COVID Transmissions for 11-10-2020

VACCINE

Nov 10, 2020

Good morning! It has been 359 days since the first documented human case of COVID-19. It is remarkable—amazing!—that we are at just under a year from the first emergence of this virus, and at around 10 months from its first sequencing, and already talking about a vaccine. I hope you all realize how unprecedented this is. We live in a time of wonders that our ancestors would think magical.

Today it will be my pleasure to discuss topline vaccine efficacy results that have been shared by Pfizer about the vaccine they have been developing in collaboration with German company BioNTech.

Also there are a lot of other headlines today. I was not prepared for how many COVID-19 things were going to happen yesterday. Wow!

As usual, bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

Indoor-outdoor dining

In NYC, a lot of restaurants have started to construct little shacks that will allow them to continue “outdoor” dining in inclement weather in the winter. In my opinion, when you have constructed a second restaurant outside your existing restaurant, it is no longer outdoor dining.

The New York Times decided to take on this topic today: https://www.nytimes.com/2020/11/09/nyregion/nyc-outdoor-dining-winter.html

What’s important to me is that airflow be maintained. I look for spaces with at least two large, open-air openings. Yes, large is hard to define, and I can’t pin it down exactly. But that’s what I look for. I’m also OK with table-individualized pods, but only if they’ve been unoccupied and open to the air for awhile before I get into one.

Even when I see a space that I like, I’ll walk away if it’s too crowded. Distancing is still important.

New Jersey reinitiates limited lockdown

The state of New Jersey has brought back a large number of lockdown restrictions, but far from all restrictions, in response to growing case numbers.

This could be coming soon to an area near you. It’s time to get ready for new limitations, if you live in the US.

See details here: https://www.fox5ny.com/news/new-jersey-expected-to-implement-new-coronavirus-restrictions

Two things that jumped out at me is that indoor dining will be closed after 10 PM and that tables must be 6 feet apart indoors unless barriers are placed between tables.

I don’t agree with the way these are being implemented. I don’t think that plexiglass barriers make it safe for tables to be closer together than 6 feet. I don’t think that the virus only transmits between people in restaurants after 10 PM.

I don’t think indoor dining right now is a good idea in any state in the US.

Eli Lilly antibody drug issued EUA

Eli Lilly’s antibody drug has been given an emergency use authorization (EUA) by the FDA: https://www.cnbc.com/2020/11/09/us-allows-emergency-use-of-eli-lillys-covid-antibody-therapy.html

This is a super interesting drug because it is intended for patients with mild-to-moderate COVID-19 who are not hospitalized. The point of this drug is to keep people out of the hospital. That’s a really important weapon to have in our arsenal—provided that it can accomplish that goal when made available at scale, something that hasn’t been demonstrated in a clinical trial. If it had, this would be an approval and not an EUA.

Pfizer vaccine reportedly effective

Today, Pfizer issued a press release that the vaccine they have been developing in collaboration with German corporation BioNTech is over 90% effective.

I will write about this at length in today’s in-depth.

Biden announces COVID-19 task force

Yesterday, President-elect Biden announced his COVID-19 task force. It is made up of some very high caliber names, most of which I recognize. You can read its full makeup here: https://buildbackbetter.com/press-releases/biden-harris-transition-announces-covid-19-advisory-board/

One big concern that I have about this group is that no one on it is specifically a coronavirus expert, but it’s still an incredible list of people with staggering accomplishments in public health and infectious disease management.

What am I doing to cope with the pandemic? This:

Planning the next several months

Look, this section can’t always be fun. For a few months now, I’ve been warning that things are going to get bad again, and they’re getting bad again. I also learned today that my company is going to be giving me some extra time off in holidays towards the end of the year. I’m trying to figure out what I’ll be able to use that time for in a world where case growth continues.

Right now, I’m thinking I’m either going to learn to bake finally, or I’m going to start taking long hikes along the avenues of New York City.

Of course, this is part of a bigger question of how to plan sanity-maintaining activities over the next several months. I think I am going to have to dust off a lot of what I did last spring when lockdown was in full force. I will cover some of those activities here as the weeks go on. My main message right now, though, is to get ready.

The Pfizer-BioNTech Vaccine: Questions

The word “vaccine” comes from the Latin for “cow,” because the first vaccination, against smallpox, was thought to be derived from the cowpox virus. It turns out that that vaccine is more closely related to horsepox, but for some reason we don’t call it “equination.”

