As I wrote in this post and this post we know that the first two COVID-19 vaccines are highly effective in preventing COVID-19 disease. We don’t know if these vaccines prevent infection, however, and that quandary has created a lot of questions. Today my goal is to provide a more in-depth review of vaccine prevention of infection and disease, and how COVID-19 compares against other vaccine-preventable diseases. Then in the next post I’ll connect these concepts to the level of our individual families and the population as a whole.
Please see this post to review some basic definitions. I’ve also pasted that list below along with some new definitions. (If you already know or remember these definitions, just skip to the next heading.)
COVID-19 infection. This is defined as, uh, well, infection with COVID-19. (You subscribe to this blog for that level of analysis, right?). This definition includes people who have “disease” as well as people with no symptoms.
Asymptomatic infection. People who are infected but who do not develop symptoms.
Incubation period. The average time from infection to onset of symptoms.
COVID-19 disease. A patient who is infected with COVID-19 and has symptoms of that infection (including anything from a low-grade fever all the way to severe pneumonia requiring mechanical ventilation).
Severe COVID-19 disease. There is no strict definition of the word “severe.” Obviously being hospitalized is an example of severe disease, and just having a minor cough is not severe. For purposes of this discussion, it is best not to quibble about definitions and use the term “severe” in its standard English meaning.
Infectious. A person who can spread COVID-19 to other people. Both those with asymptomatic infection and those with COVID-19 disease are infectious and can spread the virus. There is some evidence that people who never develop symptoms are less infectious than those who eventually develop symptoms, but we don’t know that for certain.
Carriers. We don’t really have COVID-19 “carriers.” A carrier usually refers to someone who is infected with a microorganism and carries that organism in their body for an extended period of time, like months. Bacteria provide the best example of “carriage.” Although we don’t know how long patients who have asymptomatic infection with COVID-19 have viable virus in their respiratory tract (and are therefore contagious), it’s probably no more than 10-14 days.
Antigen. The part of a virus or bacteria that causes your body to generate an immune response. Not all antigens are proteins, but many of the best ones are.
Antibody. A protein produced by the body that attacks pathogens like bacteria and viruses. Antibodies are produced either in response to infection or immunization.
Neutralizing antibodies. Antibodies that neutralize a pathogen (didn’t see that one coming, did ya?)
Cell-mediated immunity. Immunity that uses or requires cells. There are many different types of immune cells. Some cells directly kill pathogens (natural killer cells). Some cells produce antibodies (called B-cells). Some cells help other cells do their jobs (helper T-cells). Different infections may require different types of an immune response. The most protective and longest lasting types of immunity usually need both antibodies and cells.
Respiratory mucosa. The innermost lining of the mouth, nose, and the airway that extends all the way down to the innermost depths of the lungs. This lining is where COVID-19 infects the human body.
Sterilizing immunity. Immunity that prevents infection.
Viremia. Viral replication in the blood. Although COVID-19 does not primarily infect the blood, there is some evidence that the virus can infiltrate the blood, which is likely how the virus spreads from the respiratory tract to other organs. There is also some evidence linking viremia with severe disease (not surprising).
Vaccinology is a lot like real estate
When you are looking to buy or sell a home your realtor shows you a list of “comps,” homes that are similar in location, size, and style to give you an idea of what the market value might be for a home.
Vaccines are similar. We try to get an idea of what to expect from a new vaccine by comparing it against other pathogens and vaccines. The problem is that (to use a phrase my editor wife absolutely despises) COVID-19 is really unique.* Ideally we would have another respiratory virus that infects and replicates in the same place in the body using a similarly effective antigen as the spike protein that also has a similar incubation period and causes disease in the same way as COVID-19. But as I’ve pointed out before, this virus has a unique combination of factors we have never seen before. This “uniqueness” (my editor wife is in agony over that word) is why we’re in this mess and means we don’t have any great “comps.”
*Technically something can’t be really unique. If it’s unique, then by definition it is one-of-a-kind. Something can’t be really one-of-a-kind. Thank you to my eleventh grade English teacher for drilling that into our heads.
You don’t know the power of the spike protein
One of the primary determinants of a vaccine’s effectiveness, especially immediately after vaccination, is the ability of the vaccine antigen to get the body to produce an immune response. Thankfully the COVID-19 spike protein is highly immunogenic (creates a strong immune response) which is great for immunizations but bad for people who are infected with COVID-19.
In fact, the potent immunogenicity of the spike protein is probably the single most important factor behind the remarkable effectiveness of the Moderna and Pfizer vaccines and what makes me optimistic for future vaccines as well. That immunogenicity is vital because I think it may also help COVID-19 vaccines overcome some of the challenges inherent in preventing COVID-19, such as location of disease.
Location, location, location
The first rule of real estate also applies to immunology. For a vaccine to prevent infection, it has to provide an immune response where the virus infects and replicates. This means the COVID-19 vaccines need to provide a sufficient immune response, in both quantity and quality, in the respiratory mucosa. This is a bit tricky because we inject the vaccine into the upper arm and not into the lungs. So for the vaccines to prevent infection, the immune response that begins in the muscle must go to the nearby lymph nodes and then develop into a whole body immune response. We know from studying blood samples of COVID-19 vaccinated patients that such a systemic immune response occurs; that’s obviously a good thing.
