Why are there so many vaccines being developed for COVID-19? What is the difference between each? Which vaccines will succeed and which will be ready first?

To understand how vaccines work, we’ll first need to quickly review some immunology fundamentals; for more, see our Path of the Virus explainer.

When your immune system meets a viral threat, it begins fighting with a generic response, which is not specific to any particular virus. But over the first one to two weeks after infection, your adaptive immune cells kick in. These cells are specialized for the particular virus you are fighting; they can learn to recognize specific structures of the virus (called antigens) and train to effectively kill them. These cells produce antibodies, which you’ve probably heard a lot about lately. Antibodies are large proteins created to target and stick to the antigens on the virus, and kill it.

Importantly though, the adaptive immune cells do more than just produce antibodies to kill the current virus. Some of these cells also become “memory cells,” long-lived cells that remain in your body, ready to quickly ramp up a fight against re-infections of the same pathogen. These memory cells, along with antibodies which also stay around in your body, are key to viral immunity.

All of this describes what happens if you actually become infected with a virus, like SARS-CoV-2. But this also parallels how vaccines work. The goal of most vaccines is to simulate the infection in a safe manner so your body will produce memory cells that will be ready if the actual infection occurs. This is how the annual flu vaccine works.

To do this, the vaccines have to somehow mimic the virus so the immune cells can undergo the learning process and train to target its antigens. Then, the key question for vaccine development is: how do you simulate an infection without actually infecting people with the virus?

There are a number of different approaches for vaccine development. The techniques can be broadly divided into four categories: (1) killed/weakened virus, (2) viral vector, (3) nucleic acid, (4) protein-based. We’ll give an overview of each and their significance for COVID-19.

Types of Vaccines

Killed/Weakened Virus Vaccines

This method, the most traditional, involves using the virus itself as a vaccine. Basically, these techniques introduce the virus into the body, so the body can produce antibodies and memory cells pretty much the way it would normally do. You may ask: “How could you possibly do this safely?” The answer is that the virus must be weakened enough that it cannot successfully infect cells, but not so much that it loses its structure. This way the adaptive immune cells can still see the viruses’ antigens and make memory cells poised to respond if there is exposure to the real SARS-CoV-2.

There are multiple ways to weaken the virus. One method is to grow the virus in cells of other animals. The virus will be tricked into mutating in a manner that allows it to better infect those cells instead of human cells. A second method is to use heat or chemicals to weaken the virus. Both of these methods result in a virus that is safe and does not harm humans, but still has the antigens that adaptive immune cells can learn to target. Measles, polio, and some flu vaccines are three prominent examples that use weakened or killed viruses.

Take-home point: this method is how humans have been making vaccines for the past 100 years and it works for many diseases, but they take a lot of effort to manufacture!

Viral Vector Vaccines

Memory cells and antigens are formed to target the antigen portion of the virus. However, the antigen alone doesn’t make you sick. This means that if you could somehow introduce the antigen into your body, without the rest of the virus, you might be able to get your body to make memory cells without getting sick.

This is the basic idea behind the other three vaccine approaches. They differ in how they introduce the antigen. First up: the viral vector approach, in which a live, genetically engineered virus is used to introduce SARS-CoV-2 DNA to our cells.

The goal of this method is to hijack our own cell’s machinery to make SARS-CoV-2 antigens. The key to this method is the use of a different, controlled virus to deliver SARS-CoV-2 DNA into our cells. Your cells are designed to be hard to break into. Viruses, though, are really good at getting in (this is part of the problem!). But in this case we can use a virus that’s safe as a way into the cell. Scientists have learned how to control and use certain viruses as “vectors” to deliver specific DNA to our cells.

So what can our cells do with the DNA? These DNA encode SARS-CoV-2 antigens and our cells can use it as a recipe to start producing antigens. This response trains the adaptive immune cells and forms memory cells.

Over the last few years, the method has been used more frequently—two Ebola vaccines have been developed using viral vectors. It has some limitations (for example, if you’ve already been infected with the virus that is used as a vector, this will not work), but it is an area of active research.

Take-home point: viral vectors are promising, but not the most battle tested type of vaccine.

Nucleic Acid Vaccines

Nucleic acid vaccines work on the same principle as the viral vector approach, but with a different delivery vehicle. One way this is done is with an oil-like structure which can pass through human cell membranes without disrupting them. Another approach, called electroporation, uses electric shocks to briefly open up small holes in our cells, allowing DNA to enter. In either case, once the DNA is inside, our cells begin reading the DNA instructions and produce SARS-CoV-2 antigens.

As the newest mode of vaccine design, no vaccines have yet been approved with this approach; however, several COVID-19 vaccine candidates using this approach have shown promising results (of note, the Moderna vaccine). One of the biggest advantages of nucleic acid vaccines is the impressive speed at which they can be designed, allowing researchers to quickly produce potential vaccine candidates.

Take-home point: nucleic acid vaccines will be easier and faster to develop, but are untested at this point.

Protein-Based Vaccines

Finally, we have a more direct approach for introducing antigens into your body: a protein-based vaccine, which directly provides your body with SARs-CoV-2 antigens. This straightforward approach avoids obstacles in the delivery of viral vector and nucleic acid vaccines, and because only a non-infectious portion of the virus is added, there is no risk of infection.

One potential problem here is antigen manufacturing. In the previous two vaccine methods, antigen-coding DNA is given to our cells, which then make the antigens. In the protein-based method, the antigens have to be produced outside our body (i.e. by a vaccine company), which may slow things down.

Another challenge to protein-based vaccines is that when antigens are added directly, our immune system may need to be stimulated in parallel to respond and start making memory cells. Additional ingredients called adjuvants are added to the vaccine to elicit this response. Adjuvants are well understood chemicals, but adding additional ingredients means more development challenges.

When done well though, this approach has been shown to be highly successful. For example, Hepatitis B and some flu vaccines use this method.

Take-home point: protein-based vaccines are harder to manufacture but have many examples of successful vaccines.

Read about current vaccine progress and developments here.