Ebola update:

Coronavirus Update:

–Not much changing in case load and the shutdown front. I think it’s safe to say this is a bona fide second wave. Even Sweden is restricting social gatherings at this point, and what is especially disappointing is places that have been rocked hard already are showing an uptick in new cases as well. For example, New Jersey is now matching its March-May highs, Arizona has lifted off again, even New York (largely outside the city–Buffalo appears to be the epicenter for cases in the state right now) has seen a big jump in new cases.

–Why? Not entirely clear. I think it’s multi-factorial. There may be something to colder weather = easier spread of this virus, as your main waves now have come at seasons that are a little cooler. I also think people are tired of the restrictions, and so moving around a little, coupled with lift off in rural areas that sustained long enough to find pockets everywhere–and then sustain in those. Helping that sustained transmission is the variant of the virus going around. It is still very dominantly the version that is more contagious, but probably less severe on a case by case basis.

–For example, in March-May, approximately 1 in 5 confirmed cases was reflected in hospital admissions. Currently (at least in Indiana, but seems to be true elsewhere) about 1 in 10 confirmed cases are seen in hospital admissions. Death rate is also lagging March-May, but different patient population/better treatment etc. may be contributing to that, as we have discussed.

–Now complicating that is the amount of testing currently being done, which is leaps and bounds above what it was in March-May. We know were not testing many asymptomatic cases (as we discussed). We know March-May likely missed the total number of infected people by about 7-12 fold (just in comparison to antibodies, which, for reasons also previously discussed, are likely underestimating the true number of asymptomatic or less than symptomatic cases). We are probably picking more of them up this time around with the greater amount of testing. How many more, I don’t know. That may shift the estimate of “hospital admissions per number of confirmed cases” a bit, but I doubt it shifts it too much.

–Good news in all of this? First, reinfection is still vanishingly rare. Once you have caught it, you have pretty solid immunity. Papers keep getting published every month extending the duration of anticipated immunity as well. So second, once this wave has crested and passed, there will have been a big jump in herd immunity. Any additional “rebound” waves from here on out will get smaller and more focal.

–Bad news is that again, we are going to be closer to the tail end estimates of early to mid next year for population herd immunity.

–BUT…. we of course have more news in the vaccine front this week, so let’s talk about those.

–Two front runners using the same mRNA vaccine technology (and the same target on the virus–the spike glycoprotein) are in late Phase 3 studies and press released what we call “top line” results. Moderna had the big Monday drop, with far more detail than Pfizer’s from last Monday, and showed a 95% reduction in symptomatic infections in patients who got the vaccine versus those receiving placebo. Pfizer managed to get results on a few more patients, and now shows ~95% efficacy as well.

That is made possible for Pfizer because the numbers of patients getting symptomatic SARS-CoV-2 to count in BOTH of these studies are very small. It only takes a few new people in the placebo group to get symptoms and a positive test to bump the efficacy up a bit. The opposite is true as well–one or two patients on the vaccine arm where it did not take and they get sick will drop the apparent efficacy a bit.

But you can ballpark that the vaccines will reduce symptomatic infections by at least 90%, and so far, none of the “breakthrough” positives in the vaccine arms of either study have gone on to develop severe, life-threatening COVID. That said, there are hardly any breakthrough infections, so jury is still out on if the vaccine really stops that cold.

Another real quick takeaway from the numbers they have released. Assuming both trials are fully enrolled, that’s about 22,000 people in just the Moderna study who have received placebo, with a little under 200 confirmed, symptomatic SARS-CoV-2 infections in that placebo arm. That’s about 1% incidence rate, and is probably about right for the study length and disease activity. Also broadly consistent with our back-of-the-envelope UFC estimates of new positives per time period.

So let’s talk about how these vaccines work, because, as we mentioned before, they are a radically new way to vaccinate. In all of the other vaccines out there now, you are getting either dead or non-infectious entire virus injected OR proteins purified off the virus. Your immune system processes those, and develops a defense to the virus. The vaccines under development for SARS-CoV-2 by Moderna and Pfizer work a little differently.

