COVID Transmissions for 12-16-2020
Moderna's FDA application
Good morning! It has been 394 days since the first documented human case of COVID-19.
Today we have the Moderna vaccine to talk about, because its results are under review by the FDA and will be voted on today. We may see a new emergency authorization soon.
Also, a headline about ice cream and the cold chain.
As usual, bolded terms are linked to the running newsletter glossary.
Keep the newsletter growing by sharing it! I love talking about science and explaining important concepts in human health, but I rely on all of you to grow the audience for this:
Now, let’s talk COVID.
Learning about cold chain shipping from the Ice Cream of the Future
Have you heard of Dippin’ Dots? It’s a form of ice cream that consists of small spheres of the stuff instead of a large block or scoops; it bills itself as “the Ice Cream of the Future,” although since it was invented (by a microbiologist!) in 1988, it might be the ice cream of right now at this point.
It’s a novelty that turns out to require really specific shipping temperatures. If you think about it, keeping those spheres separate is really important for the format of the product. If you let the temperature rise much above a critical point, the spheres can fuse together and the entire fun of the product is lost.
Popular Science ran an article about what this could teach us for the shipment of COVID-19 vaccines around the world, the idea of a journalist who was clever enough to realize there could be a lesson here: https://www.popsci.com/story/health/covid-vaccine-cold-chain-dippin-dots-ice-cream/
As we’ve discussed before, the various mRNA vaccines have restrictive storage temperature requirements, much like Dippin’ Dots. I thought this was a very cool article.
Moderna vaccine is formally reviewed by the FDA
Speaking of vaccines, yesterday the Moderna mRNA vaccine was formally reviewed by scientists at the FDA, who assessed it to have an acceptable balance of safety and efficacy.
You can read about the recommendation here: https://www.statnews.com/2020/12/15/fda-scientists-endorse-moderna-covid-19-vaccine-as-documents-provide-new-hints-on-efficacy/
You can read the briefing for the FDA here: https://www.fda.gov/media/144434/download
I will pick this apart at length in today’s in-depth as well.
Today, the advisory committee that reviews these vaccines will meet and vote on whether the vaccine should be authorized for emergency use. Like with the Pfizer vaccine, their vote will constitute a recommendation back to the FDA, which will then formalize the authorization over a period of days. There is a lot of formality and back-and-forth in medical regulatory decisions. It’s all part of the process that helps ensure you aren’t being sold snake oil…or cyanide.
What am I doing to cope with the pandemic? This:
Celebrating Chanuka
It’s the holiday of Chanuka for us Jews, a holiday that would be barely notable if it didn’t usually happen in December.
It’s an interesting holiday, though. It’s a holiday that celebrates rebellion against an imperial power, and that celebrates the idea of a militarily ascendant Jewish people. I’m sure there is a sociology essay in that somewhere.
The miracle of Chanuka, is, supposedly, that consecrated oil for one day lasted eight days. Of course, it’s well-acknowledged that this was probably brought to the forefront of the holiday to avoid the more uncomfortable themes of military victory, which in a way also constitutes a miracle. The victory of a small guerilla army over the impressive Seleucid Greek military also seems to be at the root of the holiday. Of course, it was substantially more complicated than that, and was partly a civil war between Hellenized Jews and traditional Jews, but let’s not get into that.
Whatever may be miraculous about Chanuka, it is a holiday designed with the principle of advertising. Lighting the Chanuka lights is actually an effort to publicize the holiday, and you are encouraged to make sure as many people as possible see them. In that vein, please have a look at my menorah from last night:
Something that’s interesting about Chanuka is that as one of the later innovations in the Jewish holiday calendar, it does not carry restrictions against the performance of work, thus allowing the use of electronics, cooking, and other activities that are usually forbidden for at least a portion of other holidays. Normally that just means it gets shoved to the side while you go about your business, but this year it means Chanuka is set apart. Specifically, we’ve been able to see family for this holiday, using Zoom. This wasn’t possible on our other major holidays because electronics aren’t allowed. It’s really nice to be able to get together with family again, even remotely, and even on a somewhat minor occasion.
Moderna vaccine data
Like Pfizer before it, Moderna has now submitted their vaccine data for the world to see, so that the FDA can review their results. That means we get a chance to pick apart the Moderna vaccine’s results ourselves and understand these vaccines a little bit more.
The Pfizer and Moderna vaccines are both very similar, using mRNA technology to cause cells in the body to express fragments of the virus, which then elicit an immune response. We have covered previous work, describing that immune response, in the newsletter before. What we didn’t know at the time was whether this immune response was protective.
Now we know—for both vaccines. However, before these briefing documents came out, we didn’t have all of the details.
I do want to call out a couple of points before we dive in, however. First, the Moderna vaccine candidate is not the same as the Pfizer candidate in its design. While both target the spike glycoprotein of SARS-CoV-2, they use different strategies to do so, so there may be some variations in how they work. Second, the Pfizer results that were submitted were final results, but Moderna sent in a mixture of both interim and final results. Frankly, this probably reflects the relative experience and resources of the two companies, as well as the fact that Pfizer’s trial seems to have matured a little sooner than Moderna’s did. The Moderna report contains a brief addendum with results of its final analysis, and it’s interesting to compare these data to the interim data.
