COVID Transmissions for 11-24-2020
Another vaccine, with chimpanzees
Good morning! It has been 373 days since the first documented human case of COVID-19. Welcome back from another weekend.
It seems like Monday has become “vaccine news day,” because as of yesterday we have new data from a third vaccine. Today’s issue will focus on that, although I do have a couple of headlines for you too. I will continue to walk through the duration of immunity paper later this week, but the vaccine story is higher priority.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
People in the US are traveling for Thanksgiving
CIDRAP reports that over the weekend, more than 3 million Americans passed through airport security checkpoints: https://www.cidrap.umn.edu/news-perspective/2020/11/despite-wide-us-covid-19-surge-travelers-move-thanksgiving
This is terrible news. People are going to die as a result of this movement. It’s irresponsible, and unnecessary. We have remote technology that allows people to be connected despite the pandemic. No, it’s not perfect, but it’s better than being dead.
If you’re one of these people, and I sincerely hope that after all my warnings I hope you aren’t, I recommend your family be prepared for medical and potentially funeral expenses. Maybe your traveling won’t kill you, but it might kill someone you’re responsible for.
I’m so disappointed about this. The trick to preventing viral spread is that the virus doesn’t spread if we don’t spread it. Apparently we can’t quite get the hang of that.
More patients are surviving COVID-19, but that may not last
With a new array of treatments, more patients are surviving COVID-19, as STAT news reports: https://www.statnews.com/2020/11/23/hospitalized-covid-19-patients-surviving-at-higher-rates-but-surge-could-roll-back-gains/
The hospital mortality rate for selected patients, which was once 11.4% (March 2020), is now 3.7% as of September. That’s incredible progress.
However, we now have more cases in the United States than ever before. Hospitals could become overwhelmed, and no matter how good your medicines are, if you don’t have the capacity to give them to patients, people will die. We need to do everything we can to prevent that situation, and stop a coming tide of deaths.
What am I doing to cope with the pandemic? This:
Rewatching The West Wing
The West Wing was really a landmark television show, and when it was on the air, gave people a much more “inside” view of White House politics than was previously available. During the chaos of this year’s election, I started re-watching it as a form of escapism because it depicts a version of the US where honest debate of tangible issues was a significant part of government.
I’m nearing the end of it now, and while the show’s best writing is displayed early on, there is one episode I watched last night that really was a brilliant concept—The Debate. In this episode, two Presidential candidates, played by Jimmy Smits and Alan Alda, engage in a televised debate. Breaking from the show’s format, the episode was shot and performed live, using broadcast news cameras. This changed the entire look of the show, in addition to the episode’s content. It did not have typical behind the scenes political moments, focusing on staffers and aides. It did not have scenes. It was one, single scene, shot live, portraying a presidential debate. The actors go off script; they flub lines. They act like real people in a real debate. This is interesting because one of the themes of the episode is the candidates’ desire to have a “real debate.”
The episode was actually filmed twice, for live broadcast. One filming was broadcast live for East coast time zones, and the other for West coast time zones, so that the live format would be the same for audiences in prime time.
It’s an interesting experiment, to make a fictional story so real and at such great effort. It feels like a real debate. What’s especially interesting, though, is that at the end of it, I am always left both impressed and kind of annoyed. I usually wonder, at least once: “Wait, I don’t even really like real presidential debates that much. Why did I just watch one for a totally fake election?”
The answer is because it was damned good television, and is reminiscent of a time when American political discourse was a bit more substantive.
AstraZeneca-Oxford vaccine data
Yesterday, the AstraZeneca-Oxford University vaccine read out initial data from its interim analysis. All in all, we have good news on this front but there are some strange details that we’d better walk through together.
First, let’s introduce our main character: the vaccine. The AstraZeneca-Oxford University candidate, once called ChAdOx, is a chimeric viral vector vaccine. In the 9-1-2020 issue of COVID Transmissions (found here: https://covidtransmissions.substack.com/p/covid-transmissions-for-9-1-2020), I explained what that is:
…there is another strategy that has become popular in the past couple of decades: chimeric viral vectors. These are fancy products of genetic engineering. A hybrid virus is created from something that is known to be relatively harmless in humans combined with the pathogen of interest. The “vector” is that harmless backbone. You’ve heard of this strategy, in this very newsletter: This is what the ChAdOx vaccine is based on, using a chimpanzee adenovirus backbone as a scaffold to deliver SARS-CoV-2 antigens.