To expand on our previous discussion of these differences, we need to go over the Central Dogma of molecular biology, and suuuuuper basic immunology. Don’t worry–I will keep this simple.

The Central Dogma is this: As you know, your DNA encodes your genes. A “gene” is just section of DNA that provides instructions for how to build something. So your genes, when assembled, will build you, much like Voltron, Defender of the Universe, or the cheap live action knock off that was the Power Rangers. You will notice that you are not 100% DNA though. That’s because the instructions to build encoded in each gene are really instructions for each of your cells for how to build proteins (in general, fellow science major raising your hand in the back). In fact, as a historical aside, protein was thought to be what encoded your genes for a very long time until experiments in the middle of last century proved that nope, it was DNA all along. So to build you from your DNA, your cells do this:

1. Open a section of DNA with instructions for a protein (a gene)
2. Make a copy of those instructions in RNA. This is called messenger RNA, or mRNA for short.
3. The mRNA message is sent to the ribosomes, the part of the cell that makes new proteins.
4. The ribsomes “read” the message in the mRNA, and build the protein that message tells them to build

DNA —-> mRNA —–> protein is the Central Dogma of molecular biology.

Got it? Good.

So, SARS-CoV-2 is what we call a positive single-stranded RNA virus. That’s a fancy way of saying “SARS-CoV-2 is one giant mRNA”. Like all coronaviruses, SARS-CoV-2 skips that whole DNA nonsense completely. Once it gets inside the cell, it is already messenger RNA, ready and rearing to go.

Of course, the mRNA of SARS-CoV-2 is not for proteins to make you, but instead is code for how to make proteins of SARS-CoV-2.

Your ribosomes cannot tell what is a message from your DNA, and what is a message from SARS-CoV-2. So once the virus is inside the cell, and its mRNA makes it to the ribosomes, it’s off to the races. Your ribosomes will dutifully bang out copy after copy after copy of all the virus proteins on SARS-CoV-2 mRNA, which then assemble themselves into new protein and new copies of its mRNA, and then it is off to infect another cell to do it all over again.

The problem the virus runs into is the basic immunology we are going to cover here. By “law”, all of the cells in your body have to show what their ribosomes are actually making to the immune system–just to prove they are not, you know, making billions of new virus particles. To do this, your cells run a “factory QC” on the ribosomes by breaking down examples of the proteins they are making. To comply with the “law”, they have to show these pieces to T-cells passing by as their “ID card.” Your T-cells know what pieces of the proteins that actually make you look like. If there is ANY change in those pieces, dem T-cells notice and notice fast.

What happens next is a lot like “Among Us,” the game your kids are playing on their phones and tablets. An emergency meeting of the T-cells are called. The cell showing the protein fragments your T-cells don’t recognize is called “sus”, even “very sus” in the chat. Then it is voted off as a suspected imposter (killed by the T-cells, and taking the virus hijacking the ribsomes inside the “sus” cell with it).

The pieces of the weird protein that got our poor “sus” cell killed are gathered up and shown to the B-cells. The B-cells will make an antibody to those pieces and start spraying antibodies in case more of the virus encoding those proteins are loose in your body, or in case you run into it again (antibody mediated immunity). At the same time, T-cells specializing in recognizing those specific weird proteins will fire up too, and start looking for them on all the cells of your body, trying to hunt down and eliminate all the infected cells–and thus, the virus (T-cell mediated immunity).

So when you get SARS-CoV-2, it enters your cell as a mRNA. That will be important to remember when we talk about how these new vaccines work. Your ribsomes cannot tell human mRNA from viral mRNA–all they see is mRNA–and start making SARS-CoV-2 proteins. Some of those proteins get swept up in the cell’s “factory QC” program. Eventually, a T-cell checks the ID badge of an infected cell, which is made of the protein pieces from “factory QC”, and recognizes a SARS-CoV-2 fragments as not belonging to you. This alerts your immune system that the virus is there, and both B- and T-cell responses are triggered. Ultimately, they wipe the virus out entirely, and a few of the SARS-CoV-2 specific (the ones most adept at finding SARS-CoV-2 specifically) B and T-cells are kept around to fire up quickly in case you run into SARS-CoV-2 again. This is immunity.

