There are over 90 coronavirus vaccines in development, and people want to know which work best. I mean, who doesn’t want to know? WHO (the World Health Organization) does, so they’re proposing a unique international vaccine trial, which is just one of the ways these vaccines will be put to the test. 

As I mentioned above, to my knowledge as of writing (5/4/20), there are over 90 coronavirus vaccines being developed. They all aim to do the same thing – introduce a person’s body to the coronavirus that causes Covid-19 (i.e. the SARS-Cov-2 virus) or some part of that virus in a harmless form. This allows the person’s immune system to learn what the virus looks like without the person having to get sick. This learning involves developing little proteins called antibodies that (by combining unique variable regions with generic constant regions) specifically bind parts of the virus but don’t bind the person’s own molecules. This way, if the virus does try to infect the person, that person’s immune system can flag it right away and destroy it. 

The 90+ vaccines all have this same general goal but they take different approaches – some take more traditional approaches like injecting killed or weakened versions of the whole virus, others inject only parts of the virus – like one of its proteins, and others introduce the genetic instructions (gene) for making a viral protein, but rely on the injected persons’ cells to do the actual making (e.g. DNA & mRNA viruses). I’m not going to go into detail here, because I went into a lot of detail yesterday. So, if you’re interested: https://bit.ly/coronavirusvaccinetypes 

And here’s a link to the WHO’s list of vaccine candidates: https://bit.ly2L5mrSB 

Some of these are likely to fizzle out early, but how will the rest get tested and proven?

It’s “easy” to show (at least initially) if a vaccine is safe – inject someone (with their consent, after animal testing, following guidelines etc.) and see if they have a negative reaction. Drug companies do this sort of thing all the time in “Phase I trials.” But how do you know if a vaccine works? (does it show efficacy?) 

An early hopeful sign is if people given the vaccine start producing antibodies against the virus – and this can be tested using antibody blood tests like an ELISA. https://bit.ly/covid19testtypesBut that doesn’t tell you about what “kind” of antibodies are being made, and what they really want to see are neutralizing antibodies – these are the kinds of antibodies that actually prevent a virus from infecting other cells, as opposed to “binding antibodies” which bind a viral part and can call in the immune system to help out, but they can’t actually keep the virus out of cells. (Don’t get confused by the names – neutralizing antibodies bind as well, they just happen to bind in a place that the virus uses to get inside our cells. For example, neutralizing antibodies might bind the receptor binding domain (RBD) of the virus’ spike protein (the one that juts out of the membrane crown-like) in such a way that it blocks the virus from latching onto our cells’ ACE2 receptors and sneaking in.  

To look for this kind of antibody, scientists can use a more involved/time-consuming technique called a plaque reduction neutralization testing (PRNT), where they put virus & antibodies onto a layer of non-infected cells in a dish and see if the virus infects those cells. If the antibodies are neutralizing, the virus can’t get in, so the cells survive. But if the antibodies are not neutralizing, the virus will infect cells and, since these cells are just in a dish (no immune system backup), those cells will die – and they’ll infect nearby cells, so you have whole regions of cells dying, leaving dead-cell zones called plaques. The “better” the neutralizing antibodies (either stronger antibodies or higher concentration of them) the fewer plaques will be seen. I plan to do a separate post on this because it’s pretty cool, but I’m guessing many of you (sadly) aren’t so I won’t bore you here…

Just know that this PRNT is one of the early ways scientists can test if a vaccine shows promise – immunize a lab animal (and, if that pans out, a person) and test that animal/person’s blood to see if neutralizing antibodies are made. This is far from proof a vaccine is safe & effective, but it’s an important first step before further testing. 

Producing neutralizing antibodies is a good sign, but it’s one thing to prevent infection in a dish – it’s a whole other thing to prevent infection in a body… Animal testing can be used to see if the vaccine prevents infection in monkeys, etc. but that still isn’t a guarantee that it will do so in people. But testing this is tricky.

Normally it would require massive “placebo-controlled trials” for each vaccine – give thousands of people the vaccine you now know is at least safe, and give thousands of people a placebo (fake). Then compare the infection rates after some time. 

To do this you need thousands of people who haven’t been infected in an area where the virus is still widely spreading. And you have to wait and wait and wait because they could get infected at any point. That works if you’re just trying out a new vaccine for a virus that there’s already a vaccine and/or cure for. But that’s not the case, so people are looking for ways to safely speed things up. 

On April 9, 2020, the World Health Organization (WHO) proposed plans for an international, randomized, clinical trial testing multiple vaccines at once (i.e. a person is randomly chosen to receive vaccine A, or vaccine B, or vaccine C…. or a placebo) https://bit.ly/3fbEsfI 

Called the Solidarity Vaccine Trial, it’s flexible and “rolling” – it allows new candidate vaccines to enter the trial at any point and vaccines that don’t seem to work will be removed. And participants can also be enrolled continuously. At this point it’s still in the planning phase, but, with 90+ potential vaccines, people are talking about trying to prioritize the most promising https://go.nature.com/3d9DLBS 

“Most promising” is hard to determine because even if 2 vaccines are both found to have the same safety and efficacy, one might be much easier/cheaper/faster to make and/or deliver. Another thing to keep in mind is that some of the easier/cheaper/faster vaccine types (like the DNA & mRNA vaccines) haven’t been used before – for any virus. So those need additional safety testing compared to more traditional vaccines where the general safety of the method has been shown with past vaccines. 

And even if a vaccine is “the best,” unless the vaccine developers know the system well and can easily get funding, scale up production, etc. that vaccine probably won’t stand a chance – so this favors the established players in the game, the ones you hear about the most.

