No evidence that COVID-19 vaccines cause more severe disease; antibody-dependent enhancement has not been observed in clinical trials
Antibody-dependent enhancement (ADE) occurs when antibodies are unable to neutralize a virus’ infectivity, but instead enhance a virus’ ability to infect cells. Although ADE has been observed in humans who received the dengue vaccine, as well as in individuals that received a vaccine candidate for the respiratory syncytial virus, the evidence from COVID-19 vaccine clinical trials so far have not shown more severe disease occurring in vaccinated participants. People who have been given the COVID-19 vaccine will continue to be closely monitored to determine whether ADE occurs.
Unsupported: Antibody-dependent enhancement (ADE) is theoretically a possible side effect of a COVID-19 vaccine. However, clinical trials so far have not shown ADE occurring in vaccinated participants.
Inaccurate: Some posts inaccurately suggest that non-neutralizing antibodies are irrelevant to protection. Although non-neutralizing antibodies can result in ADE, such antibodies can also participate in a process called antibody-dependent cell cytotoxicity, which kills infected cells and is an important part of a protective immune response.
A Facebook post claiming that the COVID-19 vaccine will lead to more severe disease, was published in November 2020 and went viral on the social media platform. Similar claims have also been published in other social media posts, like this one and this one. The claim is based on the observation of more severe disease occurring in individuals who received a dengue vaccine and a vaccine candidate for the respiratory syncytial virus. Both are likely due to a phenomenon known as antibody-dependent enhancement (ADE), however ADE has not been shown to occur in individuals that received COVID-19 vaccines to date. One of the authors of these posts previously claimed to be a toxicologist, despite lacking the necessary training and credentials for that title.
Health Feedback reached out to experts to find out how ADE works and whether the claim is supported by scientific evidence [See scientists’ feedback in full].
Angeline Rouers, a research fellow at the Singapore Immunology Network, explained, “ADE is a well-known mechanism which was described for the first time in dengue patients. It occurs when antibodies do not neutralize the virus to prevent its entry into the target cells, for example, but instead facilitate the infection of other cells, such as macrophages (a type of immune cell).” However, Rouers added that there is “no clear evidence” showing that the virus which causes COVID-19, SARS-CoV-2, can infect macrophages.
Walter Orenstein, a professor at Emory University’s School of Medicine and associate director of the Emory Vaccine Center, said, “Vaccine-enhanced disease is theoretically possible with SARS-CoV-2 vaccines, but it has not been seen as of yet in the clinical trials reported.”
Sanjay Mishra, a staff scientist and project coordinator at Vanderbilt University Medical Center who is also working in the COVID-19 and Cancer Consortium, concurred. “The major vaccine candidates that have so far progressed in the large-scale Phase 3 trials, such as the ones by Moderna, Pfizer, and AstraZeneca, have all ruled out any serious safety concerns,” he said.
Overall, all three scientists agreed that close monitoring of vaccinated people is important to ensure that ADE can be safely ruled out as a side effect of COVID-19 vaccines, but for the moment, the evidence has not shown the vaccines to have such an effect.
Indeed, preliminary findings released by frontrunners Moderna, Pfizer, and AstraZeneca have shown that among the trial participants who did develop COVID-19, those who received the vaccine did not show higher rates of severe disease compared to those who received the placebo. The vaccines were also able to prevent COVID-19 at a high efficacy. However, an important caveat of these findings is that these trials are still underway, and the number of people included in these interim analyses is relatively small.
Apart from the post’s unsupported claim linking ADE with COVID-19 vaccines, its suggestion that non-neutralizing antibodies are always ineffective for protection is inaccurate. The immune system has several ways to deal with viruses, and “Antibody-dependent cellular cytotoxicity, which can involve non-neutralizing antibodies, is another mechanism that is distinct from neutralization, that is also important for a protective immune response,” Rouers pointed out.
And contradicting Everly’s claim that “no one is concerned about it,” Health Feedback was able to find multiple articles published over the course of 2020 that discussed concerns about ADE with respect to the COVID-19 vaccine. Some examples are this article in The Scientist, this article in PNAS and these two articles in Nature[1,2], the latter two being highly respected journals in the scientific community.
Overall, while ADE is a theoretical possibility with a COVID-19 vaccine, clinical trials in people so far have not shown that participants who received the vaccine have a higher rate of severe illness compared to participants who did not receive the vaccine. Given the paramount importance of vaccine safety, scientists continue to encourage rigorous safety monitoring so as to completely rule out ADE as a potential side effect.
Staff Scientist, Vanderbilt University Medical Center
Antibody-dependent enhancement (ADE) of virus infection is a phenomenon in which virus-specific antibodies enhance the entry of a virus and in some cases, ADE can even facilitate the infection. ADE has been well-established in dengue and Zika viruses, and any poor-quality antibodies that bind the virus but do not neutralize can cause ADE. Indeed, some vaccine candidates, such as one against the respiratory syncytial virus resulted in deaths due to ADE. However, no definitive role for ADE in human coronavirus diseases has yet been established, despite the concerns raised[7,8].
