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COVID Crisis Post 36: Antibody-Dependent Enhancement.

The immune system is incredibly fascinating.

And understanding its role in COVID-19 is essential to our fight against it.

A silver lining of this pandemic is its numerous opportunities to learn because I am by no means an expert on COVID-19. I prefer to read objective (read: rooted in actual science) literature to grow my knowledge but am open to consider opinion pieces beyond that as well. This pandemic is awful, but I am grateful for these teaching moments.

I want to talk about vaccines, specifically in regards to COVID-19. Though I understand there are some who are against vaccines, the purpose of this post is not to serve as a forum for those who disagree with me. Any argument made over social media is typically ineffective, especially when it comes to topics where they elicit strong emotional responses. So please refrain from posting anything anti-vaccine on my page, just as I would respectfully decline posting anything pro-vaccine on yours.

So here's my mini-vaccine primer for COVID-19:

First of all, there is a great deal of anxiety surrounding the successful development of a vaccine. The University of Pittsburgh stated a couple of weeks earlier they had developed a promising vaccine candidate for COVID-19 that demonstrated a robust antibody response within two weeks, could be easily mass produced, and did not require refrigeration to maintain its effectiveness. And this sounded great.

But then they stated clinical trials could take well over a year, corroborating the comments by Dr. Fauci when he stated a vaccine would most likely require a minimum of 12-18 months to develop.

This seems extremely confusing without further explanation. The immune system is extremely complicated. It is not a simple game of introduce a disease, be protected from it. Many times, the game is that simple. But sometimes, your immune system inadvertently gets tricked into helping the disease.

And one of these tricks is called antibody-dependent enhancement (ADE) of disease.

I now realize this is what my friend and medschool classmate Dr. Pepper (no joke) was likely alluding to a couple of weeks ago when we were catching up, and he brought up his worries that COVID-19 could be the next Dengue. In those who develop Dengue, typically the disease is mild with some fever and muscle aches. But in those who get infected a second time, they have a much higher chance of developing hemorrhagic fever or progressing to shock. And this is likely due to ADE.

The specific mechanisms of ADE have proved elusive and likely vary from virus to virus. The scientific community used to be skeptical of ADE, but an abundance of evidence supporting the existence of ADE has reduced this skepticism greatly.

ADE could provide a great deal of insight in regards to understanding the severity of disease with COVID-19, and it also helps explain the difficulty in producing a vaccine in a quick and efficient manner.

Very simplified explanation of ADE:

Antibodies formed from certain prior viral infections can possibly lead to more severe illness with subsequent infection from a different strain of the same virus.

Much more complicated, and maybe scary, explanation:

Whenever our bodies are infected by a virus, our immune system develops antibodies against that specific strain of virus, and this response can vary from poor to robust. Those same antibodies sometimes are able to also provide cross-immunity towards different strains of the same virus or viruses very similar in structure, one explanation for why children may tend to have a more attenuated disease response with COVID-19.

However, there are certain viruses that can take advantage of this cross-immune response if those antibodies are only subneutralizing or nonneutralizing for the different viral strain. The virus gets bound to the antibody but not destroyed, and the antibody can actually serve as a vessel or bridge to help FACILITATE introduction of the virus into cells, dramatically increasing infectivity. This is what likely occurs with Dengue, and why subsequent disease with a different strain can be so severe.

And there is ample evidence this occurs with coronaviruses as well.

Evidence of ADE has been demonstrated in other coronaviruses, specifically SARS and MERS. And due to ADE modulating the immune response as described, it can elicit sustained inflammation, lymphopenia, and/or cytokine storm, one or all of which have been documented in severe cases and deaths of COVID-19.

So cross-immunity can be a boon to some. But devastating to others.

Thus, when developing a COVID-19 vaccine, the goal is to develop something proven safe, effective, AND reduce the chance ADE could occur should a different strain of the virus later emerge. And if ADE truly plays a role in modulating severity of response, which seemingly many virologists believe, the vaccine could be FAR BETTER than being infected with the virus itself.

Why is that? Well, viruses are oxymoronic given they are complex, simple organisms.

Typically, a weakened or inactivated virus elicits the most robust response by the immune system. But as has been made abundantly clear during this pandemic, this can be devastating. If COVID-19 could be taking advantage of ADE to increase infectivity in certain hosts, then it is essential to develop antibodies SPECIFIC to COVID-19 itself but reduce or eliminate the risk of ADE.

And that is precisely what vaccine researchers are trying to accomplish.

Much of the vaccine research has been focused on first identifying specific subunits/essential antigens found on COVID-19 that could be used as targets, with the most promising being the spike protein which serves as the virus's receptor binding site. Once this is done, recombinant DNA technology can be used to elicit a strong immune response to the specific antigen since the antigen itself is not usually enough to do so; this same technology is used in both the Hepatitis B and HPV vaccines.

This vaccine would then introduce one or more specific targets for our immune system to focus on, and thus dictate the type of antibodies formed.

This should hopefully accomplish 2 things: 1. Reduce the risk of side effects of the vaccine by avoiding the use of weakened or inactivated virus. 2. Decrease the risk of developing ADE since the vaccine should theoretically help form antibodies to specific antigens found on any strain of COVID-19.

Phew! I know this can sound scary, but I hope this was helpful in terms of understanding what we may be up against. And I also hope you realize science can be fucking cool.

Just as the illustrious Jesse Pinkman once did when he excitedly stated:

"Yeah, Mr. White! Yeah, science!"

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