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Unproven strategies lead the race for a COVID-19 vaccine

Here are some of the other options

Illustration by Ana Kova

Last week, President Trump stood in the Rose Garden and told the assembled press corps that hundreds of millions of doses of a coronavirus vaccine would be available by the end of 2020, just seven months away.

“It’s called Operation Warp Speed. That means big, and it means fast,” Trump said.

It’d be a scientific miracle if a vaccine is ready by then. Developers face two mountainous hurdles on the path toward a coronavirus vaccine: proving that what they’re making is safe and effective, and producing it in vast quantities. Hurdling even that first barrier within a year would be an astonishing achievement. The fastest vaccine ever developed, approved for the mumps in 1967, still took four years.

Nearly everything about the COVID-19 pandemic is breaking the charts, and if there was ever a time for pharmaceutical companies to deliver on their promises, it’d be now. Some vaccine development records have already been shattered: it only took 65 days from the time the coronavirus genome was posted online for the pharmaceutical company Moderna to inject the first clinical trial volunteer with an experimental vaccine. Now, more than 100 groups all over the world say they’re working on a coronavirus vaccine.

There are countless points in the vaccine development process where candidates could stall, fail, or fade away. One vaccine that looks safe in a small group of people might show side effects when it’s tested in a larger study. Another could only protect half of the people who get it from COVID-19 or offer a small amount of protection, but not enough to make a difference in the pandemic. A vaccine could work well enough, but be hard to manufacture quickly and in large quantities.

While there are scores of vaccine candidates in development, there are only a few ways for companies to make a vaccine. Each strategy has its own set of advantages or disadvantages, and keeping those in mind is one way to evaluate any bits of exciting — or discouraging — vaccine news.

The Verge talked to University of Colorado immunologists Rosemary Rochford and Ross Kedl to break down the likelihood that each vaccine strategy would make it over the finish line.

But before we jump into the types of vaccines, let’s start with the basics:

What’s a vaccine?

Vaccines work by tricking your immune system into thinking that it’s being attacked by a virus. Your immune system then churns out antibodies that are honed to that virus. That way, if you’re exposed to that virus in the future, your body can quickly squash it out before it makes you sick.

CHINA-HEALTH-VIRUS Photo by Nicolas Asfouri / AFP via Getty Images

Triggering that immune response takes two main components: a bit of the virus so the body knows what it’s looking for and some kind of irritant to stir the immune system into action against that viral bit.

“If I just put purified protein under your skin, nothing would happen. You have to get the immune system kicked up,” Rochford says.

The different approaches to vaccine development package those two components in different ways. Rochford says it’s good to see developers working on all of the possible options. “I think we need all hands on deck. Any way we can go at this. We have to throw everything at it and see what sticks,” she says.

Here’s a rundown of the four basic approaches scientists are throwing at the virus:

Gene-based vaccines

Unproven, but fast and easy to make

Approved for: there are no approved vaccines for humans that use this method

Gene-based vaccines are the much-hyped underdog in the race to create a coronavirus vaccine. Most of the vaccine candidates that grabbed headlines or sent the stock market soaring are gene-based. Moderna, which was the fastest to start testing its vaccine in volunteers in the US, has a gene-based vaccine. So does Pfizer, which is also in clinical trials.

Instead of directly delivering bits of virus to the immune system for target practice, gene-based vaccines give the body tools to make them on its own. The vaccines are made up of pieces of genetic material, either mRNA or DNA, that encode the instructions for making the protein. The mRNA or DNA then enters cells, which read the instructions and churn out copies of the protein for the immune system to rally against.

“Rather than producing the vaccine outside the patient, you make the patient make their own vaccine,” Kedl says.

Most of the coronavirus vaccines that use this method are introducing the gene that encodes a bit of protein on the outside of the virus called the spike protein. The virus depends on the spike protein to break into cells and replicate. If the immune system is trained to recognize and block that protein, the virus can’t attack cells and continue to spread.

Pros: These types of vaccines are relatively easy for companies to make once they know the genetic sequence they’re targeting. That’s why Moderna was able to get a vaccine ready and start testing it in people so quickly. They’re also easy to manufacture: if they work, companies could quickly generate millions of doses. “From a manufacturing standpoint, if you could shift everything to a nucleotide system, that would be brilliant,” Kedl says.

Cons: But despite their simplicity and decades of work, gene-based viruses are still largely experimental, at least for people. There’s never been a gene-based vaccine approved by the Food and Drug Administration. If a gene-based coronavirus vaccine makes it over the finish line, it would be the first of its kind.

mRNA and DNA vaccines sometimes work well in animals like mice, but they have previously sputtered out when they’re introduced to humans, Kedl says. He says it may be because these vaccines aren’t good enough at spurring the immune system to create antibodies.

Production of Ultrix Quadri flu vaccine in Ryazan Region, Russia
Influenza viruses are grown in eggs before being inactivated.
Photo by Alexander Ryumin / TASS via Getty Images

Inactivated virus

Proven, but hard to manufacture

Approved for: Polio, influenza

Inactivated virus vaccines are the kind that you may have learned about in high school biology class. Scientists can take a virus and kill it with heat or radiation — rendering it harmless, but still recognizable by the immune system. A handful of Chinese companies are developing coronavirus vaccines using this method. One company, Sinovac, showed that its vaccine could protect monkeys from COVID-19. Human trials are ongoing.

