern that the vaccine may lead to “antibody-dependent enhancement”, or ADE for short. In a nutshell, ADE is a process where antibodies developed in a body against a certain disease could lead to an over-activation of the immune system against that disease the next time the body encounters the pathogen. Should it occur, the antibodies won’t improve the body’s reaction to the disease, but rather lead to a more severe condition.
Scaremongering on social media, such as talk of “vaccine addiction” or claims that “the decrease in antibodies will lead to the fatal disease ADE within six months” are based on partial truths, cherry-picking (taking information selectively out of context) and lack of understanding. ADE is a well-known phenomenon and was already investigated at the early stages of the vaccine’s research and development process. This is not a new topic or a secret in hiding, and it was the topic of numerous studies and discussions ever since the initial stages of the corona outbreak. It is important to understand that ADE is a property of the disease itself, and not of the vaccine against it. Currently, the most recent findings do not indicate that this phenomenon is caused by COVID-19.
In order to understand further, we must first understand a little about how the immune system works.
Viruses, Antibodies, and the Vaccine Between Them
Viruses are incapable of reproduction by themselves, and replicate using a host cell. They attach to the cell and infiltrate it using surface proteins on their exterior envelope. For example, the coronavirus SARS-CoV-2, the pathogen of the pandemic we face today, has a “spike” protein that attaches to a protein named ACE2 at the external side of some of our cells. This “lock” and “key'' pair determines which cells the virus can attach to and infiltrate, and subsequently replicate in, spreading new copies to the rest of the body.
When our adaptive immune system meets an unknown pathogen, it studies it and creates antibodies and immune cells specifically against it. This process can take between two to three weeks, during which the pathogen could cause major damage. Therefore, in addition to the production of antibodies, the immune system creates and stores memory cells as well. This way, if the pathogen invades once more, the memory cells will allow a more rapid response: the moment the pathogen is recognized, the suitable memory cells will activate and quickly produce the required antibodies fitting for the pathogen. This way it will be neutralized and disintegrated before the damage is done. This is immunological memory.
The current corona vaccines, including Pfizer’s and Moderna’s, encourage the immune system to react to the described spike protein, and so the body can create antibodies and memory cells against the protein without encountering the virus itself. Should the body get infected with the virus, it will already have the required cells and antibodies to fight it in a precise and efficient manner the second it enters the body, and so the disease will be prevented.
This process of creating immunological memory includes the creation of “Neutralizing Antibodies”. Their job is to prevent the spike protein from attaching to ACE-2 and so to inhibit the virus’ infiltration mechanism. Apart from neutralizing, antibodies that attach to the virus also alert killer cells that engulf the antibody along with the virus it is attached to (Phagocytosis).
“Antibody-Dependent Enhancement”, or ADE, is a phenomenon in which the presence of antibodies could under certain conditions enhance the severity of viral infections. It was first reported as a part of the immunological response to the Dengue Virus roughly 20 years ago and was also seen in Yellow fever, Zika, West-Nile fever and HIV (the pathogen of AIDS) in addition to several viruses of the respiratory system.
ADE can occur in two pathways. The first occurs when the antibodies are not effective enough in neutralizing the pathogen, and the other when the antibodies attach to the virus in a way that causes an over-reaction of the immune system and inflammation. The pathway depends on the type of virus.
Combined reaction: B cell with antibodies (red) and a helper T cell (turquoise) attack coronavirus (above). | Illustration: ANATOMIC GROOVE / SCIENCE PHOTO LIBRARY
Enhanced infection due to the use of antibodies
The role of non-neutralizing antibodies is to attach to the virus’ envelope and signal phagocytosing immune cells to come over and engulf the invader. The antibody is used as a kind of anchor, or bridge, between the immune cell and the virus. Viruses that attack cells of the immune system itself use this anchor to get closer to the immune cell and infect it. In this case, not only is the cell not engulfing the virus and disintegrating it, it’s used as a host for the virus to replicate within it. This way, phagocytes become an easy target for the virus, and instead of becoming a part of the solution they worsen the severity of the disease.
Dengue Virus, which attacks phagocyte cells of the immune system, is a classic example of such a “Trojan horse” mechanism. If the antibodies do not match the virus precisely, they can’t fully neutralize it and the virus makes its way into replicating within the phagocytosing cells.
