‘A huge experiment’: How the world made so much progress on a Covid-19 vaccine so fast

Never before have prospective vaccines for a pathogen entered final-stage clinical trials as rapidly as candidates for Covid-19.

Just six months ago, when the death toll from the coronavirus stood at one and neither it nor the disease it caused had a name, a team of Chinese scientists uploaded its genetic sequence to a public site. That kicked off the record-breaking rush to develop vaccines — the salve that experts say could ultimately quell the pandemic.

The colossal impact of the coronavirus is motivating the speed, opening a spigot of funding and inspiring research teams around the world to join the hunt. But the astonishing pace of the progress is also a consequence of the virus itself: It is, scientifically speaking, an easier target for potential vaccines than other pathogens, and a prime candidate for cutting-edge vaccine platforms new to scientists’ toolkits.

“Once we got the sequence, we pulled the trigger to ask how fast we could go,” said Barney Graham, the deputy director of the National Institutes of Health’s Vaccine Research Center. “And because it was a coronavirus, we could get into a Phase 3 trial in six months instead of two years.”

Of course, progress so far remains just that. The vaccines are now facing their real tests: the monthslong, Phase 3 trials that will demonstrate whether or not they protect people from the virus.

“This is a huge experiment and no one knows how it’s going to turn out,” said James Le Duc, the director of the University of Texas Medical Branch’s Galveston National Laboratory.

Vaccines typically take years, if not decades, to reach people; the record now is four years for the mumps vaccine. Here’s what has propelled the Covid-19 endeavor to eclipse prior efforts so far.

A familiar family

It’s difficult to associate anything with this pandemic with good fortune, but the fact that the culprit was a coronavirus — one that was strikingly similar to others that had previously leapt from animals to people — meant scientists could quickly rejigger vaccine projects in the works for those. It was almost like swapping a blue Lego for a red one in their assemblies.

Many of the teams pursuing vaccines for SARS-CoV-2 (the scientific name of the new coronavirus) have previously worked on vaccines for the original SARS virus, which caused a 2003 outbreak that killed some 800 people, and MERS, which has caused 2,500 cases since it started spreading in 2012.

The earlier projects had pointed to a component of the coronaviruses called the spike protein as a ripe target for a vaccine, which gave scientists a head start for crafting their candidates. Work on SARS also illuminated stumbling blocks in designing coronavirus vaccines that Covid-19 immunizations have so far avoided.

“What really helped was the knowledge gained from the SARS-1 infection,” said Rama Rao Amara, an immunologist and vaccine researcher at Emory University. “SARS-2 is quite similar to SARS-1, especially in that spike protein. People could take a very educated guess that this is the protein that we need to be going after.”

An acute, not chronic infection

SARS-CoV-2 causes an acute disease, Covid-19. It’s an infection that most people will clear on their own, which means there’s a vanquishing immune response that a vaccine can aim to induce in order to protect people.

That’s not true for something like HIV, a virus for which there is no vaccine despite decades of research. HIV causes a chronic infection and integrates itself into people’s genomes; there’s no natural immune response that eliminates the virus that a vaccine can mimic. HIV also mutates much faster than coronaviruses do, meaning it’s more difficult to rally a lasting defense.

It’s possible, then, that a pathogen that’s harder to design a vaccine for than the coronavirus could ignite the next pandemic.

“We were more prepared for a coronavirus than for any other family,” NIH’s Graham said. “To me, this is a wake-up call that we need to have a more systematic universal approach to developing vaccines and other countermeasures for virus families ahead of time.”

Cutting-edge approaches

Vaccines train the immune system to recognize a pathogen it hasn’t yet encountered.

Normally, our immune system builds that memory by battling an infection, so that it can halt a virus in its tracks should it try to invade a second time. A vaccine acts like that first exposure, but without making people sick.

With SARS-CoV-2, researchers are working with new ways of providing that first look, building vaccines on adaptable platforms engineered to easily pivot from pathogen to pathogen.

Older strategies for developing vaccines, such as obtaining the virus and weakening or inactivating it, are lengthy processes. But the cutting-edge approaches require scientists only to know the virus’ genetic sequence. With that, they can string together the right pieces of code to synthesize vaccines.

That’s allowed scientists to move with record speed. Less than 10 weeks after the Chinese scientists published the SARS-CoV-2 sequence, a team from the National Institute of Allergy and Infectious Diseases and the biotech company Moderna had a candidate ready for a Phase 1 trial.

The Moderna/NIAID vaccine was built with mRNA, a piece of genetic code containing the instructions for the coronavirus’ spike protein. The vaccine shuttles the mRNA into cells, which “read” those instructions and churn out the protein — providing the immune system with that first peek to the spike, like giving a hound a scent.

