COVID Transmissions for 8-11-2020

What can a vaccine do, anyway?

John Skylar, PhD

Aug 11, 2020

Greetings from an undisclosed location in my apartment.

It has been 268 days since the first documented human case of COVID-19.

Housekeeping note:

Short headlines section today because there’s a longer in-depth piece.

Today’s in-depth builds on some of the concepts from the HHMI talk that I shared from Dr. Florian Krammer yesterday.

Glossary terms are bolded words with links to the running newsletter glossary.

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Now, let’s talk COVID.

Nearing 20,000,000 cases worldwide:

Although I am in the US, I try to take as global a view as possible when it comes to public health. Worldwide, we are reaching 20 million documented cases in the pandemic. CIDRAP has a roundup of how the fight against the pandemic is going around the world as we approach this milestone: https://www.cidrap.umn.edu/news-perspective/2020/08/countries-face-diverse-challenges-pandemic-total-nears-20-million

An experiment to show the effectiveness of masks:

CNN reports on a study that used laser visualization of airborne particles to compare the effectiveness of various masks: https://www.cnn.com/2020/08/08/us/duke-university-face-mask-test-trnd/index.html

This is a cool study that shows the relative ability of different mask types to block particulates. Most interesting to me is that rolled bandanas, which I see a lot of people wearing, don’t seem very effective at reducing the dissemination of small particles in the experimental system.

On the other hand, we don’t actually know what minimum effect on particles is needed to slow transmission of COVID-19 because we do not have good transmission models. So while this study can show us the relative ability of different masks to limit particle movement, all of these masks, or only some of these masks, may be effective at limiting transmission of COVID-19.

Full study here: https://advances.sciencemag.org/content/early/2020/08/07/sciadv.abd3083

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

Return from vacation

As a best practice on returning from my vacation, I got a COVID-19 test today. While I encouraging finding a safe way to get away, remember also that nothing is 100% safe. So, out of an abundance of caution, I got tested. If it returns positive, I will self-quarantine for a period of 14 days at minimum, or for the full duration of any symptoms that emerge plus an additional 7-14 days after symptoms resolve.

Cooking

Still killing off leftovers from the great blackout. Thankfully my parents have their power back—thanks to those of you who asked about this.

Before I went on vacation, we had about four pounds of cucumbers that we needed to deal with. They were going to turn into a puddle of goop if I didn’t do something with them, so I made pickles with a relatively quick recipe.

Image is a group of pleiomorphic pickles, both pickle-chip and long-cut varieties.

To make pickling liquid, I added about 1.5 to 2 cups of vinegar to about 3 cups of water (this was mostly Bragg’s apple cider vinegar but I did have to supplement with some white vinegar as well to make the full 2 cups). I let this simmer in a pan with a little bit of salt (2-3 teaspoons, max) and some of Fairway’s pickling spices. If you don’t have access to pickling spices, you can make them with peppercorns, some red chili flakes, coriander seed, cloves, and just about anything else that has a spicy flavor that you like. To finish it all off, I added few tablespoons of maple syrup (you can use sugar, but I don’t keep sugar at home). You can also add some garlic—one to three cloves should do for these proportions, but it really all depends on what you like. After letting that simmer for about 10 minutes, I transferred it to a jar and put it in the fridge to cool.

The cucumbers you want to use for pickles are ideally smaller, bumpy examples that aren’t what you’d use in a salad. I wasn’t working with preselected pickling cucumbers, but if you want to try this, I’d recommend that you do since the more salad-appropriate types won’t get you the best texture in the end. I sliced them both lengthwise as well as crosswise to make pickle chips; I have a mandolin slicer that can do this very nicely, but beware if you use one of those—they can be dangerous!

Anyway, once all the pickles were sliced and the liquid cooled to fridge temperature, I packed the pickles tightly into a container and filled the empty space in the container with the pickling liquid previously prepared. Left to sit in the fridge for 24 hours, they’ll be ready to eat. They should last about a month in the fridge after that.

What can a vaccine do, anyway?