This, however, is not the biggest question about vaccines that we’re here to discuss. The concept of a vaccine has changed a lot since an animal pox virus was injected into humans to prevent smallpox. We now live in a world where weakened viruses, synthesized proteins, and all kinds of other technologies can be used to make vaccines. In fact, we are living through, right now, a major advance in vaccination technology.

You know that I’m writing about the Pfizer-BioNTech vaccine, of course. It is an mRNA vaccine, made just of nucleic acid molecules that can make our cells produce components of the virus. The immune system then reacts to those virus components. The vaccine contains a recipe for itself; your body makes the ingredients. In a way, you vaccine yourself. This on its own is so flabbergastingly amazing that I could write a (pretty useless) article about how cool it is.

The problem with things that are flabbergastingly amazing is that they often just don’t work. I could also write a pretty useless article about vaccine technologies that did nothing.

Luckily, we now know that the Pfizer vaccine works. Today, the company issued a press release indicating that the vaccine is over 90% efficacious, on the basis of 94 infection events, in a population of about 44,000 patients. This is very interesting news, and it is very good news, but we really need to pick it apart to understand why it’s good—and why it isn’t.

The first thing I want to headline is that this is good news because it means that a vaccine can prevent COVID-19-the-disease. That’s what we’re talking about when we say that it’s 90% efficacious—that in a population where 100% of people receive it, 90% of disease cases will be eliminated compared to a population where 0% of people received the vaccine. This is on the basis of a fairly small number of events; specifically, 94 total. The implication, then, is that 10 times the number of cases occurred in the placebo arm compared with the vaccine arm. That means something like 8 or 9 cases occurred in the vaccine arm, while around 80-90 cases occurred in the placebo arm. That is quite remarkable.

Now, I’m estimating all of that. The only thing that has been released is the 90% efficacy number and the 94 events number. The details of how this breaks down are something I have estimated, and no other data have been released. This is a big problem. I don’t like science-by-press release. I like data. They didn’t give me data.

However, I don’t think Pfizer is lying about their topline data. I think their vaccine works under the idealized conditions of a clinical trial, and I think what they’ve proven with this press release is that it’s possible for manmade immunity to SARS-CoV-2 to prevent COVID-19. This is not something that we knew before. This was something that was completely up in the air. This is a big deal.

It also suggests that previous illness with COVID-19 can induce protection against future disease, but please take that with some degree of caution. The vaccine has been explicitly designed out of a goal to induce immunity. The virus has not been designed with any intent at all; it was shaped through natural selection. Natural selection does not incentivize viruses that induce perfect immunity every time. So while we now know that it’s possible to become immune to this virus, through immune responses induced by components of the virus, we don’t know if any specific person’s infection led to them being immune. We might have some insight on that, though, when we get the full results from this vaccine study. I’ll get to that.

What we do know is that we can create a vaccine that can protect people from COVID-19—the disease. Now let’s move on to what we don’t know, at least within the context of COVID-19 vaccination. I have a lot of questions about this vaccine.

The most important—the most important—question here is this: does the vaccine prevent transmission of the disease?

In a past issue of the newsletter, I discussed the important difference between protective immunity and sterilizing immunity. Sterilizing immunity is the prevention of infection, while protective immunity is the prevention of disease. As it turns out, the human body is frequently host to various infections. Most of these you do not notice because they are well-managed by your immune system. In fact, the human body is host to all kinds of things your immune system takes care of without you ever noticing—including cancers that are neatly cleaned up by immune cells.

It’s when you notice the immune insult that it has transitioned to becoming disease. We’ve known for quite some time that it is possible for SARS-CoV-2, the virus, to infect a person without causing disease. It has actually been quite a big problem, since it is also possible for infected people without disease to transmit the virus to others. Someone can be walking around and if they are not wearing a mask and not distancing, they could give someone else an infection that might or might not lead to COVID-19.

Based on the data that Pfizer has made available, we don’t know if their vaccine will provide sterilizing immunity that could prevent infection entirely. However, I would say it is very unlikely. There are few—if any—vaccines that provide sterilizing immunity. A much larger group of vaccines provide varying degrees of protective immunity, however. When Pfizer reported a 90% vaccine efficacy, my understanding is that protective immunity is what they were talking about.

