COVID Transmissions for 9-1-2020

Vaccine formulation and design

Sep 01, 2020

Greetings from an undisclosed location in my apartment.

It has been 288 days since the first documented human case of COVID-19.

Housekeeping note:

Today, and throughout this week, I’m doing a multi-part in-depth on how vaccines can be put together; this will be an explainer to help us understand some of the vaccines that are being put forward. This will also offer some insights into basic vaccinology.

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

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Now, let’s talk COVID.

25 million cases worldwide

Yesterday we reached 25 million global cases.

US situation report—6 million cases

While certain states that had spikes in case numbers earlier this summer have started to see an ebb in their outbreaks—for example, Texas and Arizona—26 states are still seeing substantial case growth.

COVID-19 isn’t over.

Herd immunity in the US

The Washington Post has a story about a new advisor to President Trump who is advocating a “herd immunity” strategy where we try to encourage COVID-19 to move through the population until we reach a threshold level of protection: https://www.washingtonpost.com/politics/trump-coronavirus-scott-atlas-herd-immunity/2020/08/30/925e68fe-e93b-11ea-970a-64c73a1c2392_story.html?hpid=hp_hp-banner-low_virustrump-7am%3Ahomepage%2Fstory-ans

There are some assumptions being made under this strategy; I’ll list a couple. First, that immunity from natural infection is durable in the vast majority of people. We still don’t know if this is true.

Second, that the country is prepared to deal with the consequences of uncontrolled spread of disease. Estimates are that 2.13 million deaths would be associated with reaching sufficient levels of exposure to achieve 65% population immunity. That number of deaths would be similar to killing the entire population of Houston, TX.

I would not advise the President to opt for this strategy.

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

Biking, more

I bike about 15 miles twice a week, and based on the foot traffic I see in the West Side’s parks along the river, rumors of New York City’s untimely death have been greatly exaggerated.

Vaccine formulation, delivery, and design, Part 1

If there’s anything you can learn from reading my writing, it’s that vaccines can be really complicated to create. There must be a thousand different ways to make a vaccine, and every infectious disease has its own quirks that advantage certain strategies over others.

Image is a stock photo of a row of glass vaccine vials that I took from the CDC. I took the photo from them, not the vials, I mean.

The most basic kind of vaccine supplies proteins from the pathogen of interest, in a purified form, to induce an immune response from the host. In a normal infection, the immune system generates antibodies that largely react to foreign proteins created by the invader. This is not without exceptions, but as a loose rule, the immune system responds to proteins and creates antibodies that recognize proteins.

The thing is, though, that the immune system is exposed to a lot of proteins a lot of the time. You eat food, you breathe air, and you move through the world, among other things. These activities expose you to outside organisms, in volumes that would be truly frightening if we did not have a robust immune system.

Most outside threats are dealt with by our most important immune defense—our skin. However, we choose to ingest a large amount of protein, our skin isn’t a perfect barrier, and invaders can be quite wily.

One of the bigger problems in immunity is how we deal with all of this without attacking our own bodies, a problem which is also directly tied to why there need to be vaccine designs that are more complicated than the simple one that I’ve just described.

The immune system closely patrols the body with a sophisticated system of surveillance. This system of surveillance includes mechanism that are able to suppress immune responses that are inappropriate. For example, we aren’t allergic to absolutely everything we put in our mouths. That in itself is a feat of immune regulation.

Since the immune system can be so damaging, we have evolved a lot of controls like this that keep it from doing damage inappropriately. Some of these controls are evolved to detect patterns that resemble outside invaders. These have a fancy technical name—Pathogen Associated Molecular Patterns, or PAMPs—but the key thing to learn about them is that these signals, when detected, alert the body that it has been infected with something dangerous that needs to be controlled.

An inert injection of proteins does not always display a pattern that activates the immune system in this way. Sometimes the body just recognizes that kind of vaccine as junk and doesn’t react to it.

To fix this issue, additional designs features are needed. Most of these encourage the body to recognize the vaccine as being similar to a natural infection, and we’ll walk through a few of them.

One simple way to present a pathogen-like pattern is to use an inactivated, sometimes referred to as “killed,” version of the pathogen. This provides some molecules that signal the presence of an invader, but since the pathogen doesn’t replicate or grow, it’s far from a perfect simulation of a natural infection.

For plenty of pathogens, this type of inactivated vaccine is sufficient. For a long time, the only available seasonal influenza vaccine was an inactivated one. The Salk poliovirus vaccine is also an inactivated vaccine.

However, sometimes it’s not enough to just inactivate the pathogen, and this strategy doesn’t adequately simulate natural infection.

This shouldn’t be a surprise, but there are several COVID-19 vaccines in development that use inactivated virus.

Another way is the use of an adjuvant. In other medical contexts, “adjuvant” just means “helper” treatment. Vaccine adjuvants are, generally, some type of irrelevant additional irritating substance. In a vaccine, an adjuvant acts to induce an inflammatory response that signals to patrolling immune cells that there may be an infectious pathogen present.

There is a tricky balance to strike with adjuvants; they cause an inflammatory reaction, so if you add too much of them, you could make people really uncomfortable, or potentially elicit worse reactions. If you give too little, you may not get the immune response that you want. Since the amount of adjuvant that will be helpful is dependent upon the adjuvant’s properties as well as those of the antigen that goes into the vaccine, this is not always a balance that is possible to strike. Sometimes, it just doesn’t work.

Several candidate COVID-19 vaccines are designed to include adjuvants.

The whole point of antigens is to convince the immune system that a real infection is taking place. Another option to convince the immune system of this is to actually have a real infection take place.

The most basic “real” infection is the “live-attenuated” vaccine strategy. A live attenuated vaccine uses a weakened pathogen that can infect the host, and may even be able to cause extremely mild disease. The classic live attenuated vaccine design is the Sabin polio vaccine. This vaccine uses a weakened polio virus strain that still infects the host but that, generally, does not cause any disease. This strain is easily defeated by the immune system, but also generates a robust immune response.

One problem with live-attenuated vaccines is that in some cases, in some people, they can cause illness. For example, in a very small number of cases, the Sabin polio vaccine can revert to cause a vaccine-associated paralysis. This happens in about 1 out of every 3 million vaccinations, a rate that is much lower than the rate of paralytic polio in an unprotected population.

Still, the Sabin polio vaccine is no longer used in the US because of this risk, but that comes with disadvantages as well—which we will discuss later in this series.

Another problem with live-attenuated vaccines is that it is not always possible to attenuate the pathogen of interest without substantially compromising it, moving into the realm of a totally inactivated vaccine, which as we discussed before, might not help you too much.

As with the other vaccination strategies, several COVID-19 vaccines are in development that use a live-attenuated strategy.

When live attenuation doesn’t work, 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.

These different strategies all get at the concept of simulating a live infection, but there are other important concepts and limitations in vaccine development that we will address in the next parts of this series. Not only does a vaccine need to elicit an immune response that is similar to natural infection, it also needs to do this in the appropriate compartment of the body, and it needs to do this in a way that can be delivered by methods that are economically feasible for the target population. We’ll discuss all of these issues in coming parts of the series.

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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