In theory, the chimeric strategy is great. It uses a mechanism that is similar to natural infection, it delivers your protein of interest, and it is, in a way, programmable. If you develop a vaccination platform that uses a specific backbone, you could change the sequence to deliver many different antigens of interest.
One problem with this strategy is the possibility of prior immunity to the backbone. This is a real problem that we saw with a Chinese vaccine that is based on human adenovirus 5. Almost half the patients in the Phase 2 trial of that vaccine had preexisting immunity to the vector. If the immune system is responding to the vector, it may not yield a strong response to the antigen of interest that the vaccine is designed to protect against.
Another issue is that the vaccine may generate a better immune response to the vector than it does to the pathogen of interest, which is something that can at this point only be determined by experimentation.
Additionally, even if a meaningful immune response to the pathogen of interest is generated, there is the potential that there will still be a meaningful immune response to the vector as well. This means that each vector might only be useful in a patient once; it may be that if you get the ChAdOx-based SARS-CoV-2 vaccine, you might not benefit from future vaccines that use the ChAdOx backbone.
That said, the viral vector method has a lot of advantages, but it’s also a relatively new strategy. I do not believe that there are any current FDA-approved chimeric vaccines. This is not because of any inherent danger from these vaccines, but rather evidence that this technology is new on the scene and hasn’t had the time to get to market yet. Perhaps COVID-19 will change that.
So, we are talking about a vaccine that uses another virus as a scaffold to carry SARS-CoV-2 antigens into the body, thus simulating a natural virus infection. In this case, the scaffold is a chimpanzee virus, giving rise to the tagline of today’s email.
Something that’s exciting about this vaccine is that it can be stored for a long period of time at just refrigerated temperatures. Specifically, it can remain stable at between 2 and 8 degrees celsius for 6 months. That’s about the temperature of a home refrigerator. Neither of the other vaccine candidates come close to this type of shelf stability, but shelf stability doesn’t matter at all if the vaccine doesn’t work.
Now, in the past, we’ve seen data showing that this vaccine can generate an immune response that is specific for SARS-CoV-2. That was covered in COVID Transmissions for 7-21-2020: https://covidtransmissions.substack.com/p/covid-transmissions-for-7-21-2020
At the time, I felt that the results were promising and justified the initiation of a Phase 3 trial in humans. Now we have interim results from that trial.
As I’ve described before, this was an “event driven” trial; the interim analysis was triggered by reaching a certain number of COVID-19 events in the trial population. This number of events was specified in advance, as a total across both the control arm and the vaccine arm of the trial. A total of 131 events triggered this interim analysis.
Unlike the Pfizer and Moderna trials, the AZ-Oxford trial had 2 dose regimens being tested. One regimen, which I have called “Regimen 1,” involved 2 full doses of the vaccine being given, 1 as the “prime” dose and the second dose as a booster given at least 1 month later. The second, “Regimen 2,” involved a half-dose being given as the “prime” dose followed by a second, full dose being given as a booster at least 30 days later.
Regimen 1 enrolled 8,895 patients. Regimen 2 enrolled 2,741 patients. There was total vaccinated enrollment of 11,636 patients, according to the AstraZeneca press release. The number of placebo patients was not clearly reported, or at least not such that I was able to readily pick it out from the press release, but my presumption is that patients in each group were randomized equally to either receive the AZ dosing regimen described, or a similar regimen of the control. In this trial, the control was not a placebo. Instead, it was an irrelevant vaccine—specifically, a vaccine against meningitis. This is an interesting design because, when the control is an active treatment, it is a closer simulation of the effects of the treatment being studied. The meningitis vaccine would be expected to have similar safety effects, and participants would not be able to figure out whether they got the COVID-19 vaccine candidate or the control. If they don’t know that, then the “placebo effect” is in full force and the trial avoids potential bias.