We got all of that?

Great.

What are the Moderna and Pfizer vaccines doing then?

Here’s a simple explainer:

What they have done is take just the spike protein from SARS-CoV-2, which is the protein on the outside of the virus that it uses to get inside new cells. Instead of injecting the purified protein as the vaccine though, they have taken the mRNA for the spike protein, and made that the vaccine.

So just like SARS-CoV-2 infects a cell and is a mRNA already, going straight to the ribosome factory where more SARS-CoV-2 is immediately made, the mRNA vaccine “infects” cells with a mRNA for the spike protein.

I want to be clear on this point, because I have seen some misconceptions online. The vaccine mRNA is NOT converted into DNA, does NOT modify your DNA at all, and does NOT get expressed in your cells forever.

Since the mRNA is for the spike protein ONLY though, it’s not a full copy of the virus, and no new infectious SARS-CoV-2 is made. ONLY its spike protein is made by the ribosomes, which again, cannot tell the vaccine mRNA from the mRNA that is coming from your DNA.

Yes, ribsomes are pretty dumb — “Well, there’s an mRNA here. Guess I’ll just make this protein and see what happens! Oops, a virus. Better try that again and maybe it won’t be a virus this time…“

Fortunately for the ribosomes in the case of the vaccine mRNA, the copies of the virus spike protein they start running off go through “factory QC”–just like all proteins made by the ribosomes because, let’s face it, while your cells love their ribsomes dearly, they know your ribosomes are morons. The pieces of the spike protein encoded by the vaccine mRNA trigger the exact same immunology cascade above, leading to both the T- and B-cell responses that all of these vaccine manufacturers have reported in papers we covered earlier.

So why this strategy? Because you can make a lot of these kinds of vaccines very quickly–faster than a traditional vaccine where you have to grow the virus and inactivate it and then bottle it up or grow the virus, isolate the protein you want to purify from it, purify it, then bottle it up.

On the downside, because this is a new strategy for generating a vaccine immune response, it’s been an open question about how well it would work.

Turns out to be about 90-95% or better at reducing clinical COVID cases in the clinic, at least according to these press releases. With the HUGE caveat that only a few hundred people in each of the trial actually caught symptomatic COVID, so view that 90-95% as a “best guess” based on some fairly small numbers.

Both the Pfizer and Moderna vaccines are taken in two doses. You get one shot first, and then you’ll be asked to come back in about a month for a booster for the full immune effect (again, broadly–listen to your licensed medical professional and only use these vaccines in accordance with their labeled indication and instructions).

But what are the risks? Well, as mentioned earlier, in the safety studies of these vaccines there were some side effects. The most common were fever, muscle ache (especially at the injection site), headache and fatigue–and that is broadly true for both of these vaccines. Moderna did a better job discussing these in their press release, but Pfizer has been out this week with some clarifications as well.

Most of them appear to be happening after that “return in a month” shot. The rate of these side effects is also much lower than reported in the original safety studies. In part, that is because, as we mentioned at the time, the dose they brought into these Phase 3s was the lowest dose that got the desired immune response for the least amount of side effects in those original safety studies. For Moderna, this dose had an ~40% rate of some of kind of adverse event, mostly fever, headache and body aches.

BUT, in those original safety studies, participants were asked to not take ibuprofen or acetaminophen before or after the shots (so they would not mask any possible side effects of the vaccine like pain and fever).

At least according to the press releases, the main side effects of fever, headache and/or bodyache are at an ~2% rate. Now, because they have press released and not published, I don’t know if that is 2% of the entire tens of thousands study population, or just a subset of it. Full safety data will be coming in the final publication. But in these Phase 3s, patients were allowed to take pain killers/fever reducers around the shots (I’m sure), and it does suggest that for most people, that’s enough to control the main side effects.

So far so good.