ADE is caused in this example due to the fact that there are four variants of the Dengue Virus: when the body has antibodies for one variant, they don’t neutralize viruses of the other variants at the event of infection with maximum efficiency.
Cuba, for example, saw an outbreak of one of the variants of Dengue virus in 1977. Twenty years later, in 1997, a different variant had an outbreak on the island. Studies have shown that in the second outbreak the morbidity was much higher among those who were previously sick with the first Dengue virus variant. Unfortunately for the Cubans, in 2001 a third variant of the virus arrived at the island, and nearly all of those who were sick in 1977 and were reinfected, experienced a severe disease.
Evading destruction by immune cells and even replicating within them. Dengue virus particles in the blood | Illustration: SCIEPRO / SCIENCE PHOTO LIBRARY
An enhanced reaction of the immune system
When antibodies are not adequately effective against a virus, they can create Immunological Complexes. These complexes can aggregate in infected tissues (for example lung cells) and cause strong inflammatory reactions that increase the severity of the disease. This mechanism exists among respiratory viruses such as RSV (Respiratory Syncytial Virus) that causes an inflammation that could lead to an obstruction of the airways and even respiratory distress. The inflammatory process itself is a vital part of the immunological system, but when there is a disturbance in the balance, inflammation continues to erupt uncontrollably as seen in ADE, and an increased severity in the disease’s symptoms occurs.
This mechanism of ADE can be seen for example in measles, when monkeys that were vaccinated with an inactivated virus and were infected with the measles virus experienced the disease more severely.
As vaccines simulate a “light case” of a disease, ADE can develop not only with past multiple infections but also when a person is first infected with a virus that he was vaccinated against. That is why ADE posed a problem in the development of vaccines against Dengue, Ebola, RSV, HIV and several viruses of the corona family. The possibility of ADE reactions against SARS-CoV-2 posed a concern at the beginning of the current pandemic, as it would have disrupted the development of an effective vaccine against it.
A complex leading to an inflammatory process: the “Common Cold Virus” (Rhinovirus) wrapped in antibodies | Computer simulation: THOMAS SMITH / DANFORTH CENTER / SCIENCE PHOTO LIBRARY
ADE and Coronaviruses
Some of the viruses from the coronavirus family presented similar phenomena to the ones seen in animals infected with Dengue fever. For example, ADE was described with a virus called FIPV (Feline Infectious Peritonitis Virus) of the corona family, that invades phagocytes called Macrophages. In this case, the first pathway of enhanced infection using antibodies was used.
However, despite its familial relation to FIPV, the current coronavirus, SARS-CoV-2 does not attack the same cells. Studies have shown that while the current coronavirus can on occasion invade macrophages, it cannot replicate within them. In fact, the phagocytosing cells take on a positive role in the battle against the disease when the antibodies are around, as they assist in decreasing the viral load. Therefore, it appears that the ADE pathway based on invading cells of the immune system is not relevant to the current coronavirus.
Much like his family members, SARS-CoV-1 and MERS-CoV, SARS-CoV-2 specializes in invading epithelial cells that are found at the thin layer separating organs from their surroundings. It mainly attacks the epithelial cells of the lungs, and so causes respiratory disease. Therefore, the concern regarding the current coronavirus was from the second pathway of ADE -- causing an inflammation that activates the immune system uncontrollably within the airways, risking respiratory distress.
During experiments performed in the processes of creating vaccines against MERS and SARS, based on inactivated or engineered viruses, ADE was observed in some cases after experimental animal subjects encountered a live virus. Therefore, in pre-clinical trials the concern was raised, especially in experiments in mice and in-vitro, though in other cases the phenomenon was not noted. Studies have shown that the adjuvant, a substance added to the vaccine in order to increase its efficiency, had an important role in the occurrence of ADE following the vaccine. Another important variable was the inactivation process of the virus during vaccine development.
Later on, solutions were developed, and research performed and completed on rhesus and macaque monkeys demonstrated that no ADE was observed after vaccination. In the end, it seems that developments of SARS and MERS vaccines were not halted due to the concern from ADE, but rather from lack of interest and funding of pharmaceutical companies as the threats from these diseases subsided. The decrease in incidence happened naturally to SARS, while MERS was discovered to be barely contagious in human-to-human transmission.