That summarizes the design. It’s time for the results. In the full patient population, the vaccine had 70% efficacy. It’s tempting to compare this to the Moderna and Pfizer vaccines—which showed much higher efficacy—right away, but that isn’t fair. Those other vaccines had trials that only had 1 dosing regimen. They had entirely different patient populations. They were conducted in a different country. It is not fair to make cross-trial comparisons. To really compare two vaccines, you need to study them in the same trial.
Now that I have stated that rule, I’ll warn you I’m going to break it momentarily. While you can’t make direct comparisons, we can informally compare some aspects of these study results.
First, though, I’d like us to look at the individual regimens. In Regimen 1, the vaccine efficacy was 62%. Six weeks ago, I would have told you that a vaccine with more than 50% efficacy counts as a success. However, in the world we’re living in now, this seems low.
Thankfully, in the Regimen 2 arm, the vaccine efficacy was around 90%. That’s more like what we’ve seen in the other trials. Let’s bear in mind, though, that the Regimen 2 patients were a much smaller population, so the results there may be more subject to individual variation. Still, there is a potential other explanation for why this condition has better results than Regimen 1. Earlier, in the paragraphs I quoted about the vaccine design, I noted that chimeric viral vector vaccines can have problems if the recipient has an immune response to the virus that was used as a scaffold for the vaccine.
One of the issues with the prime-boost approach for a vaccine with this design is that the prime dose could yield a strong immune response to the scaffold virus, and then the boost would reinforce that, leaving the response to SARS-CoV-2 to the wayside. It’s possible that that’s what happened in the Regimen 1 design, as a result of the full prime dose being given. The Regimen 2 design may have avoided this by using a lower initial dose.
Ultimately, these are interim results and we will probably learn more about this question as the results mature further, but these possibilities are worthy of consideration.
In terms of safety, the interim results press release is light on details. It says, “No serious safety events related to the vaccine have been confirmed. AZD1222 was well tolerated across both dosing regimens.” This doesn’t tell us anything. Previously, there was a safety event that halted the trial globally, so I want to hear more about safety than was reported here.
That brings me to another big criticism: once again, like for the other two vaccines, this was science by press release. There is no paper. We can’t see the immune responses, the detailed safety data, or really anything. There are a lot of questions we could answer if we had real data. I don’t love this situation where this type of data reporting is becoming commonplace.
Still, we have learned a lot about the three leading vaccine candidates. To summarize what we know so far, I produced a graphic that appears below. Again, these are different trials, so I wouldn’t recommend making direct comparisons of these candidates. However, these results confirm pretty definitively that COVID-19 is a disease that we can readily prevent using vaccination. We developed these vaccines in about a year from when the disease first emerged. That is an historic triumph.
You might have some vaccine questions! Send them in.
I also want to answer your questions on different topics, so please don’t hold back if you’re interested in asking me anything.
Join the conversation, and what you say will impact what I talk about in the next issue.
Also, let me know any other thoughts you might have about the newsletter. I’d like to make sure you’re getting what you want out of this.
This newsletter will contain mistakes. When you find them, tell me about them so that I can fix them. I would rather this newsletter be correct than protect my ego.
Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.
Correction: Yesterday’s “Pandemic Life” section carried over the wrong title from the previous issue. It should have read “Philcon.” This has been corrected in the online edition.
See you all next time.
Always,
JS
Obviously they used a chimp adenovirus on the belief that few humans would have been exposed to it. The Astra Zeneca Oxford vaccine seems to be a lot cheaper than either Moderna's or Pfizer's version. The two-dose regimen is a definite drawback; humans are notoriously bad at coming back for the second dose. Ideally, a nasal spray would make it more palatable, as there's a lot of needle phobia out there, and some wacko conspiracy theories.
When I was a kid, vaccines were mandatory and administered in school. Unfortunately, that's no longer the case. It does seem like unless we get the entire world vaccinated over a month period this will be a chronic problem. Or maybe we'll get lucky and the virus will mutate into something more benign.