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A brief overview of all the Covid-19 vaccines in the pipeline

A black and white grainy image of Dr. Jonas Salk looking at vaccine viles.
AP Photo/File
Back at the drawing board.
  • Katherine Ellen Foley
By Katherine Ellen Foley

Health and science reporter

Right now, the best bridge to a new normal is a successful vaccine against Covid-19. Scientists are racing to develop one on an unprecedented timeline, but it could still take a year to 18 months—possibly longer.

Vaccines are harder to make than ordinary pharmaceuticals. Typical drugs carry out a specific process in the body, and they only have to work only until the kidneys and liver filter them out. Vaccines, though, have to do a bit of biological catfishing: They dupe certain cells in our blood, called B-cells, into responding to a pathogenic threat that doesn’t actually exist.

Tricking those cells into producing antibodies against a disease it hasn’t yet faced is a difficult process. Scientists need help from benign viruses and bacteria, gene editing tools, and even copies of the infectious pathogen itself—and sometimes combinations of all three. And right now, scientists are throwing all of these strategies at Covid-19 to see what sticks.

At the time of writing, there are 123 vaccine candidates in various stages in the research pipeline. In a best-case scenario, multiple kinds of vaccines would be found safe and effective, so there would be several options for drug manufacturers and distributers to make and ship across the globe. Here’s your guide to understanding the different approaches.

Inactivated or weakened viruses

The most effective way (pdf) to generate antibodies against an infection is to actually get sick. The next best option? Show your B-cells a copy of the same pathogen—but genetically modified or kneecapped with a chemical like formaldehyde so it can’t cause an infection. These vaccines can cause a minor infection if the virus is merely weakened and still capable of replicating, but it’s not nearly as dangerous as if it were at full-strength.

Scientists have developed inactivated or weakened vaccines for illnesses like measles, chicken pox, and polio. These vaccines are tried and true, but finding a new one requires a delicate balance: It has to be as close to the actual virus as possible, but not capable of replicating like it normally would.

If for some reason, the virus does start replicating, a perfectly healthy person would become sick. This is why safety testing is so critical for these vaccines. Currently, only two vaccine candidates in this category are in early clinical trials: one being developed by the Wuhan Institute of Biological Products, and one by Sinovac Biotech, which is also based in China.

Protein subunit vaccines

Instead of showing B-cells the entire pathogen, protein subunit vaccines only show the body parts of the virus. For Covid-19, most developers are going after the spike protein that SARS-CoV-2 uses to enter our cells. The hope is that by showing B-cells that characteristic protein, they’ll be able to recognize it on the pathogen itself, too. It’d be like showing your B-cells a novelty bedazzled bowling hat, and telling them to watch out for any invader wearing it in the future.

Protein subunits aren’t able to turn into a full-blown infection. But the immune responses they produce get weaker over time, which means that a person may require boosters throughout their life. Some annual flu vaccines take the form of protein subunits, as does the HPV vaccine. So far, none of the protein subunit vaccines have made it to testing in humans.

Nucleic acid vaccines

Protein subunit vaccines require manufacturers to genetically modify a microbe, like the bacteria E. coli, to produce the desired protein. Then these proteins have to be purified and mixed with adjuvants, which signal to B-cells to pay attention to them. So to speed up the process, scientists have worked out a way to get the body to produce these desired subunit proteins themselves.

Nucleic acid vaccines use either double-stranded DNA (the same genetic material stored in each of our cells’ nuclei), or messenger RNA (mRNA). These forms of genetic material contain the recipe for the desired proteins, just like our DNA does (mRNA is genetic material that is just a little farther along in the process). Cells within the body translate this foreign genetic material into target proteins, which B-cells then create antibodies against.

The advantage of this approach is that it’s relatively fast; once scientists have genetically sequenced a novel pathogen, they can isolate target proteins for the body to recreate. The challenge, though, is getting the body to actually respond to them.

Nucleic acid vaccines made with DNA have to get through the cell membrane and the cell’s nucleic membrane, which protects your DNA. Those with mRNA only have to get through the cell membrane, but there’s still an additional hurdle: Even if the cells make the desired protein, they have to fold it into a shape that resembles the actual viral protein. It’s like the difference between using a boxed cake mix to make 12 cupcakes versus two round cakes.

A nucleic acid vaccine has never been approved for use. But one of the leading vaccine candidates for Covid-19 uses this approach. It’s an mRNA vaccine created by the Cambridge-based company Moderna, and the US government has already invested millions in it, even though it’s still in early clinical testing.

Viral vector vaccines

Another way to get around B-cells’ failure to respond to subunit vaccines or nucleic acid vaccines is to try a hybrid approach: using other weakened or inoculated viruses to transport genetic material that codes for bits of SARS-CoV-2, the coronavirus that causes Covid-19. The carrier virus can make its way into our cells like other infectious diseases would—but once it gets there, it produces SARS-CoV-2 proteins that generate the correct antibody response.

Some of these carrier viruses, called viral vectors, are capable of reproducing to a small degree, while others don’t at all. Either way, they shouldn’t cause an actual illness. The only reason these vaccines would be ineffective is if the recipient already has some form of immunity against the knocked-out vector—making it impossible for the virus to enter our cells. One virus that scientists like to use is an adenovirus, for example, which often causes the common cold.

The newly-minted Ebola vaccine, which the US Food and Drug Administration approved in December 2019, is a viral vector vaccine. There are two promising vaccine approaches for Covid-19 using this platform, one by researchers at Oxford University, and one from the drug company Johnson and Johnson.

Virus-like particle vaccines

The last main tactic that developers are exploring is another variation of subunit vaccines. Instead of getting B-cells to recognize only certain viral proteins, virus-like particle vaccines introduce all the proteins on the outer shell of SARS-CoV-2. It’s like showing B-cells only the menacing trench coat of a potential pathogen. Underneath the trench coat, though, there’s nothing—no genetic machinery to reproduce and destroy cells.

Currently, there are no virus-like particle vaccines in human trials—but Medicago Inc., a company based in Quebec City in Canada, is hoping to start theirs in July.

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