Pros: These types of vaccines have been around for decades, and scientists understand them well. They’re the type of vaccine that Jonas Salk created to fight polio. “This is sort of a bread and butter thing to do,” Rochford says.

Because these vaccines contain the whole (but non-replicating) virus, they’re good irritants for the immune system. “It’s got bacterial cell walls and all sorts of viral capsules and proteins and things that stimulate immunity very robustly,” Kedl says.

Cons: Unlike gene-based vaccines, though, inactivated virus vaccines are hard to make. Manufacturers have experience with them, but they have to grow — and then zap — massive amounts of virus. It’s a slow process. “It’s really hard to scale up and create enough of that,” Rochford says. The immunity generated by these types of vaccines also tends to fade, and people may need booster shots.

Whole virus vaccines are also more likely to come with side effects, like mild fevers or muscle soreness. But Kedl thinks that people will take some soreness if it means they’ll be immune to COVID-19. “Global tolerance to injection reactions is probably pretty high,” he says.

Adenovirus vector vaccines

Good at provoking an immune response but still experimental

Approved for: There are no approved vaccines for humans that use this method

Adenoviruses can cause pink eye and diarrhea.
Photo by Cavallini James / BSIP / Universal Images Group via Getty Images

A whole, live vaccine is one of the best ways to create long-lasting immunity. That’s the strategy used to make vaccines for the measles and the chickenpox. They’re made from live — but heavily weakened — versions of the viruses. The viruses are so weak that they don’t make you sick, but they still make your body think it’s infected and set off the immune system.

It takes a long time to alter a virus so that it becomes weak and safe enough to be used as a vaccine, though. To speed things up, vaccine developers aren’t even attempting to do that with the entire coronavirus. Instead, some teams are inserting sections of the coronavirus gene into weakened, live versions of other viruses.

These viruses, called adenoviruses, usually cause symptoms like diarrhea or pink eye. Scientists have already broken them down to a weakened state so that they’re harmless. The University of Oxford, which is promising vaccines by September, has built its candidate using an adenovirus.

These vaccines work a bit like the gene-based vaccines: the engineered adenovirus dumps a piece of genetic material from the coronavirus, usually the piece that encodes the spike protein, into cells. Then, the cells create copies of the protein. In this case, though, the adenovirus is in charge of activating the immune system — which, because it’s a live virus, it does very well.

Pros: Because this vaccine is based on a weakened, but living, virus, the immune system mounts a strong response against it. “When a live, attenuated, vaccine works, they tend to give you longer immunity and a more robust and more durable immunity,” Kedl says. With these vaccines, one shot may be enough — you wouldn’t need a booster.

Cons: Even though we regularly use live virus vaccines, the adenovirus platforms are still experimental. They’ve never been used for infectious diseases. There’s also a concern, Rochford says, that some people may be immune to the adenovirus that’s shepherding the coronavirus gene into the body. “Adenoviruses circulate through the human population,” she says. Even though research groups are using adenoviruses that are relatively uncommon, some people may have seen them before — so the vaccine wouldn’t work for them.

Protein subunit vaccines

A well-known platform but hard to scale

Approved for: HPV

HPV Vaccines In Corpus Christi Texas Photo by Matthew Busch for The Washington Post via Getty Images

Protein subunit vaccines directly deliver the specific bit of the virus scientists want people to develop antibodies against (rather than the gene for the protein). For the coronavirus, in most cases, that’s the spike protein. These vaccines contain copies of the spike protein and a bit of something to stimulate the immune system.

The HPV vaccine uses this method, and it’s the approach many scientists are taking in their efforts to create a universal flu vaccine.

Pros: Scientists are familiar with this approach, and it’s worked well for other types of diseases. “We very much know exactly what we have to be going after,” Kedl says. Because the vaccine only contains a piece of the virus, it’s also less likely to trigger side effects.

Cons: Because these vaccines only use a piece of a virus, they sometimes aren’t able to push the body to generate a strong enough immune response, even with a good irritant built in. People often need multiple shots to build up enough immunity to the disease. That’s why, for example, most people get multiple doses of the HPV vaccine. During a pandemic, creating enough vaccines to give each person one shot is already a challenge.

Building the protein is also a challenge, Rochford says. Developers have to make sure that the version of the spike protein they build has the same properties as the one that’s naturally on the virus. “Batching them up to scale is very challenging. It’s not impossible, but it’s a challenge,” she says.

The bottom line

There’s a long history in vaccinology of trying multiple approaches to the same end goal, Rochford says. It’s particularly important for efforts to develop a coronavirus vaccine: no one knows which strategy or which vaccine candidate will work best.

Winnowing down the slate of candidates takes time. Companies are starting the laborious process of testing vaccines in increasingly larger groups of people, and they’ll have to wait to see if someone actually develops immunity to a disease after they’re given a trial vaccine. “You have to wait around,” Kedl says. “You can’t speed that up.” They also have to watch for any safety concerns, either short-term side effects or problems that crop up over time.

Testing dozens of options simultaneously, though, ups the likelihood that a few will be successful. We’ll probably need more than one to work. A single company with a single, effective vaccine won’t be able to make enough to meet the demand of the entire world.

“We have to spray it with whatever we’ve got and hope for the best,” Rochford says. Hopefully, that best comes sooner rather than later.