Like I mentioned in the opening note, Florian Krammer’s HHMI talk from August 6th is making me think a lot about vaccines. So that you don’t have to dig up the email, here’s a link to the talk again: https://hhmi.hosted.panopto.com/Panopto/Pages/Viewer.aspx?id=9be1b267-f975-4a6e-9544-ac100134313a&fbclid=IwAR3fhMl538t-3d1RN-lIns18vgICbd-0YRJAwTvqp8unwdwNK6HiJm9LcrQ

I’m going to take a minute to talk about who Florian is and why I listen to him. He is an Austrian scientist who began a postdoctoral fellowship at Mount Sinai while I was still in graduate school there. One of the key projects at Mount Sinai is the quest for a “universal” influenza virus vaccine. This would be a flu shot that you can get, ideally, just once in a lifetime. Realistically, it’s expected that the first generation of such a vaccine is more likely to be a once or twice a decade experience, though the goal is still a vaccine that you only need once. Florian entered an environment where novel strategies were being used to identify antigens within the influenza virus that might produce antibodies that would cross-react to very different influenza strains. Florian worked on a variety of projects related to this, but the one that sticks out in my mind is his creation of a robust platform that used an insect cell line and insect viruses to manufacture large amounts of flu antigens. He quickly became one of the most productive scientists in the department. Fast forward to the COVID-19 pandemic and he has become a leader there too, because his lab was able to quickly produce large quantities of the first SARS-CoV-2 antibodies and antigens that allowed for the earliest large-scale human antibody testing programs for the virus.

I tell this story to establish his caliber as an expert on antibodies, antigens, and viruses. This is a person you want to listen to when he starts talking about vaccines, because he will be informative and thought-provoking.

Florian’s talk made me realize that my past in-depth articles on vaccines have focused on too narrow a question regarding vaccination. All this time, I have been asking “will a vaccine be protective?” This is an important question, but it collapses a complex topic into a simple yes or no.

Instead, I should have been asking, “What can a vaccine do?”

The ways that our immune system protects us are many and varied, and I think we fail to appreciate a lot of the time how amazing immunity really is. Using a specific arsenal of tools, our bodies can respond to threats like cancer, large parasitic worms, nanoscopic viruses, and microscopic bacteria. To do this, we use a combination of antibodies and purpose-built cells that attack invaders or support the creation of an environment that is toxic to them, as well as a cast of chemical signals—chemokines and cytokines—that regulate the ballet of immune responses.

File:2220 Four Chain Structure of a Generic Antibody-IgG2 ...

Image shows two cartoons of an IgG antibody molecule. On the left, a 2D cartoon displays the fork structure, showing the two heavy chains (blue/red) and two light chains (yellow/green) of the antibody, as well as the constant (containing the Fc region, which communicates to immune cells) and the variable region (which contains the antigen-binding sites). On the right side of the image, a 3D structure with the same color-coding is shown, giving a sense of what the antibody molecule would actually look like if it were large enough to see. Image via wikimedia commons, originally from a textbook by OpenStax College: https://commons.wikimedia.org/wiki/File:2220_Four_Chain_Structure_of_a_Generic_Antibody-IgG2_Structures.jpg

Antibodies are a mighty tool. They are about 10 nanometers in size—very small compared to a 100-nm virus particle, for example—but they can take down things like large parasites that are centimeters long. A centimeter is ten million times the size of a nanometer. A similar scale of warfare would be trying to destroy Earth’s moon (3500 km in diameter) with arrows (less than a meter in length).

Of course, antibodies are supported by and can recruit bigger guns in the immune system to help them fight, but they are really amazing molecules. And despite this, it has always baffled me—and generated debate among other scientists—that they can do anything to combat viruses.

Viruses have one function: making more viruses. They are stripped down and optimized for producing billions and billions of copies of themselves in a single infection. The volume of virus particles that can be made is meant to overwhelm and infect. There is a reason that the rapid spread of online communications at an unstoppable rate is called “going viral.”

At that scale of material being produced, if you destroy one virus particle, within the same drop of fluid there are at least tens of thousands more to take its place. That’s what antibodies are up against. It’s amazing that they can stand up against such an onslaught.

Probably because this is a difficult scale problem of buzzing virus particles being taken out by antibody flak, there are other mechanisms that the human body uses to control viruses. Our immune systems hit the virus at home—in the cells that it has infected. Immune cells patrol the body to kill infected cells, shutting down factories of virus production. If antibodies are the flak cannons shooting down invading aircraft, these immune cells are the bombers that go and find the enemy aircraft factories.

The problem is, a small number of virions can turn a nearby cell into a new factory, with relative ease. So the flak and the bombers often have to work together, limiting the spread of the virus from cell to cell as well as shutting down the cells producing new virus particles. The antibodies and cells are manufactured at increasing rates as well, helping to eventually match the ability of the virus to produce itself and thus contain the infection.

Continuing the war metaphor, the United States did not have the military power to defeat the lightning-strike effectiveness of Germany, Japan, and Italy at the start of World War II. Instead, the US coordinated with its allies to contain and delay the Axis powers until its massive production facilities could match the military power of these quick-hit foes. This is a lot like what the immune system attempts to do—contain the infection, and then ramp up production of the immune arsenal until the trapped enemy can be destroyed.

