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Ask a Caltech Expert: Dr. Alex Cohen on Vaccine Boosters

Published on Tuesday, November 23, 2021 | 6:20 am
Alex Cohen, Ph.D.

Caltech postdoctoral scholar Alex Cohen (PhD ’21) explains how booster shots strengthen an immune system response and addresses the question of mixing COVID-19 vaccines produced by different manufacturers.

Cohen, a researcher in the lab of Pamela Bjorkman, the David Baltimore Professor of Biology and Bioengineering and a Merkin Institute Professor, develops vaccines for a wide range of related coronaviruses, with the aim of preventing future pandemics.

What happens in the body when you get your initial vaccine?

Whether you received the Moderna, Pfizer-BioNTech, or Johnson & Johnson vaccine, all contain the genetic information for the spike protein on SARS-CoV-2, the virus responsible for COVID-19. This protein is a key part of how the virus gains entrance into your cells, so the vaccine is teaching your body how to recognize it quickly, in case of real infection. Upon exposure to the spike protein via the vaccine, your immune system has two pathogen-specific main responses:

  1. A type of immune cell called B cells will produce antibodies, proteins precisely shaped to clamp onto the spike protein and neutralize it. B cells also store a “memory” of the virus that enables a rapid response in case of future infection.
  2. The body activates so-called “killer” T-cells (also known as cytotoxic T-cells), which are programmed to find cells that have been infected and destroy them to stop the virus from spreading. Additionally, there are also “helper” T-cells that help direct the antibody and killer T-cell responses. The activation of helper T-cells is important in the process of making good antibodies, and the vaccines are actually pretty good at activating helper T-cell responses.

These are considered to be part of the “adaptive immune response,” which is specific to the particular pathogen presented in a vaccine. The body also has a broader, so-called “innate immune response,” which plays a role in non-specific protection against pathogens and also orchestrating the adaptive response.

What happens when you get a booster shot? Is the body’s response different from the initial vaccine?

A booster shot is a way of strengthening the body’s immune memory, a reminder of what a virus looks like. It’s like when you’re trying to study for an upcoming exam, it helps your memory to revisit the subject matter multiple times.

When your immune cells are activated by the first vaccine, they also make a copy of themselves that will survive in your bloodstream or in different tissues for some time. These are your memory B and T cells. In the case of a booster, instead of teaching your cells from scratch how to make antibodies and recognize the virus and so on—a process which takes between seven to 14 days—a booster activates memory cells rapidly, and they will jump into action and go back to making antibodies or killer T cells.

The idea is that if you are infected with SARS-CoV-2, you want your immune system to react as quickly as possible; you want the virus to have as little time as possible to replicate in your body. The boosters keep your immune system’s memory sharp so that it can react quickly.

Take B cells, which make antibodies, for example. Antibodies produced in B cells are secreted into your bloodstream, and can enter the lung tissue or the nasal tissue, where they block the virus from taking hold. But over time, the number of antibodies wanes to a kind of background level, which might not be high enough to protect you from getting very ill. One point of a booster is to stimulate those B cells to make more antibodies.

Some vaccines give lifelong protection—for example, the polio vaccine—while others require boosters, such as tetanus, which requires a new one every 10 years. Why does the immune system have a good memory for certain pathogens and not others?

That’s a million-dollar question, because we really don’t know what allows for robust memory versus not-robust memory. For example, the Hepatitis B, HPV, and yellow fever vaccines give you protection for a very long time, perhaps even for life—and they’re all different types of vaccines too.

As an example of the diversity of vaccines out there: the Hepatitis B vaccine is made of protein-based particles (no mRNA). The yellow fever virus vaccine is an actual live, but attenuated (or weakened), virus that was developed in the 1930s. It’s one of the best vaccines ever made in that you take one or two doses of it, and you have lifelong protection against yellow fever. The Tdap vaccine against tetanus, diphtheria, and pertussis gives you strong protection, but it’s not as long lasting, and you need boosters every 10 years or so.

What differentiates these in terms of the levels of protection you get? In terms of your body’s immune memory? We’re still trying to understand that.

What role do the vaccines play in inducing this really long-term memory that will always be with you? For measles, for instance: is it the repeated low-level exposures to the measles virus in the environment that acts as a natural booster itself, or does the body simply have really good memory initiated by the vaccine?

In the case of the COVID boosters, we know that, at least short term, having a booster does increase protection against both infection and severe disease and death. So, will that mean that we need to eventually take an additional booster? I don’t know. Are two or three shots enough to really get that memory going so that your immune system remembers the virus over time? These are all good questions that researchers are working on.

How might mixing and matching the vaccine types influence the body’s immune response?

Truthfully, we don’t know yet. One of the reasons we don’t know is because we don’t have a perfect read on the cellular differences between immune responses elicited by the different types of vaccines. When you get a particular vaccine, what are the levels of antibodies elicited? What are the levels of killer T cells, which are contributing the most to protection against SARS-CoV-2? Are killer T cells as important as antibodies? These are all open questions.

For instance, the immunity that’s provided by the Johnson & Johnson vaccine might not be identical to the immunity provided by the mRNA vaccines. The Johnson & Johnson vaccine has been shown to elicit better T-cell responses, whereas the mRNA vaccines have been shown to elicit better antibody responses. If both are required for good protection, then you might want to mix and match for that reason, for example.

We need more data on mixing and matching to see what produces the best protection. We have to study the people who got Pfizer and boosted with Pfizer, those with Moderna and boosted with Moderna, and the mix-and-match group, and you have to track them all over time.

There’s actually no reason not to mix and match because available evidence shows this is safe. So, it’s just as safe to mix and match as it is to take the same a vaccine as a boost. They all encode for the spike protein. You’re responding to the same protein really, in all of the vaccines.

One open question is, does mixing and matching the vaccines improve immune memory? How does mixing and matching impact the reactivation of memory? That’s something that probably will be looked at.

What has been shown is that people age 65 and older definitely benefit from a booster. That makes sense because we know that after a certain age, your immune system is not as robust as it used to be. For that group, as well as younger people who are immunocompromised or have underlying medical conditions, it is really important to get a booster shot. And we may find out that boosters offer increased protection for everyone against variants of SARS-CoV-2, some of which are more transmissible.

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