So what are the theoretical risks of this new vaccination strategy? Without going into way more gory molecular biology detail, the main risks are that spike protein or its mRNA are too similar to a normal human protein and the body starts schwaking the normal human protein and cells making it by mistake or the mRNA has bits of code too close to normal human mRNA and that interferes with normal human proteins that actually ARE supposed to be getting made.

There is a very low probability of either of these. I don’t want to say it’s zero, but it’s close. First, the vaccine uses the same spike protein that SARS-CoV-2 brings to the party already. If that protein was close enough to cause the kind of side effects I am talking about here, we would know about it as a major symptom or lingering symptom of COVID. We have not seen anything that raises my suspicion of that. BUT, normal SARS-CoV-2 infections are limited in the cell types they can get into–mostly lung cells, and possibly endothelial cells, which express a lot of the protein the virus uses to get into the cell. The vaccine is under no such restriction and can get into any cell in the body. Most of it will be taken up by cells nearest the injection pretty fast. But if the spike protein is similar to proteins in say, brain cells, to cause this overlap issue, we might not have seen it yet to be worried about it with normal COVID, since the virus does not appear to directly infect, say, brain cells.

But there is no indication of that so far in any of these studies. On the other hand, we do need full safety data from the 44,000 patients being enrolled in these.

Second, running both the mRNA and the spike protein itself in silico against the human genome does NOT identify any immediately obvious areas of concerning overlap.

So the chance of an overlap of the mRNA and protein with human mRNA and proteins that would cause a problem is very, very low. Almost zero percent.

If it happens, figuring out how it happened would probably get you a Nobel Prize.

But, just because it’s unlikely doesn’t mean that it cannot or will not rarely (like lottery ticket level) happen. Again, that’s why we need the full safety data from as many patients as possible.

I am not sure if anyone knows how long the vaccine mRNA sticks around in the cell making new copies of the spike protein. The median half-life for mRNAs in humans is 10 hours, meaning that nearly all of the vaccine mRNA should be gone within 2 days of the injection if it behaves like a “normal” mRNA. I would say that it probably is behaving close to a normal mRNA in its longevity in a cell (some number of days tops), as this is consistent with needing a couple injections of it to get the immune response desired. If the mRNA for the first injection just lingered and lingered and lingered, the ribosomes would dumbly be making spike protein ad infinitum and you probably would NOT need a booster. But you do, and my best guess is that you do because the mRNA, like most mRNA, has a lifespan measured in hours to days.

So overall, the side effect profile has no show stoppers (that we know about so far), and theoretical risks, while not zero, seem very, very small too.

Would I get the vaccine? Well, let’s see the full published data first. Right now, I will definitely take Pfizer’s CEO up on his pledge and let him get the first dose. Again, we’ll have to see what the published data–not merely the best and rosiest, market moving data in a press release–show.

So we’ll have more to talk about on the risk/benefit once the full data sets from these Phase 3s are available.

–Last, super quick point on testing. The Lucira at home COVID test was just approved. The best way to think of it is the world’s smallest PCR. In comparison to already proved, big system PCR for COVID, the Lucira performed pretty well. It will lose sensitivity on the low end, so if early infection or just an unlucky swab that did not get a whole lot of virus, the test may whiff. But with a solid swab, and a good amount of virus present (the kind that typically has symptoms), the assay appears to work really, really well. Results in 30 minutes, at your own home. Not sure on price or availability yet–you can probably check their website.

–Social issues-wise, I would listen to UPS, FedEx and the Post Office as they are telling you this year that packages may be delayed. Also hearing of occasional random shortages in supermarkets again, as new restrictions are popping up. Continue to keep some extra supplies handy, and consider a donation in kind or money to your local food banks this time of year.

–And finally, my son got out of COVID quarantine just in time for the county the school is in to decide to go all virtual again through the New Year, starting next week. C’est la vie COVID. He never had symptoms. Neither did any of the rest of us, and no other confirmed cases in his class.

–Yeah, I did hear the director of the CDC at the press conference today say the CDC does not recommend closing schools.

–Your chances of catching Ebola are equivalent to the tumbleweed above ever stopping.

–Your chances of catching coronavirus remain excellent nearly everywhere in the world. Continue to be prudent.

<Paladin>