Types of COVID-19 Vaccines

How They Work: Differences and Similarities

Young woman getting vaccinated

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Very soon after the first appearance of the new coronavirus (SARS-CoV-2) that causes COVID-19, scientists began working to develop vaccines to prevent the spread of infection and end the pandemic. This was a huge task, because little was known about the virus initially, and at first it wasn’t even clear if a vaccine would be possible.

Since that time, researchers have made unprecedented strides, designing multiple vaccines that may ultimately be utilized on a much faster timeframe than has ever been done for any previous vaccine. Many different commercial and non-commercial teams over the world have used some overlapping and some distinct methods to approach the problem.

General Vaccine Development Process

Vaccine development proceeds in a careful series of steps, to make sure the final product is both safe and effective. First comes the phase of basic research and preclinical studies in animals. After that, vaccines enter small Phase 1 studies, with a focus on safety, and then larger Phase 2 studies, with a focus on effectiveness.

Then come much larger Phase 3 trials, which study tens of thousands of patients for both effectiveness and safety. If things still look good at that point, a vaccine can be submitted to the Food and Drug Administration (FDA) for review and potential release.

In the case of COVID-19, the CDC is first releasing qualifying vaccines under a specialized Emergency Use Authorization (EUA) status. That means they will be available to some members of the public even though they haven’t received as extensive study as is required for a standard FDA approval.

Even after the release of vaccines under Emergency Use Authorization, the FDA and Centers for Disease Control and Prevention (CDC) will continue to monitor for any unexpected safety concerns.

COVID-19 Vaccine Update

A COVID-19 vaccine developed by Pfizer and BioNTech was granted an Emergency Use Authorization on December 11, 2020, based on data from its Phase 3 trials. Within a week, a vaccine sponsored by Moderna received an EUA from the FDA based on data of effectiveness and safety in their Phase 3 trials.

Johnson & Johnson's COVID-19 vaccine from its pharmaceutical company Janssen is in Phase 3 trials and applied for an EUA on Feb. 4. The FDA has a meeting scheduled to discuss it on Feb. 26.

AstraZeneca has also released preliminary information on its Phase 3 trials, but it has not yet applied for EUA from the FDA.

As of February 2021, over 70 different vaccines worldwide have moved into clinical trials in human beings. Even more vaccines are still in the preclinical phase of development (in animal studies and other laboratory research).

In the U.S., an additional COVID-19 vaccine candidate from Novavax is also in Phase 3 trials. About a dozen other Phase 3 trials are ongoing worldwide. If they demonstrate effectiveness and safety, more of the vaccines under development may ultimately be released.

Even though COVID-19 vaccines have been released by the FDA, not everyone will be able to get a vaccine right away, because there won’t be enough. Priority will go to certain people, like people who work in healthcare, residents of long-term care facilities, frontline workers, and adults ages 65 and older.

As more vaccines become available and even more information about safety and efficacy become known, more people will be able to get these vaccines.

How Do Vaccines Work Generally?

All the vaccines designed to target COVID-19 share some similarities. All are made to help people develop immunity to the virus that causes the symptoms of COVID-19. That way, if a person is exposed to the virus in the future, they will have a greatly reduced chance of getting sick.

Immune System Activation

To design effective vaccines, researchers leverage the natural powers of the body’s immune system. The immune system is a complex array of cells and systems that work to identify and eliminate infectious organisms (such as viruses) in the body.

It does this in a lot of different complex ways, but specific immune cells called T cells and B cells play an important role. T cells identify specific proteins on the virus, bind them, and ultimately kill the virus. B cells perform critical roles in making antibodies, small proteins that also neutralize the virus and help make sure it is destroyed.

If the body is encountering a new type of infection, it takes a while for these cells to learn to identify their target. That’s one reason it takes you a while to get better after you first become sick.

T cells and B cells also both play an important role in long-term protective immunity. After an infection, certain long-lived T cells and B cells become primed to recognize specific proteins on the virus right away.