The opinion piece being cited in the viral Facebook post itself concluded that “the risk of ADE remains theoretical” in vaccines being developed against SARS-CoV-2. The major vaccine candidates that have so far progressed in the large-scale Phase 3 trials, such as the ones by Moderna, Pfizer, and AstraZeneca, have all ruled out any serious safety concerns. While more data is still needed, randomized controlled trial with convalescent sera has also shown to be beneficial in COVID-19 patients with moderate disease severity. Just like other things related to this pandemic, we should wait and watch for better evidence to completely rule out ADE, but no evidence for ADE has been found so far.
Senior Research Fellow, A*STAR Infectious Diseases Labs
ADE is a well-known mechanism which was described for the first time in dengue patients. It occurs when antibodies do not neutralize the virus (to prevent its entry into the target cells, for example) but instead facilitate the infection of other cells, such as macrophages. It might also happen with coronaviruses but for the moment, there is only in vitro demonstration of this with regards to SARS-CoV-2. The mechanisms in vivo might be different and there is also no clear evidence showing that SARS-CoV-2 can infect macrophages.
As a note, it is false to say that non-neutralizing antibodies are inevitably non-efficient and potentially dangerous, as suggested in the Facebook post. Antibody-dependent cellular cytotoxicity, which can involve non-neutralizing antibodies, is another mechanism that is distinct from neutralization that is also important for a protective immune response.
This claim is particularly alarming for the public and unnecessarily invokes a conspiracy theory: “Most people don’t know this. Most people have never heard of this. Maybe the big media networks don’t find this important to share with the public, or maybe it’s just plain censorship. It’s probably censorship.” In fact, ADE is an immune response that is well-known to scientists and is described in immunology textbooks. ADE has to be assessed from the earliest stage of vaccine development. There is nothing hidden from the public—if ADE is detected during vaccine development, it will simply stop the trials. We can never be 100% sure it will not happen in some way at a later stage of clinical trials, but in the whole history of vaccines, this phenomenon is very rare.
The post also mentions that (a) antibodies might not be the most protective aspect in the context of SARS-CoV-2 and (b) there is a positive correlation between severity and level of antibodies in the patients. These claims are true but require more context to avoid readers’ misunderstanding. (a) Cytotoxic T cells have indeed been shown to be very important to fight the virus, however, antibodies are also doing part of the job and should not be neglected. (b) The level of antibodies is not necessarily predictive of their efficiency. Indeed, a high level (quantity) of antibodies might not be protective, and can even make things worse in the case of ADE. But a high level of efficient (i.e. neutralizing) antibodies is generally a good prognosis.
Overall, it is very important to keep in mind the difference between what is observed in the patients and what a vaccine aims to do. A vaccine does not aim to reproduce the immune response observed in an infected patient; on the contrary, it aims to elicit a neutralizing antibody response to fight the virus—this is something that is rarely observed in severely ill patients.
ADE is a concern that scientists have in mind and will assess carefully. Some vaccine candidates may have led to ADE at the early stages of trials, which halted their development. This demonstrates that the scientific community is careful and will do everything possible to release a safe vaccine for people. In conclusion, ADE is a theoretical danger in SARS-CoV-2 vaccine development, but it is taken seriously into consideration and very close monitoring will be applied.
Thus far, there are no data supporting vaccination as a cause of vaccine-induced enhanced disease. Such enhancement has been seen with other vaccines such as the dengue vaccine. But for the vast majority of vaccines in use today around the world, such enhancement has not been seen.
There were concerns seen in animal studies with earlier coronavirus vaccines for SARS-CoV-1 and MERS. But not in human studies to date.
Vaccine-enhanced disease is theoretically possible with SARS-CoV-2 vaccines, but it has not been seen as of yet in the clinical trials reported. In contrast, SARS-CoV-2 is killing more than 1000 people a day in the US alone.
It will be important to monitor to see if enhanced disease happens. But there is no evidence for it in humans to date. In contrast, there is good information on efficacy.
- 1 – Lee et al. (2020) Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nature Microbiology.
- 2 – Arvin et al. (2020) A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature.
- 3 – Tirado and Yoon. (2003) Antibody-dependent enhancement of virus infection and disease. Viral Immunology.
- 4 – Dejnirattisai et al. (2010) Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans. Science.
- 5 – Halstead and O’Rourke. (1977) Antibody-enhanced dengue virus infection in primate leukocytes. Nature.
- 6 – Kim et al. (1969) Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. American Journal of Epidemiology.
- 7 – Ho et al. (2005) Neutralizing Antibody Response and SARS Severity. Emerging Infectious Diseases.
- 8 – Zhao et al. (2020) Antibody Responses to SARS-CoV-2 in Patients With Novel Coronavirus Disease 2019. Clinical Infectious Diseases.
- 9 – Li et al. (2020) Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19. JAMA.