But that response is probably not equal at all places in the body. In order to prevent infection, the right antibodies and cells have to travel via the blood and go through a fancy process called transudation to cross from blood vessels to the respiratory mucosa. Based on the extraordinarily high effectiveness of the mRNA vaccines produced by Pfizer and Moderna, it is pretty clear that there is a good immune response, at least enough to prevent disease, in the respiratory tract. Unfortunately, measuring the immune response in the respiratory tract is not nearly as easy as measuring it in the blood, so we don’t know the quality or size of the immune response in the respiratory tract.
Our experience with other pathogens that primarily replicate in the respiratory tract, however, is that even when there is a good immune response in the respiratory tract, the protective effect against infection is usually less than 100%. Some examples may help. Vaccines that protect against viruses that replicate primarily in the blood (think measles, hepatitis A and B) often provide sterilizing immunity, meaning immunity that prevents infection. This is partially because the immune response generated by those vaccines occurs primarily in the blood where the virus replicates. Contrast this with influenza virus which replicates primarily in the respiratory mucosa. Influenza vaccines do not produce sterilizing immunity (or at least not a lot) in part because of the location of viral replication versus where the vaccine produces immunity. The analogy between influenza and COVID-19 is imperfect, however, because instead of one highly immunogenic protein, influenza virus has multiple different versions of two proteins that are not as immunogenic as the COVID-19 spike protein.
It’s pretty clear based on Phase 3 clinical trial results that COVID-19 vaccines will not provide complete 100% sterilizing immunity. But they may still be effective in reducing the number of infections, albeit less than 100% effective. Just spitballing here… maybe about 70% effectiveness? But less than 100% prevention of infection is fine. We don’t have to have 100% effectiveness against infection to protect individuals, control the disease, and get back to a more normal life.
So if a vaccine doesn’t fully prevent infection, how can it help prevent infectiousness and disease?
Even if a vaccine doesn’t protect against infection, it still has the potential to prevent disease in that person as well as transmission from that infected individual to other non-vaccinated people. Another analogy may help explain why.
If the virus infects an immunized person, there is a race between the immune system and the virus. Except instead of a race with a finish line measured in distance, this finish line is measured in time. Specifically the incubation period of the virus is the finish line of this race. The shorter the incubation period, the less time the immune system (whether vaccinated or not) has to prevent disease (of any severity). In the case of COVID-19, the average incubation period is five to six days, and nearly everyone who will get symptoms gets them by day 10. Although this incubation period is relatively short, it is longer than influenza virus and many other respiratory viruses which usually cause symptoms by one to two days after infection. This longer incubation period is another important difference between COVID-19 and influenza, and may make prevention of COVID-19 disease and infectiousness via immunization a more achievable prospect than for influenza.
In this race, your immune system is trying to minimize the number of infected cells and any damage the virus causes, and the virus is trying to maximize the number of cells it infects. Your respiratory mucosa may not have a sufficient vaccine-induced immune response to prevent infection, but it may have enough of an immune response to limit the spread of the virus. And the less virus-infected cells there are (i.e. the lower the viral load), the lower the chances of transmission and the lower the chances of disease.
In addition, we know that COVID-19 can be present in the blood, which should be one of the places with the strongest vaccine-induced immune response. This immune protection could be important in preventing the severe immune response that causes so many of the terrible outcomes of COVID-19 disease.
So think of vaccination as erecting a series of immune barriers. Obviously we’d like the first barrier to be 100% effective in preventing infection. If that were the case then there’s simply no chance of contagiousness or disease. But each immune barrier in succession plays a role in reducing infectiousness and preventing disease.
So how effective are the barriers that the mRNA vaccines create?
Well, we don’t know, but we can assemble some pieces of evidence to get an idea.
Think of a series of steps, each with its own probability of happening. The first step is infection, the second step is sufficient replication to cause transmission and disease, the third step is really bad disease.
We now have two vaccines that are roughly 95% effective in preventing that second step, and should be even more effective in preventing the third step, really bad disease. We also have some information for the Moderna vaccine (which almost certainly applies to the Pfizer vaccine as well) showing a potential effect in reducing asymptomatic infection after just one dose. If this is borne out in future data then we know the mRNA vaccines prevent infection to at least some degree which means the vaccine directly reduces the spread of the virus.
Here’s another way to look at things. If disease is reduced by 95% by the mRNA vaccines, it is very hard to believe that all of that 95% reduction occurs after infection has already taken hold. I cannot think of any other vaccine that is this effective at preventing disease but has no effect on infection and transmission. But, as I said above, we don’t have a great “comp” for COVID-19, so we still need data.
My hunch (and that’s as firm a statement as I can make) based on the data above is that these first two vaccines prevent infection and reduce contagiousness by a measurable degree. I am hopeful that we’ll have data in the next few months to support that conclusion.
Stay tuned for my next blog post where I explain the effect the above concepts have on control of the disease at both a population and an individual level.
Stay safe, and go make some lemonade.
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The Infectious Pharmacist 
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