COVID Transmissions for 1-26-2021
The Moderna vaccine is tested against different variants
Good morning and welcome to COVID Transmissions. I hope you all had a nice weekend!
It has been 435 days since the first documented human case of COVID-19.
Some important work in the headlines section today, specifically about how effective the Moderna mRNA-1273 vaccine is against the B.1.1.7 and B.1.351 SARS-CoV-2 lineages.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
The Moderna vaccine remains effective against the B.1.1.7 and B.1.351 lineages
Moderna and the NIH released a preprint today where they examined the ability of the Moderna mRNA-1273 vaccine to induce immunity against the B.1.351 SARS-CoV-2 lineage first identified in South Africa and against the B.1.1.7 lineage first identified in the UK.
You can find this preprint here: https://www.biorxiv.org/content/10.1101/2021.01.25.427948v1
The bottom line is, the vaccine still works against both of these variants. However, this comes with a couple of limitations that we need to walk through.
OK, let’s walk through this figure. In this paper, the researchers created some virus-variant models, and then they made a number of simulated viruses that represent a spectrum of mutations “along the way” from the more traditional SARS-CoV-2 (we will call this “wild-type” here) lineages to the B.1.1.7 and B.1.351 lineage. Basically, they added a few mutations in each condition to make intermediate viruses. This is a common technique if you want to understand what changes are important by only changing a little at a time. Having done this, they tested the ability of human serum from Phase 1 trials of mRNA-1273 to neutralize these virus models.
To do this, they assessed “reciprocal ID50 titer,” which takes some explaining. ID50 means “infectious dose 50.” This is the dose at which 50% of the cells in a tissue culture dish are infected with the virus being tested. “Titer” means they did some kind of dilution to get to their number; specifically, in this case, they diluted human serum serially until they reached a level of dilution of that serum where it didn’t neutralize the virus being tested anymore. If the serum is very potent and has a high concentration of effective antibodies, it will take more dilution to reach the point where it no longer works. A sample that no longer neutralizes virus after a 1:10 dilution is less potent than one that fails after a 1:100,000 dilution. Here’s where the word “reciprocal” comes in: to make the graphs easier to interpret, instead of showing 1:10, 1:100, etc, which would make more potent titers look like a decrease on the graph they took the reciprocal of these fractions, so that 1:10 became 10:1, or just 10.
In this case, they graphed their dilutions as “log10,” meaning each number is a power of 10. So the “4” there stands for 10,000 and the “2” stands for “100.” What you can see in the B.1.1.7 experiments in panel A is that across the spectrum of model viruses, from wild-type to the B.1.1.7 mimic, the reciprocal titer was around 1000. That means you have to dilute the serum 1:1000 before it loses potency. This suggests that B.1.1.7 is just as susceptible to a vaccine-induced immune response as the wild-type virus. When directly compared in panel B, you see that it’s basically the same titer for wild-type vs B.1.1.7; the ratio of neutralization titers between the two is 1.2, so not really different at all. Good news. We can expect the mRNA-1273 vaccine to be about as potent against this strain as it is against other strains.
In panels B and D we are working with B.1.351, and we see a different story. The neutralization titer weakens gradually as the model virus becomes more similar to B.1.351 and less similar to wild-type. So we see that this variant has done some amount of immune escape. In panel D, it is quantified: the neutralization titer is 6.4 times weaker against B.1.351 than wild type. That sounds bad, but it’s not too worrying actually. The reason is that we started around a potency of 1000, and 6.4 times less than that is a potency just over 100. So you still need to dilute the serum 1:100 before it stops working well against B.1.351. Human serum does not naturally dilute itself by 100x, so it seems a pretty safe bet that the mRNA-1273 vaccine will also still work against B.1.351.
However, it does illustrate that the virus has a capacity to mutate such that the potency of the immune response against it is weakened. This is an important takeaway for us to understand, because it means with even more mutations, there could eventually be a virus that escapes the vaccines that we have. We need to take this as a warning shot.
Moderna is, in fact, taking this as a warning shot. They are already adapting their vaccine to match the B.1.351 variant, so that they can provide a third “booster” dose to patients that will update their immune response to cover this variant as well, in the event that it becomes necessary to protect more people against this variant specifically. This is a strength of the RNA platform; it’s relatively easy to edit the sequence and generate a new vaccine that responds to mutations in the virus.
The “furin cleavage site” appears to be important in SARS-CoV-2 pathogenesis
Something that made a lot of headlines early on in the pandemic is that the SARS-CoV-2 spike glycoprotein contains a “cleavage site” for something called “furin.” Furin is a protein-cutting enzyme that cuts at specific recognition sequences called “cleavage sites.”
In a lot of viruses, some kind of protein-cutting enzyme is needed to process the surface proteins so that they can function properly. In SARS-CoV-2, there is a site for furin, and this site seems to allow a protein cut that enhances the ability of the virus to bind to the ACE2 receptor, a critical step in the infection process.