There is a third concept, however, that is not covered in these two extremes: immunity that is capable of preventing transmission. We can easily convince ourselves that sterilizing immunity also prevents transmission. After all, if the infection never takes place at all, then the person cannot spread it. They never produce any virus. On the other hand, what about someone with protective immunity? They do get infected, and they do produce virus. Can they still transmit the virus?

Since we know that people who are asymptomatic can transmit SARS-CoV-2, we know it’s possible for disease to be absent but transmission to still be possible. On the other hand, we don’t know if this vaccine has some effect that interferes with that mechanism. Perhaps the vaccine so inhibits the virus that it is not capable of growing sufficiently to transmit efficiently, even though the patient still becomes infected. We will need to see data describing the infections that took place in the Pfizer clinical trial before we can really answer this question. It’s the biggest question that I am hoping to answer, for a number of reasons.

First and foremost is that a vaccine that doesn’t prevent transmission will mean that SARS-CoV-2 is here to stay. We will never be rid of it. It will always be something that humans have in our circulating population of viruses, and everyone will likely either receive the virus or a vaccination as a child, from here on out. It would also mean that a vaccine might not be great news for at-risk populations; if the vaccine does not work well in those populations, and the vaccine doesn’t prevent transmission, then even if everyone on the street gets a vaccination, the person at risk is still at risk.

This brings us to another huge question: how does the vaccine perform in patient subgroups according to different demographic characteristics? Does it perform equally well in patients of different races? What about patients of different ages? What about patients with preexisting diseases that might increase their risk of a severe outcome?

A good paper from this study is going to contain this type of subgroup analysis. I am eager to see it, as I am many parts of the analysis.

The other big chunk of data that I am looking for from this study is anything that could give us a sense of correlates of protection. As discussed a little earlier, we still don’t know what part of the immune response may make you protected from COVID-19. Is a robust antibody response indicative of protection? Or is it, instead, the populations of immune cells like T-cells that make the difference?

I’m interested in these questions for more than just academic reasons. These are really practical questions, and this is our first opportunity to answer them. For the first time, we have a patient population that we can demonstrate to be protected from the disease, alongside a similar population that we know isn’t protected. We can see what makes them different from each other, to understand those correlates of protection.

An understanding of correlates of protection would mean we could design patient testing. All of you readers who have had COVID-19 might be able to go to a doctor’s office and get a test that definitively tells you that you are immune. You could periodically check your immunity, even, to check that it is still in force.

Additionally, we could use these correlates of protection to speed the development of other vaccines against SARS-CoV-2, even beyond the current breakneck pace. Understanding what we need to look for to indicate protection is present would mean new trial designs would be possible. Instead of waiting over time for infections to occur, it might become feasible to design trials where the vaccine is given and then the primary endpoint measured is the presence of the correlates of protection. This would make the length of trials substantially more predictable, and potentially shorter. That would be a huge benefit on its own.

That sums up the questions that I have about the vaccine, but I want to note a couple of things about limitations as well. What Pfizer has reported is an interim analysis; this means that the trial isn’t finished yet. The vaccine efficacy of 90% is eye-popping, and much higher than the 50% threshold that was set as the minimum for approval, but I want to caution that it will probably not bear out over time.

This is not because the vaccine is ineffective, or that it will wane over time. When the final analysis is completed, if the vaccine is only 75 or 80% effective, do not be alarmed. This is normal. The time that this trial has run is short. The number of events is a little more than half of the number that will be required to trigger the final analysis. A lot can happen in that time. It is possible that this early result is an outlier, and that over time, more patients in the vaccinated arm will get COVID-19. There will be a certain regression to the mean, and we should anticipate the vaccine efficacy to go down somewhat in the final analysis.

Likewise, this analysis is being performed early on, when patients will have a strong vaccine-induced immunity. Vaccine immunity can weaken over time. It happens with a lot of vaccinations. It may still be sufficient to protect against the disease, but it’s usually at its best early on. This is another reason that I expect the final analysis will show a slightly lower vaccine efficacy.

All of that being said, I remain very encouraged by, and curious about, these results. I will continue to explore further questions about this vaccine in in-depth pieces as time goes on (likely there will be another this week) and as the availability of data permits.

On yesterday’s edition, I received several comments to which I would like to respond. Unfortunately, yesterday’s remarkable amount of news has gotten in the way of my ability to reply. I will be certain to provide replies in this space to those comments tomorrow.

Likewise, I am sure that you all have questions about the Pfizer vaccine and what it may imply. Please do ask; I will answer tomorrow and in the days to come.

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.

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