BY LATE JULY, MORE THAN 20 VACCINE CANDIDATES for COVID-19 had entered clinical trials. All of them try to kickstart the body’s immune system, mobilizing it to recognize and attack the SARS-CoV-2 virus.

But each candidate attempts that job in subtly different ways—and in some cases the technology is uncharted territory. In general, the efforts can be placed into three broad categories: vaccines that use the virus itself; vaccines that trick the body into producing antigens; and those that use viral proteins, or fragments of proteins.

1. Vaccines That Use the SARS-CoV-2 Virus

2. Vaccines That Produce the Antigen in the Body

3. Vaccines Using Viral Proteins

Vaccines That Use the SARS-CoV-2 Virus

Once the immune system has detected the virus, it mounts a full force attack. Part of this response involves recognizing a shape known as an antigen on the viral surface that’s unique to that particular virus. The body can recognize millions of antigens and support as many as a quintillion antibodies—Y-shaped proteins, produced by the body, that latch on to known viruses and help neutralize them.

INACTIVATED OR ATTENUATED VIRUS VACCINES
This approach, tried and true, has been used for more than 100 years. In an inactivated virus vaccine, the core of the vaccine is the pathogen itself, which has been bombarded with heat or chemicals to make it unable to replicate. In an attenuated virus vaccine, the virus has been weakened, usually by passing it through a series of hosts. In both cases, the tamed version of the virus itself is injected into the body.

Considerations: The approach has an outstanding track record, and many researchers have experience creating vaccines based on a live or inactive virus. But using the virus itself means walking a tightrope: Modify the virus too aggressively and you might erase the surfaces needed to spark an effective immune response; treat it too gently and it could revert to an infectious state. Further hindering this approach, attenuating a virus can take a long time, and to remain effective, these vaccines must be kept cold until they’re injected in a patient.

Progress: By early July, the Chinese government had greenlit a phase 3 clinical trial of a vaccine from the pharmaceutical company Sinovac Biotech, and a phase 1/2 clinical trial of one from the Wuhan Institute of Biological Products, that use inactivated viral particles. Attenuated live viruses are getting a try, too, from groups in India and Germany, although none of those efforts has advanced to clinical trials.

Some preliminary studies have also found that vaccination with the BCG vaccine, a live vaccine used to protect against tuberculosis, seems to correlate with a lower risk of death from COVID-19.

Vaccines That Produce the Antigen in the Body

VIRAL VECTOR VACCINESVaccines in this category aim to get around the problems of using the virus itself. Instead, they trick the body into fighting something that “looks” like SARS-CoV-2. Cells in the body create a facsimile of the antigen, and the immune system learns this shape, putting it on guard against a future attack from the real virus.

Why would the body create such an antigen? In the viral vector vaccine approach, “tamed” viruses—a handful of known strains that have been engineered to be mostly safe—invade cells in the body and hijack their metabolic machinery, much as any virus might do in nature. But these friendly viruses carry blueprints of the COVID-19 antigen and force the body’s cells to produce them. Both the tamed virus and the new antigen trigger a protective immune response.

Considerations: Viral vectors have shown promise for treating or preventing a range of diseases, but three decades of work have failed to deliver many effective therapies, and no viral vector-based vaccine has been approved by the U.S. Food and Drug Administration for use in humans. (About a dozen are approved for veterinary use.)

Progress: One viral vector vaccine is being developed by CanSino Biologics and the Institute of Biotechnology in Beijing. It uses an engineered adenovirus (the culprit behind the common cold) to provoke a strong immune response in the body. Another has been developed by a group from Oxford University. On July 20, both groups presented data showing that their viral vector vaccine created an immune response in human subjects.

DNA VACCINES
This strategy is similar to one using viral vectors. Cells in the body are tricked into producing an antigen like the one in the virus, and the immune system creates a defense to match. But instead of using a virus to deliver instructions to the cell, this vaccine uses circular strands of DNA injected directly into the muscle or skin. These rings, called plasmids, can reproduce independently of a cell’s existing chromosomes, and they induce the cells they invade to start producing the antigen, which triggers the body’s immune response. Sometimes this injection is followed by an electrical pulse that nudges cells to take up the new genes.

Considerations: Proponents say that DNA vaccines would be easier to manufacture and scale up than vaccines that need the virus to stay intact. They also remain stable at room temperature. But the World Health Organization has warned that DNA vaccines, like others that tamper with cellular DNA in the body, pose at least a small risk of harmful genetic changes and unwanted autoimmune reactions.

Progress: A few DNA vaccines have already moved to human trials, and one from Inovio Pharmaceuticals, after a phase 1 clinical trial in Kansas City and Philadelphia, has shown a successful immune response and moved to further testing. At least five other DNA vaccines are being tested in preclinical studies.

RNA VACCINES
Inside a cell, messenger RNA (mRNA) is a strip of genetic instructions that tells the cell which proteins to produce. An RNA vaccine “floats” those mRNA instructions through cells to get them to produce the antigens of SARS-CoV-2. After it delivers its messages, mRNA degrades through natural processes.

Considerations: Like DNA vaccines, RNA vaccines can be produced more quickly than traditional vaccines, and because they don’t change cells’ genetic code and disappear after use, they are likely safer than DNA vaccines. But RNA vaccines may provoke off-target autoimmune responses, and in some cases, including for an RNA vaccine for rabies now in clinical trials, researchers have had a hard time finding a dose that provokes an adequate immune response. A recent phase 1 trial suggests this may be a good approach for vaccinating against RSV, a very contagious virus common in infants.

Progress: Moderna Therapeutics and the National Institute for Allergy and Infectious Diseases have moved their mRNA vaccine through phase 1 and 2 trials, showing a safe and successful immune response in subjects. As of mid July, they are enrolling 30,000 volunteers for a phase 3 trial. At least other 10 labs are pursuing an RNA vaccine in preclinical studies.

Vaccines Using Viral Proteins

VIRAL PROTEIN VACCINESVIRUS-LIKE PARTICLE VACCINES
Using just scraps of protein from the real virus—or even molecules that look like those protein scraps—can also arm the body’s immune system. In one approach, called viral protein vaccines, researchers inject SARS-CoV-2 DNA into bacterial or mammalian cells in the lab, and then isolate the antigens those cells produce. When injected, those antigens trigger an immune defense. Another approach uses “virus-like particles,” also mined from bacteria or cell lines but reassembled to look like a virus—without any genetic material inside.


Considerations: The proteins and VLPs don’t contain any actual viral genetic material, which theoretically makes them as safe as RNA vaccines and as effective as live attenuated viruses. It can be hard to keep these proteins and assemblages from falling apart, however, which means they’re less stable than other approaches. Viral protein vaccines usually require an adjuvant to trigger a strong enough immune response, but vaccines with adjuvants have a higher risk of side effects such as redness, swelling, fever or body aches.

Progress: This approach is used to make FDA-approved vaccines for serious conditions such as human papillomavirus and malaria. The American pharmaceutical company Novavax has developed a vaccine for COVID-19 using recombinant viral proteins. It says that it will announce results of its phase 1 clinical trial in Australia in late July. A number of other candidates based on virus-like particles are in preclinical trials.