This time, if they see these same viral proteins, they get right to work. They kill the virus and shut down the reinfection before you ever have a chance to get sick. Or, in some cases, you might get a little bit sick, but not nearly as ill as you did the first time you were infected.

Activation of Long-term Immunity by Vaccines

Vaccines, such as those designed to prevent COVID-19, help your body develop long-term protective immunity without having to go through an active infection first. The vaccine exposes your immune system to something that helps it develop these special T cells and B cells that can recognize and target the virus—in this case the virus that causes COVID-19.

That way, if you are exposed to the virus in the future, these cells will target the virus right away. Because of this, you’d be much less likely to have severe symptoms of COVID-19, and you might not get any symptoms at all. These COVID-19 vaccines differ in how they interact with the immune system to get this protective immunity going.

The vaccines under development for COVID-19 can be broken up into two overarching categories:

  • Classical vaccines: These include live (weakened) virus vaccines, inactivated virus vaccines, and protein-based subunit vaccines.
  • Next-generation vaccine platforms: These include nucleic acid-based vaccines (such as those based on mRNA) and viral vector vaccines.

Classic vaccine methods have been used to make almost all the vaccines for human beings currently on the market. Of the five COVID-19 vaccines that have begun Phase 3 trials in the U.S. as of December 2020, all but one are based on these newer methods.

Live (Weakened) Virus Vaccines

These vaccines are a classic type.

How They Are Made

A live virus vaccine uses a virus that is still active and alive to provoke an immune response. However, the virus has been altered and severely weakened so that it causes few, if any symptoms. An example of a live, weakened virus vaccine that many people are familiar with is the measles, mumps, and rubella vaccine (MMR), given in childhood.

Advantages and Disadvantages

Because they still have live virus, these types of vaccines require more extensive safety testing, and they may be more likely to cause significant adverse events compared to those made by other methods.

Such vaccines may not be safe for people who are people who have impaired immune systems, either from taking certain medications or because they have certain medical conditions. They also need careful storage to stay viable.

However, one advantage of live virus vaccines is that they tend to provoke a very strong immune response that lasts a long time. It’s easier to design a one-shot vaccine using a live virus vaccine than with some other vaccine types.

These vaccines are also less likely to require the use of an additional adjuvant—an agent that improves the immune response (but which may also have its own risk of side effects).

Inactivated Virus Vaccines

These are also classic vaccines.

How They Are Made

Inactivated vaccines were one of the first kinds of general vaccines to be created. They are made by killing the virus (or other type of pathogen, like a bacteria). Then, the dead, inactivated virus is injected into the body.

Because the virus is dead, it can’t really infect you, even if you are someone that has an underlying problem with your immune system. But the immune system still gets activated and triggers the long-term immunological memory that helps protect you if you’re ever exposed in the future. An example of an inactivated vaccine in the U.S. is the one used against polio virus.

Advantages and Disadvantages

Vaccines using inactivated viruses usually require multiple doses. They may also not provoke quite as strong a response as a live vaccine, and they may require repeat booster doses over time. They are also safer and more stable to work with than with live viruses vaccines.

However, working with both inactivated virus vaccines and weakened virus vaccines requires specialized safety protocols. But they both have well-established pathways for product development and manufacturing.

COVID-19 Vaccines in Development

No vaccines undergoing clinical trials in the U.S. are using either live virus or inactivated virus approaches. However, there are several Phase 3 trials taking place abroad (in China and India) that are developing inactivated virus vaccine approaches, and at least one vaccine is being developed utilizing a live vaccine method.

Protein-Based Subunit Vaccines

These are also a classical type of vaccine, although there have been some newer innovations within this category.

How They Are Made

Instead of using inactivated or weakened virus, these vaccines use a part of a pathogen to induce an immune response.

