Sticky Serology

Today's Microbial Mondays is in answer to a question from Michael. He asked, "We’re hearing and reading a lot these days about antibodies and serology testing, and how this is fraught with challenges. Can you straighten us out a little on the basic science behind this?"

Serology tests (also known as antibody tests) are different from direct tests for viruses in that they don't actually tell you anything about whether the virus is currently present. Instead, serology tests only tell you if your immune system has responded to the virus by producing antibodies. You can think of serology testing as kind of like fingerprinting. Just because you find fingerprints in a house, it doesn't mean that the person who has produced those fingerprints is still in the house. It also doesn’t necessarily mean that that person is gone; all the fingerprints tell you is that the person was there at some point.

You might ask, then: why are we worrying about doing serology tests for COVID-19 at all, if it doesn't tell you if that cough you have is SARS-CoV-2 or just a common cold or allergies?

The answer is that with serology tests, we don't only want a yes or no, black and white answer to whether a person currently is infected or not. Rather, we want a more nuanced overview of if, and if yes how, that person's immune system has responded to the virus' presence. Serology tests can give scientists detailed information about what types antibodies people have, and whether they are 'neutralizing' for, i.e. a full knock-out attack on, the virus in question.

The basic science behind serology testing is actually very simple. Scientists simply rely on the 'stickiness' of antibodies to whatever the body has made them to attack. Antibodies are basically two grabby hands on a stick, with the singular function of grabbing on to invading microbes.

A typical antibody caught in action

When antibodies successfully grab on to microbes, there are a few possible options - none of which is usually good for the microbe. If many antibodies grab on to the same virus or bacterium, it might be sort of swarmed out of commission. Imagine if you had a gazillion tiny lego pieces stuck to every inch of your body. You'd be in no condition to be very productive. I imagine that that's basically what a bacterium might feel like if it were entirely coated with antibodies. Alternatively, if only a few antibodies grab onto that single microbe, they can still incapacitate it, for example by acting as 'eat me' signs (I like to imagine this Alice In Wonderland-style) to immune cells that will then gobble up the 'eat me'-tagged microbe.

So you see, either way, it is pretty important to their functioning that antibodies be sticky. The thing is, to test if antibodies are present, we often have to give them something to stick to. One of the simplest tests for antibodies is to simply coat a surface with protein from, for example, a virus, and see if any antibodies in the bloodstream of patients stick to it.

However, this is complicated by two factors: 1) that antibodies only stick to specific parts of specific proteins, and 2) viruses have several proteins.

Let's cover that first complicating factor, first. Indeed, antibodies only 'see' and 'grab' specific little sections on proteins. If you think of them like lego again, you'll understand. The lego pieces only fit together in certain ways, they aren't like smooth blocks that can be stacked either upside-down or right-side-up. There is a specific geometry that must be there, in order for the lego blocks to stick together. The same goes for antibodies sticking to proteins.

The second reason why serology testing can become tricky, is that viruses aren't made up of just one type of protein. They have different proteins that are in different places and have different functions for the virus. You can see in the sketch of SARS-CoV-2 below, that this virus has four proteins: The 'S' (short for 'spike'), 'M' (for 'membrane'), 'E' (for 'envelope') proteins on the outside, and the 'N' (for 'nucleocapsid') protein on the inside. The virus is more or less spherical, so you can imagine that unless its surface is compromised somehow, the 'N' protein isn't visible from the outside. That means that, for example, antibodies that stick to the 'N' protein aren't much use for neutralizing the virus. They can't see their target unless the virus is already damaged.

A remarkably realistic drawing of the SARS-CoV-2 structure, if I do say so myself

Finding the right viral proteins that antibodies must stick to in order to be neutralizing is an ongoing question for both serology testing and vaccine development. For serology testing, we want to know if we're testing for neutralizing antibodies, because it is only if a patient has these high-quality, neutralizing antibodies that they will be protected from another run with the virus. For vaccine development, we would love to know exactly which proteins are the most 'sticky' for neutralizing antibodies, so that we can design a vaccine that encourages our bodies to make lots of these high-quality virus destroyers.

In an impressively short amount of time, we are getting close to an answer. Recent research suggests that certain chunks of the 'S' protein are good targets for antibodies. Many labs are working on confirming this, and taking it further for development of validated serology tests and vaccines. But, as I've written before, vaccine development simply takes time. In the meantime, remember that you are by no means powerless against this virus. Among the best things you can do to strike back against this pandemic, are simple actions like washing your hands, wearing a mask, social distancing, and educating yourself - which you have a head start on by reading this post to the end!

Stay healthy,

~ Alex

Additional up-to-date information on serology testing against SARS-CoV-2 is available here.