Some researchers thought it would be interesting, then, to destroy this furin cleavage site, and see what it does to the ability of the virus to function. Long story short, it has an extreme effect on the ability of the virus to establish infection. Here’s an example figure, showing weight loss (a surrogate for disease severity) in hamsters infected with the unmutated virus (black line) vs the virus lacking the furin cleavage site (blue line):
In this example, getting rid of the furin cleavage site caused a clear difference. It’s like that throughout the whole paper, in other experiments and with other models.
Let’s think about what this means. It’s unlikely that the presence of a furin cleavage site specifically makes the virus make these animals (or people) particularly ill. Instead, what seems more likely is that this furin cleavage site is part of an important step in the virus life cycle: attachment and entry. Processing by furin looks important for that process, and if you stop that process, you stop everything that comes after it. Those subsequent steps are probably where proximate causes of disease start to happen, but the furin cleavage event is a prerequisite to all of that. The virus cannot cause disease if it cannot effectively enter cells, and the furin site seems to matter for that function.
There are a couple of ways that this might be applied practically. First, if you could generate an antibody that blocked furin from cleaving the spike protein at this site, you might have a pretty good therapeutic, and even more likely I think you’d have a good prophylactic drug in patients who can’t get the vaccines for whatever reason. Second, the virus mutant that they made in this paper lacking the furin cleavage site might be a good vaccine strain! Since it is so ineffective at causing disease, it could be a good way to generate immune responses.
Most importantly, though, this work teaches us more about a basic function of the virus in its life cycle. It could be vital knowledge in the future in various ways, as could any basic knowledge about the virus. When we do this kind of work we don’t always know what it could mean, but it can really pay off in the long run.
You can have a look at the full paper in Nature: https://www.nature.com/articles/s41586-021-03237-4
What am I doing to cope with the pandemic? This:
Cooking: Chili
OK, many of you are probably thinking that chili is one of the easier things you can make. And, you’re right. It is. Which is why it has become a go-to pandemic food for us.
To make a chili, you need things that are good to have on hand during a period of time when you might not be able to get to the grocery store on a regular basis: dried or canned beans, frozen or even canned meat, canned tomatoes, canned chilis, and powdered spices like chili powder. I tend to serve mine with a little bit of cilantro chopped and mixed in, but you don’t need that and you don’t need it to be fresh either—you can get it frozen.
Personally, I like a good vegetarian chili. I start with some julienned onions, which I sauté along with the chili spices I prefer (I use a chipotle chili powder, smoked paprika, cumin, and some salt). Then I add Impossible Foods ground Impossible Meat, in one of their standard 1 lb packages, and brown that on relatively high heat as I would regular ground beef. Then it’s literally a matter of mixing in about a cup of beans, 16 oz of diced tomatoes, and a can of whatever size of chilis I feel like adding (usually around 4 oz at these proportions but sometimes I go for 8). I like to start with dried beans, soaked overnight, so once this is all mixed together I add a little water, bring it to a boil, then reduce the heat and cover for about 2 hours.
This is easy and it uses things you can store for a long time and that you can buy in bulk, which is ideal if you’re trying to cut down on trips to the grocery store. Dried beans are great insurance against the unexpected; they’re packed with protein and energy, and they can go into meals like this chili. Served with rice, it makes a pretty fair number of meals. We’re two people and can usually get about three good lunches or dinners out of the proportions I just described. I even bet it would make a good breakfast with a poached egg thrown on, though I haven’t tried that.
Carl Fink, in response to my comments about Boris Johnson’s alarmism over the B.1.1.7 variant, noted that the UK actually looks like it’s starting to get its outbreak under control:
I was hoping you'd write about the odd UK communication about their famous (but disowned) variant.
Here is a chart of new cases of SARS-CoV-2 infections in the UK:
https://www.panix.com/~carlf/files/uk_figures.png
Why is BoJo screaming *now* of all times? The lockdown is working.
I don’t really get it either, Carl. But you make a good point here.
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See you all next time.
Always,
JS
You knew I'd comment, right?
"This is a strength of the RNA platform; it’s relatively easy to edit the sequence and generate a new vaccine that responds to mutations in the virus." Can you perhaps say: is it easier to update the genetic material in an mRNA vaccine, vs. an adenovirus-carrier vaccine like the AstraZeneca one now in use in other countries[1] (and others from Russia and China)? In either case you're using well-known techniques to create a nucleic acid sequence and then putting it in some kind of carrier or coating that gets it inside mammalian cells.
Would it be harder for Novavax (whose vaccine is the spike protein, created outside the body in moth cell cultures) to create a strain of moth cells that pump out a slightly different protein? (Because I nitpick myself: Novavax's vaccine is spike proteins attached to a stabilizer that isn't defined clearly in press coverage and is probably proprietary, and accompanied by adjuvant.)