We need a coronavirus vaccine, but let's be careful of antibody-dependent enhancement

By LisaMichelle Pecaro and Jacob Ingber


It’s not every day you hear about antibody-dependent enhancement (ADE). In fact, it is a little-known phenomenon that occurs when a person’s immune response worsens a viral infection, instead of eliminating the invasion.

During a typical viral infection, your immune system creates antibodies, which attach to the invading virus and prevent it from entering your cells. If a virus can’t enter a host cell, it won’t be able to replicate and will be left exposed to be killed by immune cells. This is an important way the body prevents infection. In fact, when you get vaccinated, you are actually being exposed to a non-infectious version of a virus, so that your body creates antibodies that will protect you from becoming ill, if you are exposed to the same virus later on. Antibodies will recognize viruses of the same serotype and attach themselves by binding to proteins on the virus’ surface.

Adapted from Janeway’s Immunobiology (9th Edition), by Kenneth Murphy and Casey Weaver

What is a serotype anyway?

Separate serotypes are variants of similar viruses that possess different surface proteins. These proteins determine which cells the virus can infect and which antibodies can bind to the virus. Viruses can acquire mutations that change surface proteins, leading to distinct viral serotypes. After infection with one viral serotype, the host will produce antibodies recognizing the viral surface proteins, which prevent illness upon re-infection. The development of antibodies to one serotype may not protect you from a second serotype, even if antibody-binding to the second serotype occurs.


When and how does ADE occur?

In general, ADE occurs when serotype variants of a virus exist. The antibodies produced during exposure to an initial viral serotype are capable of binding to new invaders which are a similar virus, but a different serotype. However, the antibodies can’t prevent the new serotype from entering and infecting the patient’s cells. Even worse, these antibodies promote both viral replication and an overly exuberant immune response. The antibodies cause the uptake of the newly infecting serotype specifically into immune cells, which greatly stokes up the immune response, but does not result in virus neutralization. This can occur whether the initial exposure was a natural infection or a vaccine exposure.


Does the current coronavirus outbreak (SARS-CoV-2) have different serotypes?

Researchers have not yet discovered divergent serotypes of SARS-CoV-2. However, early studies have shown that SARS-CoV-2 has already mutated and split into separate strains, since it was first discovered in China in December 2019. If future mutations specifically alter the virus’ surface proteins, we will have a new serotype circulating.


Has ADE been shown to enhance COVID-19?

Not yet. However, at present, no immunologic tests or biological markers are known to detect or predict the occurrence of ADE.

In addition, there exists a risk of ADE of COVID-19 due to the many coronaviruses circulating in the world, which commonly infect humans. For example, the MERS virus (Middle East Respiratory Syndrome) and SARS-CoV-1 (which caused the 2002-04 SARS outbreak) are both coronaviruses which are serotypically different from SARS-CoV-2 and which also infected many people around the globe. In fact, two studies showed that in a cohort of patients who have never caught SARS-CoV-2, around 30–50% already possessed immune cells capable of cross-binding with SARS-CoV-2. Antibodies previously formed to target these other coronaviruses could theoretically cause ADE of SARS-CoV-2, and perhaps even cause the severe form of COVID-19 that is associated with a failure to clear the virus, despite an extreme immune response (inflammation, cytokine storms, etc.)


What does this all mean and why should we care?

Coronaviruses generally become fatal only when acute respiratory distress syndrome - ARDS - is initiated. ARDS is caused by a lung immune response in overdrive. While we don’t yet know what causes this, it may happen as a result of ADE-induced infection of host immune cells. If this occurs naturally, because of multiple infections with different coronaviruses, it is unavoidable. However, there is no reason to allow ADE to result from vaccination.


Vaccines can actually cause this?

Yes. When a person is given a vaccine for SARS-CoV-2, they are being exposed to a dead or inactive version of the virus. Since the virus is not infectious, it cannot cause illness. Instead, the vaccine exposes the immune system to the virus for the first time, allowing antibodies to be formed against the invader. This is a great way to protect a patient against the same exact virus serotype, because any second invasion will be attacked so quickly that symptoms may not even have the chance to develop. However, given its rapid rate of mutation, SARS-CoV-2 may be able to evolve just enough to evade neutralization by the antibodies that the immune system formed when given the SARS-CoV-2 vaccine. Thus, similar to a previous natural infection with a different coronavirus, those vaccinated for SARS-CoV-2 could then be at risk for ADE.


What is the reason these antibodies can’t neutralize a different serotype?

Researchers are not sure what prevents the antibodies from doing their job. However, two leading theories are:


1. Suboptimal affinity (binding strength) of the patient’s antibodies - the antibodies can bind, but only weakly, so they can be knocked off of the virus that they are binding to.


2. The specific binding site of the attached antibodies - the antibodies bind to a part of the virus that isn’t involved in its entering host cells. Thus, neutralization doesn’t occur.


What can we do?

It is imperative that we produce a vaccine for SARS-CoV-2, but we must also conduct carefully planned vaccine safety studies to watch for signs of disease enhancement, as well as any other adverse effects. Separate animal study groups could be used to learn if there are any differences in severity of infection between a vaccinated group and an un-vaccinated control group, after subsequent exposure to SARS-CoV-2. In addition, we must be vigilant of any evolution of the SARS-CoV-2 virus which may cause a safe vaccine to suddenly induce ADE in human populations, due to serotype changes in SARS-CoV-2. Studies should also be conducted to determine if vaccines can induce the production of broadly-neutralizing antibodies. These antibodies target proteins on the virus surface that are very unlikely to sufficiently mutate to avoid neutralization.


Is a SARS-CoV-2 vaccine our only option? No. There are alternatives to inoculation with a vaccine. One such option is passive-immunity, which is induced by treating a patient with monoclonal antibodies. While there are multiple ways to produce monoclonal antibodies, a common approach for COVID-19 is to isolate B cells - which make antibodies - from patients who have been infected, and have recovered, with SARS-CoV-2 and use multiple rounds of selection to find an antibody that broadly neutralizes SARS-CoV-2. These antibodies can then be expressed in other cells, such as yeast, to produce large numbers of them.

Monoclonal antibodies can be engineered with molecular precision, are effective neutralizers, and could be mass-produced for delivery to populations around the world.


Monoclonal antibodies could have two important uses in the context of COVID-19:

  1. They can be used therapeutically in already infected individuals to boost the immune system’s ability to clear the infection.

  2. Monoclonals can be used pre-exposure to prevent infection, and shortly after exposure, prior to symptom onset, to prevent severe disease.

Importantly, since monoclonal antibodies can be carefully designed, ADE-inducing antibodies could be screened out and only safe, effective antibodies could then be produced. In addition, several monoclonal antibodies can also be given as an “antibody cocktail” to improve their neutralization abilities and limit the ability of a mutated virus to “escape” neutralization.

While monoclonal antibodies generally last for several weeks, molecular engineering may allow them to last for several months. Since we currently don’t know how long the antibody response will last following vaccination for SARS-CoV-2, this represents a safe and effective way of immunizing mass numbers of people while further vaccine studies are done.


Despite the potential risks of vaccination, vaccines that are properly studied and approved are overwhelmingly safe and effective. As of now, there is no indication that currently studied vaccines for SARS-CoV-2 will induce ADE. So, while researchers must be diligent to watch for ADE and other adverse events, vaccination remains the gold-standard for infectious disease prevention and the concerns outlined here do not negate the need for a safe and effective SARS-CoV-2 vaccine.

Results from ongoing research and the current understanding of COVID-19 are constantly evolving. This post contains information that was last updated on July 18, 2020.

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