Now, to the data. The Phase 3 trial is what we’re going to focus on. In this trial, more than 30,000 patients got 2 doses of the Moderna vaccine candidate, mRNA-1273. Doses were given 28 days apart.
The primary endpoint of the trial was the comparison of the number of COVID-19 cases in the group that received the vaccine vs the group that received the placebo, starting 14 days after administration of the second dose of either condition.
Interim efficacy analysis
By this measure, the vaccine was 94.5% efficacious, with 90 cases in the placebo group and 5 cases in the vaccinated group. As we’ve discussed before, statistics can be imperfect, so this finding may not be the “true” efficacy of the vaccine. The 95% confidence interval (95% CI) for the mean of vaccine efficacy, a range of numbers that gives us a sense of how much the number observed may vary from the “true” vaccine efficacy, was 86.5% to 97.8%. This means that we are 95% confident that the true vaccine efficacy lies somewhere between those two numbers. That range is excellent.
What’s more, the numbers bear out excellently in subgroups by age. The vaccine was marginally less protective in patients between age 18 and age 65, with an efficacy of 93.4% (95% CI: 83.7%—97.3%), but in patients over 65 years of age it appeared to be more effective. In those patients, the efficacy was 100% (95% CI: not calculable! There were no cases of COVID-19 in patients over 65 in the trial). That number probably isn’t correct; there were only about 7000 patients in the over 65 group, and there were over 20,000 patients in the other age group, so we are talking about a smaller number of patients. Still, this suggests that the vaccine is effective regardless of patient age, which is fantastic news. There were also no apparent differences in efficacy across race and sex of the patients. Additionally there did not appear to be any differences based on the patient’s estimated risk of severe COVID-19. All good news! Remember, though, we’re still in the interim analysis here. The picture in the final analysis was different, and we will get to that.
Interestingly, the vaccine also appeared to be highly effective in patients who were SARS-CoV-2 positive at baseline—here this means patients who had been infected in the past. However, there were a very small number of such patients enrolled, and the briefing suggests that we cannot draw conclusions based on the data presented in this group. So, don’t, please.
In terms of the total cases following first vaccine dose, the briefing provides us with a figure, much as the Pfizer briefing did:
That’s another beautiful curve. Look at how it starts to separate just 10-14 days after the first dose is administered. That’s around the time that the immune response to the vaccine should be sufficiently mature to protect the patient. It is an elegant confirmation of how we understand immune responses to work. The risk of exposure in these two patient groups is equal, but one has immunity after that point and the other group does not. Consequently, the lines diverge. You can’t ask for a better result that inspires more confidence in science.
Another thing to look at is efficacy in preventing severe disease. There were 11 cases of severe disease in the placebo arm in this trial, and 0 such cases in the vaccinated population. That appears to be 100% efficacy in preventing severe disease, but we are talking about a very small number of cases here, and we’re in an interim analysis. Let’s take a look at the small amount of data provided from the final analysis. Also, the report notes that there was one case of severe disease resembling COVID-19 in the vaccine group that was not scored as positive because of conflicting PCR results; it’s possible there was one severe case vs 11 in the placebo arm. This kind of clinical judgment issue on a diagnostic test is not entirely uncommon, but it can make results harder to interpret.
Final efficacy analysis
There were some changes in the final analysis, it seems.
Where the vaccine efficacy was 94.5% overall in the interim, it was 94.1% (95% CI: 89.3%—96.8%) overall in the final. That’s not a big change. Where there was a big change was in patients over 65 years of age. That 100% efficacy rate dropped to 86.4% (95% CI: 61.1%—95.5%) The thing is, this is based on the appearance of only 4 cases in the vaccinated arm vs 29 cases in the placebo arm. So, it could just be that the drop looks more severe than it really is, due to the small total number of patients and cases. The 95% CI suggests that the efficacy in older patients might be as high as in the overall population; it might also be substantially worse. Maybe we’ll learn more as we continue to get data from the trial.
I’m highlighting this example, though, to show you how things can change over time. This is still a fantastic result. An 86% efficacy rate in people over 65? That’s remarkable. That’s a lot better than the 0% efficacy you get by doing nothing, or the 10—20% risk of death in older adults with COVID-19. Perhaps it is lower than the efficacy of other vaccines will turn out to be in this group; maybe there will be some head-to-head studies to figure this out. However, it shows you that early results don’t always show the full picture. We’re going to keep learning more as time goes on.
Another example I want to highlight is a change in the severe COVID-19 group. There were 19 more cases of severe COVID-19 in the final analysis than were observed in the interim analysis. They were all in the placebo arm. After further follow-up, the vaccine efficacy in prevention of severe COVID-19 was still 100%. The only potential severe case was still that diagnostically unclear case that I mentioned before. No additional cases, potential or otherwise, were detected.
