COVID-19: Booster Doses – Part 3

In this third post on booster doses I will go into more details about the upcoming booster doses and give my thoughts on what these booster doses mean going forward.

Pfizer vs. Moderna and a note on vaccine dosing and timing

You probably have read news reports about a preprint article stating that the Moderna vaccine appeared more effective than the Pfizer vaccine, at least several months after vaccination. 

I remain skeptical that there is a meaningful difference between these two vaccines. It is “possible” that there may be some slight differences, which if they were to exist would be hard to identify.

Here is my rationale for my current perspective that the Pfizer and Moderna vaccines are clinically equivalent:

1. The antigen that both vaccines code for is identical.
2. The only structural difference between these vaccines are the small fat particles used to allow for uptake into cells.
3. The dose is higher in the Moderna vaccine than the Pfizer vaccine, BUT… all the best data for these two vaccines look extraordinarily similar, so a difference caused by the higher dose is unlikely.

“IF” there is a meaningful difference between these vaccines, I think it would be due to the shorter interval between doses one and two (Pfizer is 21 days, Moderna is 28 days). The science behind vaccine intervals is not terribly exact, but there is some evidence that longer vaccine intervals can produce a better or longer-lasting response than shorter intervals. 

BUT… even “if” the shorter interval between the first and second dose is meaningful, it is highly likely that the upcoming booster dose would eliminate any such differences between the two vaccines. Why? Because the booster dose appears to generate such a robust immune response (measured primarily by antibody concentration in the blood) that any differences at that point will be meaningless. 

Seeing as we’re on the cusp of football season, here’s a football analogy: It doesn’t matter if your team wins 65-10 or 55-10. You still crushed your opponent.

Should I stick with the same mRNA vaccine I got for the first two doses?

In general, yes. This allows for better and more consistent data gathering and analysis. While I am doubtful there would be a meaningful difference if you compared patients who received three doses of the same mRNA vaccine against those who received two doses of one mRNA vaccine and then a third dose of the other mRNA vaccine, the best bet is to get the same product you had before. If for some reason you are unable to receive the same mRNA vaccine you previously received, then go ahead and get a booster dose with the other one, and don’t sweat the details.

What about people who got vaccinated with J&J vaccines?

Due to lack of data, the CDC will not yet be recommending booster doses for patients who received the J&J vaccine. That being said, that vaccine hasn’t been used for as long, so there is more time to gather such data.

My prediction is that a booster dose will be recommended for the J&J vaccine. All highly effective vaccines need more than one dose for maximum effectiveness. I see no reason why the J&J vaccine will be different.

What about mixing and matching vaccines in general?

We now have some limited data that shows good boosted immune responses in people who receive a “mixed” vaccine series (one dose of one COVID-19 vaccine and another dose of a different COVID-19 vaccine). Similarly we have data that shows a very good boosted response in people who had antibodies from a previous COVID-19 infection who then subsequently received a COVID-19 vaccine. All of this makes perfect immunologic sense. 

Most importantly, there is no reason to worry about potential harm by mixing vaccines. Patients who end up getting a J&J vaccine first and then a dose or two of the mRNA vaccines should not be harmed by the combination and should expect a robust immune response.

What evidence is there to support the effectiveness and safety of boosters?

We don’t have a large randomized controlled clinical trial like those that got the COVID-19 vaccines their original FDA emergency use authorizations. Standard practice with updated vaccine dosing is to run much smaller studies that look primarily at immunologic responses in the blood and monitor for any unusual safety responses. We have more than 160 million people fully vaccinated with mRNA vaccines just here in the U.S. The safety and effectiveness profile is remarkably good. More randomized clinical trials to assess effectiveness and safety are impractical and unnecessary. 

Those caveats aside, the available data looks exactly the way we would want and expect from a true “booster” dose. Thanks to the immunologic memory the first two doses produced, the booster dose data show a robust and rapid increase in antibody concentrations in the blood. In addition, the frequency and kind of adverse reactions (e.g. fatigue, headache, etc.) is very similar to that seen with the first two vaccine doses. 

For those of you who felt crummy after one or both of your previous doses, I would bet on a similar experience after the booster dose. Oh, and if you don’t experience any adverse reactions, great! Don’t start worrying that your immune system isn’t working; it is. Just be thankful you feel fine. 

Didn’t you say months ago we wouldn’t need boosters?

Time for some falling on the sword. I thought we wouldn’t need additional doses. I let my optimism and excitement get in front of the need for humility and perspective. I was wrong. 

Mea culpas aside, let me give some information to justify my continued optimism that we may not need regular, recurring booster doses. 

1. As I’ve said repeatedly, these vaccines generate strong B-cell and helper T-cell responses, which are necessary for any hope of a long-lasting immune response.
2. We now have evidence that the mRNA vaccines also generate immunity centers in the lymph nodes called germinal centers. Think of germinal centers as extraordinary power plants of immunity where immune cells are activated and multiply and where antibodies are supercharged both in quantity and quality. The fancy name for this process is somatic hypermutation. 

Regardless, if you told me in March 2020 that every year or so I would need to get a booster dose to keep my risk of COVID-19 extraordinarily low, I would have danced a jig. I’ll still dance that jig now.

So what are the goals of providing booster doses?

The goal in providing booster doses to previously vaccinated patients is to create and maintain the maximum possible protective effect for the longest possible time.

What effect will booster doses have on these awful case counts we’re seeing and the crowded hospitals?

I wish I could say that these booster doses will have a dramatic effect on COVID-19 case counts, but I can’t. Because remember, community transmission and certainly the crowded hospitals are primarily due to infections in those who are unvaccinated.

I hope this series has helped you understand what booster doses are, how they work, and why they’re important.

Stay safe, and go make some lemonade.

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Past reading and definitions that may be helpful:

Please read this post for a somewhat in-depth description of how immunity prevents infection, disease, and contagiousness.

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. For COVID-19 the average incubation period is about 5 days.

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. In general, people who never develop symptoms appear to be less infectious than those who eventually develop symptoms.

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 lowest 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. The presence and the amount of viremia is associated with severe disease (not surprising).