Scientists carefully select a small part of the virus that will best get the immune system going. For COVID-19, this means a protein or a group of proteins. There are many different types of subunit vaccines, but all of them use this same principle.

Sometimes a specific protein, one that is thought to be a good trigger for the immune system, is purified from live virus. Other times, scientists synthesize the protein themselves (to one that is almost identical to a viral protein).

This lab synthesized protein is called a “recombinant” protein. For example, the hepatitis B vaccine is made from this type of specific type of protein subunit vaccine.

You might also hear about other specific types of protein subunit vaccines such as ones based on virus-like particles (VLPs). These include multiple structural proteins from the virus, but none of the virus’ genetic material. An example of this type of vaccine is the one used to prevent human papillomavirus (HPV).

For COVID-19, almost all the vaccines are targeting a specific viral protein called the spike protein, one which seems to trigger a strong immune response. When the immune system encounters the spike protein, it responds like it would as if it were seeing the virus itself.

These vaccines can’t cause any active infection, because they only contain a viral protein or group of proteins, not the full viral machinery needed for a virus to replicate.

The different versions of the flu vaccine provide a good example of the different types of classical vaccines available. Versions of it are available that are made from live virus and from inactivated virus. Also, protein subunit versions of the vaccine are available, both ones made from purified protein and ones made from recombinant protein.

All these flu vaccines have slightly different properties in terms of their effectiveness, safety, route of administration, and their requirements for manufacturing.

Advantages and Disadvantages

One of the advantages of protein subunit vaccines is that they tend to cause fewer side effects than those that use whole virus (as in weakened or inactivated virus vaccines).

For example, the first vaccines made against pertussis in the 1940s used inactivated bacteria. Later pertussis vaccines used a subunit approach and were much less likely to cause significant side effects.

Another advantage of the protein subunit vaccines is that they have been around longer than newer vaccine technologies. This means that their safety is better established overall.

However, protein subunit vaccines require the use of adjuvant to boost the immune response, which can have its own potential adverse effects. And their immunity may not be as long-lasting compared to vaccines that use the whole virus. Also, they may take longer to develop than vaccines using newer technologies.

Vaccines in Development for COVID-19

The Novavax COVID-19 vaccine is a type of subunit vaccine (made from a recombinant protein) that began phase 3 clinical trials in the U.S. in December 2020. Others may enter Phase 3 trials in 2021.

Nucleic-Acid Based Vaccines

The newer vaccine technologies are built around nucleic acids: DNA and mRNA. DNA is the genetic material you inherit from your parents, and mRNA is a kind of copy of that genetic material that is used by your cell to make proteins.

How They Are Made

These vaccines utilize a small section of mRNA or DNA synthesized in a lab to ultimately trigger an immune response. This genetic material contains the code for the specific viral protein needed (in this case, the COVID-19 spike protein).

The genetic material goes inside the body’s own cells (by using specific carrier molecules that are also a part of the vaccine). Then the person’s cells use this genetic information to produce the actual protein.

This approach sounds a lot scarier than it is. Your own cells will be used to produce a type of protein normally made by the virus. But a virus needs a lot more than that to work. There’s no possibility of being infected and getting sick.

Some of your cells will just make a little COVID-19 spike protein (in addition to the many other proteins your body needs daily). That will activate your immune system to start forming a protective immune response. 

Advantages and Disadvantages

DNA and mRNA vaccines can make very stable vaccines that are very safe for manufacturers to handle. They also have the good potential to make very safe vaccines that also give a strong and long-lasting immune response.

Compared to DNA vaccines, mRNA vaccines may have an even greater safety profile. With DNA vaccines, there is the theoretical possibility that part of the DNA might insert itself into the person’s own DNA. This usually wouldn’t be a problem, but in some cases there is a theoretical risk of a mutation that might lead to cancer or other health issues. However, mRNA-based vaccines don’t pose that theoretical risk.