Bringing this back to vaccines, the power of vaccination is that it can train our immune system to keep certain tools at the ready, so that the ramp up in production of these weapons happens faster during a real infection. A vaccine doesn’t cause us to deploy a full-scale immune response all the time for the rest of our lives. It causes our immune systems to learn what a specific pathogen looks like, and be ready to spring into productive action against it faster than if we had never seen that pathogen before. The antibodies and cells that are part of that response still face the same uphill battle that we walked through earlier, but they get a big head start.

Given the rapid pace and massive production in virus infections, this means that even the immunity that you receive from some of our best vaccines does not truly prevent virus infection. It just stops us from noticing that we got infected, by helping our immune system to ramp up and fight back before the virus can cause disease.

A great, but somewhat extreme, example of this is the polio vaccine that was invented by Jonas Salk. The Salk vaccine does not prevent you from getting infected with polio. Polio virus is a gut virus that in most people doesn’t cause notable disease. You might not even realize you’ve had it. However, in some small percentage of people, polio virus can spread to the central nervous system and cause poliomyelitis, a paralytic illness that is what we think of as “polio.” The Salk vaccine doesn’t stop the virus from infecting the gut; it merely trains the immune system to contain the virus infection in the gut so that it does not make us sick and does not spread to the central nervous system. The important symptoms of disease are eliminated but the infection is not prevented.

This illustrates an important concept in vaccinology—that there are different ways to be protected. The prevention of infection altogether is called “sterilizing immunity.” With sterilizing immunity, the pathogen is stopped before it even gets started. The incoming infection—the “inoculum”—never has a chance to initiate infection. Sterilizing immunity to a virus is extremely difficult to achieve.

Instead, we expect most vaccines to induce protection against disease by limiting the ability of the virus infection to spread within the body and cause significant damage. Hypothetically, let’s say that in a respiratory illness like COVID-19, a virus has to infect ten million cells in your lung before you start to cough. If you have vaccine-induced immunity that limits the virus infection to five million cells, you’ll never even know you were infected—but, you were.

Now, it’s rarely so binary. There’s more of a continuum of responses; a strong immune response to an influenza virus infection might allow you to avoid disease altogether, but a weaker immune response to that vaccine might make the difference between a flu that puts you in the hospital vs one that keeps you sick at home for a few days. Both of those scenarios would be considered protection, to a degree.

Vaccinologists are well aware of this subtlety. Let’s take a look, for example, at the primary endpoint of Moderna’s Phase 3 vaccine trial:

Number of Participants with a First Occurrence of COVID-19 Starting 14 Days after Second Dose of mRNA-1273 [ Time Frame: Day 29 (second dose) up to Day 759 (2 years after second dose) ]

There’s something subtle here. This endpoint is not measuring “infection with SARS-CoV-2”; the trialists do not expect that they have prevented that with this vaccine. Instead, they are measuring occurrence of the disease COVID-19. They expect that their vaccine will reduce the disease, but not necessarily prevent infection with the virus.

This expectation is even better seen in some of the secondary endpoints (emphasis mine):

Number of Participants with a First Occurrence of Severe COVID-19 Starting 14 Days after Second Dose of mRNA-1273
Number of Participants with a First Occurrence of Either COVID-19 or SARS-CoV-2 Infection regardless of symptomatology or Severity Starting 14 Days after Second Dose of mRNA-1273 or Placebo
Number of Participants with a First Occurrence of SARS-CoV-2 Infection in the Absence of Symptoms Defining COVID-19 Starting 14 days after Second Dose of mRNA-1273 or Placebo

Each of these endpoints draws a fine line between protection that prevents COVID-19 disease, protection that prevents severe COVID-19 disease, and protection that yields sterilizing immunity and thus prevents SARS-CoV-2 infection altogether.

So, we’ve established two answers to what a vaccine can do: it can prevent or lessen disease, or it can prevent infection. But there’s a third, important function of protective immunity, one that matters on a community level.

One of the big topics in COVID-19 communications is herd immunity, the ability of widespread population immunity to protect people who haven’t had a good, protective immune response.

U.S. GAO - Science & Tech Spotlight: Herd Immunity For COVID-19

Image is a graphic from the Government Accountability Office showing the difference between the absence and presence of herd immunity via crowds of stick figure-type-people. Without herd immunity, the infection (red) spreads through the population to infect susceptible people (blue-grey) unimpeded. In the presence of herd immunity, immune individuals in the population (green) are a dead end for the infection, and they get “in the way” of potential transmission to susceptible individuals. Image via the GAO and thus public domain.

