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Messenger RNA – a novel approach for coronavirus vaccines

In late 2019 a new coronavirus called SARS-CoV-2 appeared in East Asia and rapidly spread around the world. In some people this virus causes an illness called Coronavirus Disease-2019 (COVID-19) that requires hospitalization. As the virus continued to take hold around the world, scientists, policymakers and pharmaceutical companies realized that vaccines would be needed, so they set about creating, testing and manufacturing vaccines for SARS-CoV-2. In this issue of TreatmentUpdate we explore some of those vaccines.

Messenger RNA

The first two vaccines approved in Canada, the United States and many high-income countries are made by Moderna and Pfizer-BioNTech.

Scientists with these companies have used a technology not previously used in vaccines called messenger RNA (mRNA). This type of RNA encodes the instructions for making a key piece, or protein, of SARS-CoV-2. When injected into animals or people, cells take up the mRNA and begin to make pieces of SARS-CoV-2. These proteins of the virus enter circulation, where they are noticed by cells of the immune system. The cells of the immune system capture the viral proteins and take them to lymph nodes and lymphoid tissues. There, the viral proteins are displayed to many cells of the immune system.

One group of immune system cells—B-cells—begins to produce antibodies against the viral proteins. Another group of cells—T-cells, particularly CD8+ cells—learns to recognize the proteins and produces antiviral substances in response. The immune system then creates many copies of these B- and T-cells, and some of them leave lymph nodes and related tissues and enter circulation. When they encounter SARS-CoV-2 in the future, these B- and T-cells can respond with antibodies and antiviral substances and greatly reduce the risk of developing COVID-19.

In large clinical trials with tens of thousands of volunteers, the results of the mRNA vaccines have been nothing short of astonishing. Overall, after two injections of the vaccines, they were able to reduce the risk of developing COVID-19 by 95%. That scientists were able to make highly effective vaccines against a new germ in less than a year is unprecedented in human history.

Obstacles ahead

However, much work remains to be done in the field of SARS-CoV-2 vaccines. At this time, no single company has the manufacturing capacity to produce all the vaccines needed by a region, for example North America, Western Europe or East Asia. Therefore, it is likely that different vaccines will need to be used in these regions, with some people getting the Moderna vaccine and some getting the Pfizer-BioNTech vaccine.

As a result of the manufacturing shortfalls, combined with high demand for the mRNA vaccines, the rollout of the vaccines will be bumpy—with inevitable delays and temporary supply shortages. It may be that most of the people in the regions mentioned may not get vaccinated until the latter half of 2021.

Many unknowns

Studies show that the vaccines are generally safe and highly effective, but there are still areas of uncertainty such as the following:

Safety monitoring

The mRNA vaccines are generally safe, though in very rare cases serious allergic reactions can develop. More information about the safety of the vaccines appears later in this issue of TreatmentUpdate. Vaccine manufacturers and regulatory agencies are monitoring the rollout of the vaccines to assess if any other risks appear.

How long will protection conferred by the vaccine last?

Due to the public health emergency caused by the global pandemic, clinical trials with the vaccines lasted for about two to three months before licensure. As a result, no one is certain how long protection afforded by the vaccines will persist. Moderna and Pfizer-BioNTech will continue to monitor thousands of people who have been vaccinated for several years to learn about the duration of protection.

What are the elements of a protective response to the virus?

The immune system likely requires some combination of antibodies and T-cell responses to contain the virus. The relative balance of these two parts of the immune system that is necessary to prevent COVID-19 is not known. For instance, are antibodies more important than T-cell responses?

After vaccination, it is normal for levels of antibodies and antiviral T-cells in the blood to fall. This decline does not necessarily mean that the body has lost protection from SARS-CoV-2. For instance, in many other infections, long-lived cells that remember how to make antibodies and antiviral substances against a germ persist at low levels in the circulation or lymph nodes. These types of cells are called memory B-cells and memory T-cells. When the body encounters a germ—or, in this case, SARS-CoV-2—in the future, these memory cells will be activated and billions of copies will be made. The copies of memory cells can then produce antibodies and antiviral substances at the scale necessary to reduce the risk of developing COVID-19. No one is certain how long this immunological memory will remain effective.

A changing virus

All viruses change or mutate eventually. They make subtle changes to their shape or structure or to the nature of the proteins that they produce. These mutations arise from errors in the manufacture or replication of the virus from infected cells. Some of the mutations confer an advantage: The immune system may have trouble recognizing the virus and/or the antiviral response (antibodies and antiviral chemical signals) may not be as effective as it once was. The mutations that confer an advantage to the virus tend to be carried forward in future copies of the virus.

The future outcome between the virus and the immune response depends on the type and number of mutations. For instance, a minor mutation probably does not appreciably affect the immune response. However, mutations that confer significant changes to the structure of the virus or enhance the potency of some viral proteins likely have the potential to help the virus evade antibodies and/or T-cells.

The mRNA vaccines made by Moderna and Pfizer-BioNTech are designed to cause cells of the body to produce viral proteins that are in a form that likely enhances the immune system’s ability to recognize them. This may mean that, in some cases, some mutations of the virus should still be affected by antibodies and T-cells that have been stimulated by the vaccines.

Since its discovery, SARS-CoV-2 seems to undergo mutations from time to time. Some variants of the virus, such as one called B117, first recognized in the UK, can spread faster (are more infectious) than the original version of the virus. Scientists have found other variants arising in Brazil, South Africa, the U.S. and other countries that may be of concern. Such variants require understanding in laboratory experiments with cells and possibly animals to find out if COVID-19 vaccines can produce a durable and protective response against them.

As other variants of SARS-CoV-2 are likely to appear in the future, public health laboratories need to be monitoring the virus variants in circulation and pharmaceutical companies need to be ready to create either enhancements to existing vaccines or new vaccines as the need arises.

Symptoms or no symptoms

Clinical trials of the first generation of vaccines against SARS-CoV-2 were designed to assess the ability of vaccines to prevent symptoms of disease (COVID-19). These trials were not designed to assess whether the vaccines could prevent infection with SARS-CoV-2. This is an important distinction. Prior to the advent of the vaccines, scientists estimated that 40% to 50% of people who became infected with the virus could have symptom-free infection. Research needs to be done to find out if the mRNA and other vaccines are able to prevent infection with SARS-CoV-2.

—Sean R. Hosein

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