COVID Transmissions for 9-3-2020

Vaccine formulations and designs, Part 2

Sep 03, 2020

Good morning! It has been 290 days since the first documented human case of COVID-19.

Continuation of the vaccine in-depth comes today; I’m considering doing a Part 3 as well.

Bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

Rural wedding outbreak

A tale of a deadly COVID-19 outbreak originating at a rural wedding, from the Washington Post, provides us with a cautionary tale: https://www.washingtonpost.com/health/2020/08/30/coronavirus-millinocket-wedding-outbreak/

I hope that for any readers who have chosen to postpone their wedding as a result of this pandemic, this helps to soothe the pain of that difficult decision. There is a very good chance you have saved lives, both of people who would have attended your weddings as well as those of people who would have caught it from attendees later on in the chain of transmission.

Steroid use

Earlier this summer, I was surprised to learn that corticosteroids like dexamethasone appeared to reduce the odds of death from COVID-19. This was surprising because (1) dexamethasone is a super common drug and I was elated and (2) corticosteroids are immunosuppressive and can be dangerous in certain infections.

Still, I was happy to see any evidence of an effect in severe disease.

Now, it appears, we have even more data confirming that when given carefully, corticosteroids can help to control the immune response in severe COVID-19 and prevent death in a large number of patients. A study published in the Journal of the American Medical Association has collected the work of seven other studies to perform a “meta-analysis” and show definitively that this strategy can work: https://jamanetwork.com/journals/jama/fullarticle/2770279

The results were broadly consistent. The risk of death was reduced by around 10% to 30% when different corticosteroids were administered. Clearly it is preferable to use the specific drugs that had better odds of preventing death, but let’s leave those specific decisions up to the physicians.

I’m sure that these treatments have been in use medically ever since the first results appeared, and I think that this is part of the reason that the death rate from COVID-19 has appeared to go down through the summer.

It’s not the whole reason of course, but this is helping, and that’s good news, for once.

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

Gym reopening

My gym is reopening; in fact it did today. I’m going to try out a personal training session tomorrow and see how it goes. I’ll report back on how people are obeying the social distancing and masking rules.

Vaccine formulation, delivery, and design, Part 2

Image is a stock photo of a row of glass vaccine vials that I took from the CDC. Yes, I used it again. I like it.

Last time, we talked about some various different ways that vaccines could be designed to convince the body that it is facing a real infection, and thus generate the kind of immune response that we would see during a natural infection.

The broad strokes of that dealt with making microscopic systems believe that an infection was taking place. One example that I provided for that was the live-attenuated Sabin polio vaccine vs the inactivated Salk polio vaccine. If you’ll recall, the Sabin vaccine is live-attenuated but can cause a rare polio-like paralysis in very few patients.

So why use it at all?

That’s a question I wanted to give its own piece, because it is deeply relevant to COVID-19.

In previous newsletters, I’ve mentioned a problem with the Salk vaccine: if you get the Salk vaccine, and it is effective in your immune system, you’ll never get paralytic poliomyelitis. This doesn’t mean that you’ll never get infected with polio virus, though.

The Salk vaccine is an injected formulation of inactivated virus. It generates antibodies that circulate in the blood and prevent poliovirus from moving out of the gut, where infection begins, to the central nervous system, where it can cause paralysis. The antibodies that are found in the blood are generally called IgM or IgG antibodies, two types that are made at different times during infection. “Ig,” by the way, stands for “immunoglobulin,” a word which means, more or less, “immunity blob.” The other letter is just a classification system. For the virologists reading this—yes, I’m oversimplifying, because we need to get to the point.

The point is that these blood-circulating antibodies are not especially useful at producing sterilizing immunity to polio infection, or even approaching sterilizing immunity. The Salk vaccine doesn’t always stop you from spreading polio virus. Instead, the antibodies generated by this vaccine prevent severe disease. The reason that they have this limited function is simple: polio virus infects the gut, having been ingested with food. Under ideal conditions, the gut doesn’t have blood in it. Without blood, this area is not readily accessible to the kind of antibodies that the Salk vaccine generates.