At the earlier stages of development of vaccines against SARS-CoV-2, researchers noted high levels of neutralizing antibodies. Based on knowledge gained during the development of SARS vaccines, this led to the belief that there are high chances of success and low chances for ADE. Pfizer’s and Modera’s COVID-19 vaccines may work on the same mechanism of creating neutralizing antibodies against a spike protein, but they use RNA technology that does not usually require an adjuvant substance. This fact further decreases the chance of ADE that was observed during the development of SARS vaccines.
So far, there is no evidence of antibody-dependent enhancements in the current corona disease. SARS-CoV-2 viruses (yellow) as seen through an electron microscope | Source: CDC / SCIENCE PHOTO LIBRARY
ADE and the Corona Vaccine
As previously mentioned, ADE is a property of the disease itself, and not of the vaccine against it. If ADE existed in COVID-19, we would have expected to witness the phenomena among individuals who got reinfected with the virus, and not solely among vaccinated people, however, this has yet to be identified.
One could also have expected that a cocktail of SARS-CoV-2 antibodies would incite the same ADE storm. Nonetheless, pre-clinical trials demonstrated that antibodies protected rats and Syrian hamsters, without causing a deterioration in the severity of the infection or disease. Coronavirus treatments that were based on receiving antibodies from recovered individuals (plasma treatments) also reported high safety and improved the patients’ condition.
Despite the early signs that predicted there will be no ADE in the current corona disease, the concern of the phenomenon always looms over new vaccine development, and the new COVID-19 vaccines are no exception. Therefore, during the development of the current vaccine, tests were performed and trials were conducted in order to test for the possibility of an antibody-dependent enhancement. This possibility was the subject of a lively academic debate and numerous articles, such as articles published in PNAS in April, in Science in May and extensive literature reviews in Nature in July and September.
The subject was tested over and over again during the pre-clinical and clinical phases of the vaccine development process. Moreover, In March 2020 a large scientific committee gathered, including by experts from all over the world and led by the CEPI (Coalition for Epidemic Preparedness Innovation), that examined the subject of COVID-19 vaccine safety specifically with regards to ADE.
In experiments performed on mice, rats and monkeys that were given the inactivated virus, there were no signs of ADE, despite the fact that an inactivated vaccine should pose greater risk for ADE as these vaccine lead to production of antibodies against many proteins of the virus, and not just against the spike protein such as the Pfizer and Moderna vaccines. Therefore, it should offer a greater opportunity to manufacture a wide range of non-neutralizing antibodies.
In the Emergency Use Authorization that the FDA has granted Pfizer’s vaccine includes a explicit note regarding ADE (page 52): “Available data do not indicate a risk of vaccine-enhanced disease, and conversely suggest effectiveness against severe disease within the available follow-up period. However, risk of vaccine-enhanced disease over time, potentially associated with waning immunity, remains unknown and needs to be evaluated further in ongoing clinical trials and in observational studies that could be conducted following authorization and/or licensure."
The follow up on vaccinated and recovered individuals continues, despite no data indicating a risk for ADE. A woman receiving a COVID-19 vaccine | Photo: DR P. MARAZZI / SCIENCE PHOTO LIBRARY
ADE is a phenomenon seen in some viral diseases when reinfection can occasionally lead to a more severe form of the disease. There was a concern that this phenomenon would also occur with COVID-19, and so the subject was studied extensively by many specialists.
So far, the phenomenon was not seen in humans; not in the known cases of reinfection of the disease, not in plasma treatments given to recovering patients, not in the phase 3 trials of the vaccines performed on tens of thousands of people and not during the wide-scale vaccination drives worldwide. Follow up is still regularly performed, of course, among the infected, recovered, and vaccinated populations, and further tests are being conducted in animals in order to rule out unpleasant surprises.
It is important to remember that COVID-19 is a new disease. With more new variants of the disease spreading, we could further examine if any ADE cases occur when people are reinfected with different variants of the virus. So far, initial findings regarding the British variant, for example, have not reported ADE among those infected by it.
Although it cannot be unequivocally determined that the risk of ADE is nonexistent, as of today our findings show that it is unlikely, and the chances are slim. However, the danger of the disease itself and the damage it can cause, even for those who are not in a risk group, has been documented countless times.