In terms of manufacturing, because these are newer technologies, some parts of the world may not have the capacity to produce these vaccines. However, in places where they are available, these technologies have the capacity for much more rapid vaccine production than earlier methods.

It’s partly due to the availability of these techniques that scientists have been hopeful about producing a successful COVID-19 vaccine so much more quickly than has been done in the past.

Vaccines in Development for COVID-19

Researchers have been interested in DNA and mRNA-based vaccines for many years. Over the past several years, researchers have worked on many different mRNA-based vaccines for infectious diseases like HIV, rabies, Zika, and influenza.

However, none of these other vaccines have reached the stage of development leading to official approval by the FDA for use in humans. The same is true of DNA-based vaccines, although some of these have been approved for veterinary uses.

Both the Pfizer and Moderna COVID-19 vaccines are mRNA-based vaccines. Several other DNA and mRNA-based vaccines are currently undergoing clinical trials around the world.

Viral Vector Vaccines

Viral vector vaccines have a lot of similarity to these vaccines based on mRNA or DNA. They just use a different mode of getting the viral genetic material into a person's cells.

Viral vector vaccines use part of a different virus, one that has been genetically modified to not be infectious. Viruses are particularly good at getting into cells.

With the help of an inactivated virus (such as an adenovirus) the specific genetic material encoding the COVID-19 spike protein is brought into the cells. Just as for other types of mRNA and DNA vaccines, the cell itself produces the protein that will trigger the immune response.

From a technical standpoint, these vaccines can be separated into viral vectors that can continue to make copies of themselves in the body (replicating viral vectors) and those that can't (non-replicating viral vectors). But the principle is the same in either case.

Just like other types of nucleic acid-based vaccines, you can’t get COVID-19 itself from getting such a vaccine. The genetic code only contains information to make a single COVID-19 protein, one to prompt your immune system but which won’t make you sick.

Advantages and Disadvantages

Researchers have a little more experience with viral vector vaccines compared to new approaches such as those based on mRNA. For example, this method has been safely used for a vaccine for Ebola, and it’s undergone study for vaccines for other viruses such as HIV. However, it’s currently not licensed for any applications for humans in the U.S.

One advantage of this method is that it may be easier to produce a single shot method for immunization in contrast to other new vaccine technologies. Compared to other newer vaccine techniques, it also may be easier to adapt for mass production at many different facilities around the world.

Vaccines in Development for COVID-19

The AstraZeneca vaccine is based on a non-replicating viral vector. Johnson & Johnson's pharmaceutical company Janssen has also developed a COVID-19 vaccine based on a non-replicating viral vector and the company applied for Emergency Use Authorization from the FDA. (It is the only one currently undergoing Phase 3 trials in the U.S. that is a one-shot method).

Do We Need Different COVID-19 Vaccines?

Ultimately, it’s hoped that multiple safe, effective vaccines will become available. Part of the reason for this is that it will be impossible for any single manufacturer to quickly release enough vaccine to serve the population of the whole world. It will be much easier to perform widespread vaccination if several different safe and effective vaccines are produced.

Also, not all these vaccines will have exactly the same properties. Hopefully, multiple successful vaccines will be produced that might help meet different needs.

Some require certain storage conditions, like deep freezing. Some need to be produced in very high-tech facilities that aren’t available in all parts of the world, but others use older techniques that can be more easily reproduced. And some will be more expensive than others.

Some vaccines may turn out to provide longer-lasting immunity compared to some others, but that isn’t clear at this time. Some might turn out to be better for certain populations of people, like the elderly or people with certain medical conditions. For example, live virus vaccines will probably not be advised for anyone who has problems with their immune system.

However, we don’t have enough data, now, to properly compare these vaccines in terms of their effectiveness (and hopefully minimal safety issues). That will become clearer with time. 

As the vaccines are made available, it will be key for as many people as possible to get vaccinated. Only through such efforts will we really be able to end the pandemic.

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