Instead, the gut is a negative space in the body, surrounded by what’s called a “mucosal surface.” This is a layer of moist tissue that forms a barrier across which some substances are allowed to pass, but not others. Mucosa form our bodies’ internal interfaces with the outside world, largely, and they are often sites of a great deal of pathogen traffic. Everything you eat has microbes on it. Yes, even if you washed it. Your body has to handle those, and it does. A lot of them it takes care of with stomach acid, but certain pathogens have tough outer layers or otherwise can survive. Those have to be dealt with by another method.

One of the ways that the body can control pathogens at the mucosal surface is with a special type of antibody that resides there, and which is unsurprisingly called a mucosal antibody. Mucosal antibodies are called IgA, and they have a different structure from IgM and IgG, and a different function. These antibodies are secreted onto mucosal surfaces and can respond to and contain pathogens on mucosal surfaces.

Some antibodies form complexes that bind to multiple antigen molecules.

Image is a cartoon schematic of antibodies including IgD, IgE, and IgG (a simple fork-shape that is commonly associated with antibodies), IgA, which is a “dimer” of two of these fork-shaped units set end-to-end with the forked parts facing outwards, and IgM, which is a pentamer of five forked units, facing outward from a central hub. IgD and IgE are not mentioned in this piece, but IgG and IgM are found in the blood, while IgA is involved in mucosal immunity. Image courtesy of Martin Brändli on Wikimedia Commons: https://commons.wikimedia.org/wiki/File:Mono-und-Polymere.svg

The Sabin vaccine, because it is a live-attenuated virus and infects the gut just like regular polio virus, generates mucosal antibodies. The end result of this being that people who get the Sabin vaccine have an immune response that stops polio in the gut, which thus reduces the chance that they will spread polio virus to others if they become infected in the future.

Mucosal immunity provides, in this case, better control against transmission.

In COVID-19, mucosa are also important, though in a more acute sense, it’s the respiratory mucosa that are more relevant. There is some evidence of gut infection as well, but let’s focus on the respiratory mucosa for now.

A vaccine that is simply injected protein, like the simple kind we talked about in Part 1 of this series, will go into the bloodstream. There’s no evidence that SARS-CoV-2 ever enters the bloodstream, so the antibodies generated would need to be delivered to tissues that the virus infects—and they can be. But they won’t be delivered to the mucosal surface, where most of the transmittable virus is found.

For that, you need mucosal antibodies, as we’ve been discussing.

Encouraging the generation of mucosal antibodies is not an easy task. For respiratory viruses, this typically involves a vaccine that is delivered in the same way that the normal pathogen is delivered. In the case of SARS-CoV-2, we’re talking about inhalation.

You may have heard of the live-attenuated inhaled influenza virus vaccine FluMist; this is a vaccine that tries to mimic an inhalation-based virus transmission in order to generate mucosal immunity, and it succeeds in this.

For COVID-19, an inhaled vaccine is not on the near horizon. Few projects involve creating a live-attenuated virus, and I have heard of fewer that are going for an inhaled formulation. I have heard of at least one, covered by NPR: https://www.npr.org/sections/health-shots/2020/08/28/906797539/what-a-nasal-spray-vaccine-against-covid-19-might-do-even-better-than-a-shot

I don’t mean to suggest here, though, that mucosal immunity is necessary for protection against COVID-19. We have many respiratory pathogen vaccines that are injected into muscle and generate perfectly reasonable immunity. The inactivated seasonal influenza virus vaccine is one.

It’s reasonable to think that a COVID-19 vaccine that is injected will do a great job preventing disease and may even impact transmission of virus. It’s also reasonable to think that an inhaled vaccine could generate additional immunity against SARS-CoV-2 that might further reduce transmission or be even more efficient at preventing disease.

I expect the first vaccines that come to market for this virus to be injected, and I think at this point I am cautiously hopeful that they will be effective. However, I think that over time we may develop additional methodologies of vaccination, potentially including an inhaled vaccine that is either live-attenuated or is a chimera that uses some harmless virus backbone. These additional methodologies may stand on their own, or they may be combined with earlier vaccine formulations to produce a stronger or more lasting immune response. In the future, what we may see is a multi-step vaccination process, where different types of vaccines are giving across a schedule, to produce a comprehensive immune response that helps to protect society from COVID-19.

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.

Viral Transmissions

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