Herd immunity relies on immunity that prevents transmission of the virus. Remember the polio vaccine example that I gave earlier? It remains possible for someone who has received the Salk polio vaccine to transmit the polio virus. That vaccine protects against disease, but it does not protect against transmission and it does not provide sterilizing immunity.

Compare this with the influenza vaccine; the seasonal influenza vaccine is intended to protect people around you. It may lessen your ability to transmit the virus. Every time someone dies of the flu, it is because somewhere along the chain of infection, there is a person who did not get vaccinated and made themselves a willing transmitter of virus. It’s true that the vaccine doesn’t work 100% in every person, but because flu generally passes from one person to one other person, like an Olympic torch, somewhere in that chain of individual infections there is generally someone who just couldn’t be bothered to get the vaccine; because of their choice, someone downstream from them died. The seasonal influenza vaccine protects against disease, and it also prevents or lessens transmission of the virus.

One of the reasons that the seasonal influenza vaccine is able to prevent transmission is that the influenza virus is thought to be most successful at transmitting from just before symptoms begin until about a week after they start; the going thought is that if you reduce or eliminate disease, you also reduce the replication of the virus to where it is less effective at spreading to other people.

So, we have a third thing that a vaccine can do: prevent the spread of an infectious disease through the population. Since sterilizing immunity stops infection immediately, if you have sterilizing immunity, you also cannot transmit the virus. Sterilizing immunity is sufficient, but not necessary, for prevention of transmission. Other, lesser immunities may also reduce transmission of any given virus.

Unfortunately, we don’t know enough about COVID-19 to know whether reduction or elimination of disease will also lead to reduction or elimination of transmissibility. We have at this point seen evidence that the SARS-CoV-2 virus can transmit from people for two weeks before they show symptoms, and that you can also recover infectious virus from patients who never show any symptoms at all. But, we do not know for sure how much virus it takes to infect someone else, and we don’t know how much the vaccine(s) that succeed will be able to limit the amount of virus that a person sheds. All we know is that it’s possible to have a type of infection where you might be able to spread the disease, but you don’t have any symptoms.

This presents the possibility of a “selfish” vaccine that protects the recipient from COVID-19 but doesn’t protect their community or anyone around them. It doesn’t yield sterilizing immunity, and it doesn’t prevent transmission; it just eliminates or reduces disease. This would turn every recipient of the vaccine into a potential asymptomatic spreader of the virus.

If the vaccine(s) that come to market first fit this description, I fear that we might have to continue social distancing in order to protect people around us from our own ability to spread the infection. Vulnerable people in high risk groups will get the worst of this situation, with the risk of their infection not substantially decreasing. They might be able to get the vaccine, though, and lessen the severity of any COVID-19 that they might experience. If the reason someone is vulnerable also prevents that person from getting vaccinated, though? In that case, they could be in deep trouble.

This situation is likely an extreme. We still don’t believe that asymptomatic infections are as effective at spreading SARS-CoV-2 as symptomatic infections. We don’t really have evidence either way, but it stands to reason that if you are asymptomatic it is because your infection is not as intense or perhaps did not grow to as high a level as someone who has symptoms. So, you would have less virus to spread. At the very least, a person with asymptomatic infection would be expected to be coughing less, and perhaps spreading less virus in that way.

For this reason, I would expect a vaccine against COVID-19 that lessens symptoms to also lessen the amount of virus that a person has in their system to spread. It might also reduce the amount of time during which that person is able to spread the virus. All of these things will contribute to containment of the virus and reduce transmission.

While it may not completely eliminate transmission, small impacts on the velocity of the virus in the population can help us to extinguish it. Right now the regime of masks and social distancing have helped New York City to get our local outbreak under control and hovering below the critical “R=1” reproduction number where the outbreak persists because each infection leads to at least one new infection. Add a vaccine that reduces the odds of transmission just a little further, and we might drive the local outbreak to extinction. If the vaccine also reduces severity of disease, we also have less worries about the healthcare system being overwhelmed if a new outbreak should occur.

Ultimately, I think what is most likely is a vaccine that limits disease in most people and also limits transmission, at least to a small degree. I do have some worries that vaccination will not prevent transmission enough to justify ending our new masked, distanced world, but I also expect that with 140 vaccine candidates in development, we will eventually have a technology that both lessens disease as well as prevents transmission. True sterilizing immunity may not be possible, but a combination of prevention of transmission and of disease will eventually allow us to get the virus under control and end the pandemic.

Join the conversation, and what you say will impact what I talk about in the next issue.

Since there was a lengthy in-depth piece today, I’m counting on questions—so please jump in to the conversation and ask.

Also, I welcome any feedback on structure and content. I want this to be as useful as possible, and I can only make that happen with constructive comments.

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