But there doesn’t have to be just one – in fact, having multiple would spread out the vaccine-making capacity. This capacity might be a big hold-up (I mean, just look at how hard it’s been to get enough tests, or even PPE!), which has a lot of big-name manufacturers and drug designers teaming up. 

Vaccine development typically takes decades, but the timescales people are currently aiming for are much shorter (even if they seem way too long to us). If vaccines show early promise they might also be able to get emergency use authorization to give it to high-risk populations like healthcare workers, though this sort of emergency authorization for a vaccine (as opposed to drugs) hasn’t been done before https://go.nature.com/3d9DLBS 

Some people are also talking about speeding things up with “human challenge” studies where people at low risk of developing serious disease complications (e.g. young volunteers with no underlying health conditions) are immunized and then intentionally infected to see if they get sick. A lot of people have volunteered to be guinea pigs, but there’s also a lot of pushback because even young healthy people can get really sick and even die from Covid-19, and scientists can’t predict which “healthy” people are at risk. 

It’s one thing to potentially give someone a cold or something worse than a cold but with a sure cure. It’s a whole other thing to potentially give someone coronavirus. There’s still so much we don’t know about the disease like potential genetic risk factors that make some people more susceptible and, since there’s no cure, or even real treatment, purposely infecting people with the coronavirus is ethically dubious https://go.nature.com/2VX3I1O 

Another question with all of these vaccines is how long the immunity will last. There are some vaccines where you have to get “booster shots” because the immunity fades. And there are also some vaccines where you have to get “new versions” – like the flu vaccine. A hard thing about flu vaccines is that the flu virus mutates a lot – so it’s hard to “catch it” (and therefore easier to actually catch it…). Thankfully, at least so far, the current coronavirus, SARS-Cov-2 doesn’t seem to be mutating much. One reason for this is because it makes its own proofreader.

SARS-Cov-2 has one of the biggest genomes (genetic blueprints) of any virus, but it’s written in RNA. This is great for the virus because RNA is the form that protein-making ribosomes read and make proteins from. Our genome is kept in DNA, so when a cell wants to make a protein, it first makes an RNA copy. It sounds like a hassle, but there are benefits, like keeping our DNA protected. And speaking of DNA protection, our cells have a lot of DNA proofreaders because it’s really important that DNA (our permanent genetic blueprint) is copied correctly. However, there’s less urgency for proofreading our RNA – because those are just temporary copies. 

RNA viruses like SARS-Cov-2, however, have “permanent” RNA copies. So they want to protect them, and therefore they make their own proofreader (they also have to make their own RNA to RNA copier (RNA-dependent RNA Polymerase (RdRP)) because we don’t have one of those). Having to make their own proteins means they have to have bigger genomes, but, because of that proofreading enzyme, they’re able to protect their genome – much better than something like the flu. 

Flu viruses have a much smaller genome and much laxer proofreading, so they mutate a lot – and they have their genome in multiple pieces which has the consequence that if a cell gets infected with 2 flu viruses at once, the viruses can swap/combine to form a potentially more dangerous virus. You might think that all that mutating would prove fatal, but, because they have few genes and such high mutation rates, positive mutations can occur at the same time as negative mutations, and mutations can co-occur that complement one another and make the virus stronger.

So, while you might hear about the coronavirus mutating, the mutations scientists have detected so far have been few & minor ones, which is a good thing when it comes to vaccines. https://bit.ly/2WsFJqh 

There is, however, another potential problem that scientists are watching out for – a phenomenon called Antibody Dependent Enhancement (ADE). This is where antibodies, instead of neutralizing the viral threat, enhance it, making it easier for the virus to get inside certain types of cells through “backdoors” (e.g. other receptors). Scientists are still trying to figure out exactly how it works, and there are likely multiple ways, but it’s thought that if there are sub-optimal neutralizing antibodies, they might not fully cover the virus so, when immune cells with antibody receptors latch onto the antibodies that are attached to the virus and then swallow the partly-covered virus, the virus can “escape.” https://go.nature.com/2KTE9s2  

I know people really want a vaccine quickly and are getting really tired of this whole quarantine, social isolation, stuff. As someone who LOVES working in the lab, being shut in sucks, though I am incredibly fortunate and grateful to still have a “job” (yes – science grad students get paid – I didn’t know this until late in college but we do get a stipend!) Anyways, in our eagerness we must not be reckless with regards to cutting corners with safety. I’ve heard people compare this vaccine development to the development of the first HIV treatment, AZT, which was pushed through in record time despite side effects, etc. (speaking of which, those side effects could be deadly and they overdosed their initial patients https://bit.ly/3dgdp14 )

While there are *some* similarities, it’s important to recognize that there are also really important differences. HIV at the time was a definite death sentence, so the risk-benefit ratio was a lot different than with the coronavirus. Especially since we’re talking about a vaccine and not an actual treatment. The risk of dying from covid-19 if you get it is (depending on underlying conditions, age, etc.) fairly low, and that’s if you even get it. So it’s not a “what’s there to lose?” situation. Additionally, AZT was given to fewer people – – tragically high in terms of how many needed it –  but still far fewer than the millions or even billions of people we’re talking about giving this vaccine to. So those “1 in 100” or even “1 in 1000” adverse effects can really add up. 

So, safety shouldn’t be sacrificed for speed. But, that being said, the vaccines that are currently on the market – for things like measles, hepatitis, etc. are SAFE! AND EFFECTIVE! AND IMPORTANT! But some people can’t get them because of health problems, so please, vaccinate your kids to protect both your kids and all those other people. 

more Covid-19 resources: https://bit.ly/covid19bbresources

more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0 

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