The final analysis dataset presented in the report is not as extensive as the interim analysis dataset; the FDA was not able to fully independently review and confirm the results for the final analysis as it did with the interim analysis, so only those results they were able to review were included in the briefing.
Of course, there’s more to all of this than just efficacy. It’s not enough to be efficacious; the efficacy needs to outweigh any potential safety risks. People who jump out of planes without parachutes also have a low rate of future COVID-19, but I’ve heard there are some adverse effects of that approach. We don’t want to see a vaccine get to market without a good analysis of safety.
Safety results
The briefing includes extensive safety data. One thing that’s interesting is that the report tells us both about solicited and unsolicited adverse events. The difference between these is that solicited adverse events are proactively monitored and are data that the researchers were looking for when the experiment was designed. Unsolicited events are ones that were reported without being looked for in advance. One of the reasons this difference is important is that sometimes, the asking of a question can plant the idea of something and impact results. On the other side of things, a design of an adverse event form in a clinical trial might leave out unexpected events. So it’s useful to compare unsolicited and solicited adverse events.
In terms of solicited adverse events, 94.5% of vaccine recipients had any event, compared with 59.5% of patients in the placebo arm. For unsolicited events, it was 21.9% vs 19.4%. To me, that sounds like the adverse event profile was approximately what the researchers expected in advance. Unsolicited events didn’t seem to occur more frequently with the vaccine than with placebo, and while there was a high rate of solicited events, that’s not too surprising. Vaccines involve injecting something into the patient, and irritation at the injection site counts as an adverse event. If you ask “Hey, did it hurt when I jabbed you in the arm?” you’re soliciting adverse event information. I have a feeling most people who have received a vaccine would answer yes to a question like that, and that explains why we see a high rate of events in both the vaccinated and placebo groups in this trial.
Now, just because an event occurred doesn’t mean it was severe—here, severe means requiring immediate medical attention. The most severe events were substantially more rare. Severe solicited adverse events at the injection site occurred in about 9% of patients who got the vaccine vs. less than 0.9% in the placebo group. Systemic adverse events, that is, things that affect not just the injection site, happened in about 16.5% of patients who got the vaccine vs 3.7% in the placebo group. Keep in mind that systemic vs. injection site reactions aren’t mutually exclusive, so don’t add these numbers together. Some patients might have had both types of reaction, some might have had one or the other.
For unsolicited severe adverse events, rates were below 1% in both groups, so that’s good news. 4 deaths occurred in each group; none of these deaths were determined to be study-related. When you study a large group of people for a period of months, sometimes some of them die.
The local reactions that were highlighted in the briefing were things like pain, redness, swelling, and swollen lymph nodes. These are things that often happen when the body has an immune response. Pain was much more common in vaccinated patients than those who received placebo. That’s not fun, but it’s a sign that the vaccine is causing a response, and it’s a lot better than dying in an ICU.
Common systemic reactions were things like fatigue, headache, aches and pains, and nausea. Fever was also detected but was less common.
The impression that I get from this is that it’s likely you will not feel great after getting this vaccine, but it is unlikely for the reaction to be very serious, and even if it is, these types of reactions are manageable. Fatigue can be addressed by resting. Headache, aches and pains, and the local reactions can be managed medically. These are safety events that doctors know how to handle.
“Serious” unsolicited events, which in the language of clinical trials are worse than “severe” events, happened at approximately equal rates between the two groups, both vaccinated and placebo. This type of event—a serious, unexpected event—is what I was most watchful for in this report. The fact that there did not appear to be a big difference between the two groups is reassuring to me.
Safety is a little harder to make definitive statements about than efficacy. We don’t use statistics to compare the two arms, and we generally err on the side of caution. That said, there are very few things that the FDA’s briefing calls out as particularly serious. One thing that has been flagged is that there were three cases of something called Bell’s palsy in the vaccine group, and 1 case in the placebo group. These are very small numbers, but Bell’s palsy is a paralysis of the face that causes the face to “droop.” It usually occurs in response to illness, particularly viral illnesses, and it also usually resolves within six months of appearing. I can’t imagine that it’s a fun experience, but again, it is one of those things that I’d personally prefer to dying of COVID-19. I understand that the FDA is continuing to closely monitor all of the COVID-19 vaccines specifically for incidence of Bell’s palsy.
Like the Pfizer vaccine, Moderna and the FDA will continue to monitor safety for mRNA-1273 as it is slowly rolled out to market. We will learn more as time goes on.
That said, I think we have a vaccine that is relatively safe while providing clear evidence of efficacy. It may be slightly on the unpleasant side in many people, but I do not expect high rates of safety events requiring emergency medical attention. I do expect high rates of that kind of event in people who get COVID-19. To me, given the high efficacy of the vaccine, it seems obvious that this needs to come to market. It seems to me the FDA’s scientists agree. Today, we’ll find out if the outside advisors to the FDA agree as well.
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Always,
JS