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Why can’t we “amplify” our exit from the COVID-19 pandemic

Vaccine vial syringe

Although COVID-19 vaccines are credited with saving millions of lives, they have not been enough to prevent innovative infections.

You may be wondering if long-term plans for[{” attribute=””>COVID-19 pandemic call for an endless number of booster shots. They do provide a boost in immunity, at least for a little while, which can be helpful because the vaccines have failed at preventing breakthrough infections and providing long-term immune protection. However, they cannot succeed in getting us out of the pandemic because the third dose (first booster) failed at providing long-term protection against infection, and frequent boosting can lead to immune exhaustion. We will need better vaccines that will trigger a long-lived antibody response.

With yet another COVID-19 booster available for vulnerable populations in the United States, many people find themselves wondering what the end game will be.

The mRNA vaccines currently used in the U.S. against COVID-19 have been highly successful at preventing hospitalization and death. The Commonwealth Fund recently reported that the vaccines have prevented over 2 million people from dying and over 17 million from hospitalization in the U.S. alone.

However, the vaccines have failed to provide long-term protective immunity to prevent breakthrough infections – cases of COVID-19 infection that occur in people who are fully vaccinated.

Because of this, the Centers for Disease Control and Prevention (CDC) recently endorsed a second booster shot for individuals 50 years of age and older and people who are immunocompromised. Other countries including Israel, the U.K., and South Korea have also approved a second booster.

However, it has become increasingly clear that the second booster does not provide long-lasting protection against breakthrough infections. As a result, it will be necessary to retool the existing vaccines to increase the duration of protection in order to help bring the pandemic to an end.

As immunologists studying immune response to infections and other threats, we are trying to better understand the vaccine booster-induced immunity against COVID-19.

Mix and Match COVID-19 Vaccine Booster Concept

Researchers are trying to figure out why mRNA vaccines are not very good at protecting against breakthrough infections, despite being so successful at preventing serious disease.

Activating longer-term immunity

It’s a bit of a medical mystery: Why are mRNA vaccines so successful in preventing the serious form of COVID-19 but not so great at protecting against breakthrough infections? Understanding this concept is critical for stopping new infections and controlling the pandemic.

COVID-19 infection is unique in that the majority of people who get it recover with mild to moderate symptoms, while a small percentage get the severe disease that can lead to hospitalization and death.

Understanding how our immune system works during the mild versus severe forms of COVID-19 is also important to the process of developing more targeted vaccines.

When people are first exposed to SARS-CoV-2 – the virus that causes COVID-19 – or to a vaccine against COVID-19, the immune system activates two key types of immune cells, called B and T cells. The B cells produce Y-shaped protein molecules called antibodies. The antibodies bind to the protruding spike protein on the surface of the virus. This blocks the virus from entering a cell and ultimately prevents it from causing an infection.

However, if not enough antibodies are produced, the virus can escape and infect the host cells. When this happens, the immune system activates what are known as killer T cells. These cells can recognize virus-infected cells immediately after infection and destroy them, thereby preventing the virus from replicating and causing widespread infection.

Thus, there is increasing evidence that antibodies may help prevent breakthrough infections while the killer T cells provide protection against the severe form of the disease.

COVID Vaccine Booster Concept

An additional vaccine “booster” dose amplifies immune response, helping to increase the number of B cells and T cells that can respond to an infection.

Why booster shots?

The B cells and T cells are unique in that after they mount an initial immune response, they get converted into memory cells. Unlike antibodies, memory cells can stay in a person’s body for several decades and can mount a rapid response when they encounter the same infectious agent. It is because of such memory cells that some vaccines against diseases such as smallpox provide protection for decades.

But with certain vaccines, such as hepatitis, it is necessary to give multiple doses of a vaccine to boost the immune response. This is because the first or second dose is not sufficient to induce robust antibodies or to sustain the memory B and T cell response.

This boosting, or amplifying of the immune response, helps to increase the number of B cells and T cells that can respond to the infectious agent. Boosting also triggers the memory response, thereby providing prolonged immunity against reinfection.


T cell activation explained.

COVID vaccine recalls

While the third dose - or first booster - of COVID-19 vaccines has been very effective in preventing the severe form of COVID-19, the protection against infection has lasted less than four to six months.

That diminished protection even after the third dose is what prompted the CDC to approve the fourth injection of COVID-19 vaccine - called the second booster - for people who are immunocompromised and for those 50 years of age and older. .

However, a recent preliminary study in Israel, which has not yet been reviewed by colleagues, showed that the second booster did not further stimulate the immune response, but only restored the declining immune response observed during the the third dose. The second booster also provided little additional protection against COVID-19 compared to the first three doses.

So while the second booster certainly offers a small benefit to the most vulnerable people by extending immune protection by a few months, there has been considerable confusion about what the availability of the fourth injection means to the general population.

Frequent growth and depletion of the immune system

In addition to the inability of current COVID-19 vaccines to provide long-term immunity, some researchers believe that frequent or constant exposure to foreign molecules found in an infectious agent can cause immune “depletion.”

Such a phenomenon has been widely reported with HIV infection and cancer. In these cases, because T cells “see” foreign molecules all the time, they can wear out and fail to get rid of cancer or HIV.

Evidence also suggests that in severe cases of COVID-19, killer T cells may experience immune depletion and therefore may not generate a strong immune response. Repeated vaccinations against COVID-19 may cause similar T cell depletion is a possibility that requires further study.

The role of adjuvants in increasing vaccine-induced immunity

Another reason why mRNA vaccines have failed to induce a sustained response of antibodies and memory may be related to ingredients called adjuvants. Traditional vaccines, such as diphtheria and tetanus, use adjuvants to stimulate the immune response. These are compounds that activate the innate immunity that consists of cells known as macrophages. These are specialized cells that help T cells and B cells, eventually inducing a stronger antibody response.

Because mRNA vaccines are a relatively new class of vaccines, they do not include traditional adjuvants. Current mRNA vaccines used in the United States rely on small fat balls called lipid nanoparticles to provide mRNA. These lipid molecules can act as adjuvants, but how precisely these molecules affect the long-term immune response remains to be seen. And whether the failure of current COVID-19 vaccines to elicit a strong long-lasting antibody response is linked to adjuvants in existing formulations remains to be explored.

While current vaccines are extremely effective in preventing severe disease, the next phase of vaccine development will need to focus on how to trigger a long-lasting antibody response that would last at least a year, making it likely that vaccines COVID-19 has become an annual hit.

Composed of:

  • Prakash Nagarkatti - Professor of Pathology, Microbiology and Immunology, University of South Carolina
  • Mitzi Nagarkatti - Professor of Pathology, Microbiology and Immunology, University of South Carolina

This article was first published in The Conversation.Conversation

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