Feature Article — Breakthroughs, Boosters, and B cells … Oh My!

When it comes to COVID-19 vaccines, the last few weeks have been confusing to say the least! Much of the conversation has centered around whether booster doses of COVID-19 vaccines are needed at this time. And, as the normal “back and forth” of the scientific process was put on full display, it left many confused — or worse, thinking that no one knows what they are talking about. So, we wanted to try to fill in some of the gaps left between media soundbites.

First … a quick refresher on the immune system

Often when people think of the immune system, they think of antibodies, and indeed, antibodies play a starring role in overcoming most infections. However, they represent only one part of the story. Our immune systems have two parts, called the innate and adaptive immune systems. Antibodies are part of the adaptive immune system. It is the part of our immune system that generates targeted immune responses; it also takes longer to develop during the timeline of an infection.

When we are first exposed to a virus, our innate immune system uses several non-specific approaches to try to stop it. Think of this response like what you do when your “check engine” light comes on in your car — you turn your car off and on again, try to ignore it, or hope that the next time you get in your car, the issue has gone away. Sometimes one of these things works. Other times, not so much, and you finally decide to take your car to the garage, so someone with more experience can fix it. Your first responses to the “check engine” light are equivalent to the approach taken by our innate immune system. It employs a variety of generic, potentially “quick fixes” in the hope that something will stop the virus. However, if the innate immune system cannot stop the virus, it calls in the part of the immune system with more experience — the adaptive immune system. Like your efforts to avoid the garage bill, a few days will go by between the innate and adaptive immune responses. During this time, the virus has time to wreak some havoc by replicating in and killing some of your cells. How much havoc is caused depends on a variety of factors, such as how quickly the virus replicates, how large of a dose you were exposed to, and if your body recognizes the virus. Vaccination is one way your body may have been prepared to recognize the virus, but more about that later.

For now, let’s just focus on what happens after your adaptive immune response gains control. Your body will have lots of antibodies traveling around in your bloodstream looking for additional virus particles. Over time, as the infection resolves and these antibodies fail to find virus, they will diminish in number. However, what doesn’t go away are the cells that can produce antibodies against the infecting virus. They are called memory B cells. We also have memory T cells that remain after an infection. If we are exposed to the same virus again, those B and T cells will recognize it and become activated:

• The memory B cells will change into another type of B cell, called a plasma cell, and quickly start producing large quantities of antibodies. The antibodies produced by these cells are significantly more effective at stopping the virus than antibodies produced during the first encounter with a virus.
• Activated memory T cells will cause the production of chemicals critical to our immune response, called cytokines. Cytokines are the equivalent of the “check engine” light in your car. They alert the whole immune system that something is happening, causing a cascade of coordinated events that make it tough for the virus to keep reproducing. For example, changes to our blood vessels and tissues allow immune system cells to more easily enter the infected area; virus-infected cells get killed; a fever may develop to hinder viral reproduction, and more.

Most importantly, memory B and T cells cut down the length of the infection because they jump into the fight more quickly and are more efficient than immune responses that occur during a first encounter with the virus. Vaccines allow us to develop immunologic memory without chancing an out-of-control infection.

So … what does this have to do with booster doses?

At its heart, the conversation between scientists over booster doses comes down to whether it is better to have antibodies circulating in the bloodstream or if memory cells are enough when it comes to COVID-19 infections. Let’s dig a bit deeper.

Although we don’t currently know what level of antibodies will prevent someone from getting sick with COVID-19, we know that someone with a high level of antibodies in their bloodstream will be unlikely to get sick. On the other hand, even if a fully vaccinated person doesn’t have antibodies (or they have low levels of antibodies), they likely have memory cells that will activate in response to an exposure. In this scenario, while the individual may have mild symptoms for a couple of days, they will be unlikely to require medical care or hospitalization. However, during COVID-19, people have been referring to a situation in which any symptoms occur as a breakthrough infection. Traditionally, a breakthrough infection has been defined as severe disease despite previous vaccination, meaning disease that requires medical intervention or hospitalization. So, one aspect of the “scientific debate” has been what is our goal with COVID-19 vaccination? Are we trying to stop severe disease or are we trying to stop all disease?

Because we are in a pandemic, public health officials are considering more than just how well the vaccine works to protect individuals. They are also working to stop the spread of the virus because that is how to put an end to the pandemic. Stopping the spread is particularly important because children can’t yet be vaccinated and the virus is causing significant enough disease that our healthcare facilities — and healthcare professionals — are becoming overburdened. This means that not only are people dying from COVID-19, but they are also dying from other, normally treatable conditions that have “fallen through the cracks” because resources are not endless. As such, many public health officials have argued that we need to stop all disease — even mild symptoms. Their concern is that if people have mild symptoms, they may be able to spread the virus to others.

Others, however, have argued that most people do not need booster doses at this time based on three lines of thought:

1. Even if antibody levels have decreased and we are seeing some vaccinated people having mild infections, we are not seeing large numbers of vaccinated people sick enough to be hospitalized. This, they argue, suggests that the memory B and T cells are effectively doing their job.
2. Most hospitalized individuals (about 90-95%) are previously unvaccinated people, so the relative benefit of giving hundreds of millions of people booster doses may be negligible compared with the benefit that would be realized by vaccinating the tens of millions who have yet to be vaccinated.
3. We don’t yet know to what extent vaccinated people with mild symptoms can spread the virus. While some studies have suggested that infected, previously vaccinated people may be able to spread the virus, more studies are needed. Further, based on what we know about the immune response, the expectation would be that the amount of virus a vaccinated person with mild symptoms could spread would be significantly lower than what would be spread by a person without pre-existing immunity.

Unfortunately, the argument against booster dosing loses politically on both sides because many vaccinated people want boosters and many unvaccinated people do not want any doses. However, scientifically speaking, these are valid arguments, and as such, the debate has played out over the airwaves.

And, one final thought to consider: What does it say about equity when some subgroups of people in the U.S. are getting booster doses that may not be necessary while many in developing countries do not yet have access to even a single dose of COVID-19 vaccine?

For more information

• Animation describing how the immune system works
• Video about the booster dose “debate,” recently updated and featuring Vaccine Education Center Director, Dr. Paul Offit
• Story discussing what we know about viral spread by infected, previously vaccinated individuals, Vaccine Update “In the Journals” article, August 2021 issue

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