Dan Barouch, MD, PhD (Center for Virology and Vaccine Research, BIDMC) discusses the timeline and process of developing a vaccine.

Why does it take so long to make a vaccine?

It’s a tortuous path with regulatory hurdles at multiple points along the way

Life cannot return to normal as long as the novel coronavirus circulates among us, and experts agree that a vaccine would be the best way to remove that threat.

So what takes so long?

President Trump’s plan, announced Friday, to make hundreds of millions of vaccine doses available by the end of the year moves the timeline far earlier than scientists’ previous, most optimistic predictions. Most said a coronavirus vaccine won’t be on the market for a year or two.

That’s because vaccine development normally follows a tortuous path intended to make sure the drug works and won’t cause harm. The process wends from identifying a vaccine candidate, to testing it in the laboratory and in people, and then to manufacturing it, with regulatory hurdles at multiple points along the way. With the coronavirus, drug makers, researchers, and public-private partnerships are racing down that path as fast as they can.

“Historically, vaccine development for a new virus not previously seen by the human species would take decades,” said Dr. Dan Barouch, head of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, who is working on a coronavirus vaccine with Johnson & Johnson.

But humanity cannot wait decades now. The urgent demand for a COVID-19 vaccine is “probably greater than the demand for any other vaccine in human history,” he said. “For COVID-19, there is extreme pressure to go as fast as possible.”

Still, Barouch added, for every person who asks why it’s taking so long, there’s one asking whether it’s dangerous to rush the process. “In my opinion the process can be accelerated dramatically without increasing the risk to patients,” he said.

To speed things up, numerous companies are working on parallel tracks, exploring different types of vaccines; if one candidate fails, others will still move forward. Steps that would normally occur sequentially are being done simultaneously. And drug makers are taking the huge risk of manufacturing large quantities of vaccine even before they know whether it will ever be approved for sale.

A vaccine prompts the body to produce antibodies, and sometimes other types of immune cells, that will stand ready to fight off a specific infection. The trick is to find an agent that will trigger this response without making the person sick. There are many methods of doing this, including using particles of the virus’s genetic material.

Chinese doctors sequenced the coronavirus genome, or complete genetic makeup, and released the structure to the world Jan. 10. That gave researchers the basic information needed to identify parts of the virus that could spark an immune response. Researchers also benefited from previous efforts to develop vaccines against SARS and MERS, two other coronaviruses that cause severe human illness. The research on SARS and MERS identified the spikes on the surface of the coronavirus as a likely target for a vaccine.

When the coronavirus invades the body, those spikes — the prickly protrusions seen in drawings of the virus — latch onto a receptor on the cell’s surface, which ushers the virus inside to replicate.

Most vaccines in development aim to trigger the production of antibodies that attack the spike, Barouch said. If the vaccine works, those antibodies will be on hand to destroy the spike and thus prevent the coronavirus from entering the cell.

Vaccines are tested first in the laboratory, in tissue cultures and animals. With the coronavirus, Barouch said, some drug makers are doing animal studies simultaneously with human studies.

Currently, more than 100 candidate vaccines are in the works. But only eight have moved on to the next step: testing in humans.

Research on humans moves through three stages.

Phase 1 studies, involving a few dozen people, check to see whether the drug has harmful side effects; with vaccines, researchers also will measure whether it produces an immune response.

Phase 2 studies assess the drug’s effect in hundreds of people and calibrate the dosage.

Phase 3 studies test the drug in large numbers of people — with vaccines it can be thousands or tens of thousands — to verify safety and efficacy.

Ensuring safety is especially critical for vaccines because, unlike other drugs, they are given to people who are healthy. They should not make anyone worse off. Also, if any harm comes from a coronavirus vaccine, it could discourage people from receiving the many other vaccines already proven to be safe and life-saving.

Each phase can take months to years, but with the coronavirus, some researchers are combining two of the phases.

No coronavirus vaccine so far has reached Phase 3. The first company to test a vaccine in humans, Cambridge-based Moderna, predicts starting Phase 3 in July. But that’s only if all goes well in Phase 2, which hasn’t started. And even the most optimistic scenarios for Moderna do not point toward a vaccine on the market before the end of the year.

In Phase 3, volunteers receive either the vaccine or a placebo. Then they go about their lives and researchers wait to see whether, as a group, those who got the vaccine are less likely to get infected than those who received the placebo.

That can take a long time, often years.

A possibly faster way of testing the vaccine has been proposed: Conduct a “challenge study” in which young healthy volunteers would be directly exposed to the virus. Usually, such studies are done only for diseases that have cures, so that if the vaccine doesn’t work and the volunteers get sick, they can be restored to health. A proposal to conduct such a study with COVID-19, which has no cure and can kill even young, healthy people, has raised an ethical debate that’s yet to be resolved.

Once a vaccine candidate has been shown to be safe and effective, it will have to be manufactured on a scale never before seen — creating enough for most of the world’s 7.8 billion people.

That’s why, Barouch said, that multiple vaccines must be in the works at multiple manufacturers. Some vaccines may prove easier to mass-produce than others, and some may work better in certain populations. And in any case, no one company can serve the entire world.

“There’s never been a vaccine that has been produced at billions of doses before,” Barouch said.

And how long that will take is anyone’s guess.