A team from Pfizer and the German company BioNTech is also working on an mRNA vaccine, while a company called Inovio is pursuing a vaccine based on a different genetic material, DNA. Neither an mRNA nor a DNA vaccine has been approved before.

Knowing the sequence of the coronavirus has also spurred other approaches. Some groups — including Johnson & Johnson, the Chinese firm CanSino, and a collaboration between Oxford University and AstraZeneca — are attaching the gene for the spike protein to another, harmless virus that ferries it into cells. There, it gets expressed into the spike, allowing the immune system to mount its forces. Another company, Novavax, is producing versions of the spike from the gene and using them directly in its vaccine.

The spike protein is a strategic choice. The proteins, which give SARS-CoV-2 the crown-like appearance that’s characteristic of coronaviruses, attach to receptors on people’s cells, allowing the virus to enter and replicate. By blocking spike proteins, then, vaccines could prevent infection. The spikes are also the “immunodominant” piece of the virus, meaning they elicit the strongest immune response. (Some vaccines are based on the whole spike, while some include select portions.)

Researchers are not only relying on advances in vaccine platforms. Innovations in basic genetics, immunology, and structural biology have also fueled the pace at which Covid-19 vaccines are moving. One way scientists have discovered so much about the spike protein, for example, is by applying methods honed over years to research the proteins on HIV.

Money, money, money

Getting a vaccine approved is not just a scientific expedition. It’s also about money.

One reason vaccine development is so slow normally is because companies want to see candidates successfully pass through each sequence in the development process before sinking funding into the next phase.

But that playbook doesn’t fly in a pandemic.

“This is the biggest emergency we’ve had in our lifetime,” said Kawsar Talaat, a Johns Hopkins infectious disease physician and vaccine researcher. “Money is kind of no object. We don’t have time to wait.”

To rally companies, funding agencies, including governments and foundations like the Coalition for Epidemic Preparedness Innovations, or CEPI, are throwing millions — and in some cases, billions — into the hunt for vaccines. On Sunday, for example, Moderna said it had received $472 million from the U.S. Biomedical Advanced Research and Development Authority, on top of the $483 million it got in April.

The money isn’t just to cover the research and trials; it’s also to get companies to start manufacturing their products — even though their vaccines might not prove to be effective. It’s a strategy called manufacturing “at risk,” and public health experts say it’s necessary to ensure that any authorized vaccine can be rolled out to as many people as quickly as possible.

The U.S. government is also striking deals with companies to purchase their vaccines even before clinical trials are completed, including a $1.6 billion agreement with Novavax that includes 100 million doses and a $1.95 billion compact with Pfizer and BioNTech, also for 100 million doses.

“The fact that industry is able to hedge their bets like this and to make these investments is because the government has put up the money,” said UTMB’s Le Duc, who formerly led the Centers for Disease Control and Prevention’s viral diseases division. “The government has recognized that this is an incredibly important issue and we need to be going full blast knowing full well that not all these vaccines will work. Some are going to be duds, and will lose money.”

Regulatory nimbleness

In-the-weeds regulatory decisions don’t get much public attention, but they are helping expedite clinical trials and the ultimate evaluation of how effective a vaccine is.

Many of these lessons were first learned during the West African Ebola crisis, when regulators embraced a new dexterity in green-lighting vaccine trials and took a more proactive approach to communicating with companies about the efficacy thresholds products needed to meet. That’s continuing with Covid-19: the Food and Drug Administration, for example, has outlined that vaccines need to prevent infections or reduce the severity of Covid-19 in 50% of recipients to be approved.

The Ebola crisis “really did give the regulators greater experience and more comfort with the idea that they could have greater flexibility than they normally would have,” said Mark Feinberg, the president of the International AIDS Vaccine Initiative and a former executive at Merck Vaccines. “They could make decisions more quickly and really be true partners in the development process.”

Textbook clinical trials include three increasingly large phases that establish how safe and effective a drug or vaccine is. But with the Covid-19 pandemic, some of the trials have been collapsed into Phase 1/2 or Phase 2/3 trials. It’s a wonky distinction, but it can shave weeks or months off the process by saving research teams from having to write new protocols or get additional clearances.

The speed of vaccine development can also have an adverse effect. Some people have questioned how such a fast-moving process can ensure safety and might abstain from a vaccine. An Associated Press poll in May found that Black and Latinx Americans, who have been disproportionately harmed by the pandemic and have a history of mistreatment by the medical field, are more skeptical about Covid-19 vaccines than white Americans — showing the importance of outreach campaigns that public health experts say are required to increase the uptake of immunizations.

Others have raised suspicions that President Trump — whose vaccine initiative is dubbed Operation Warp Speed — might force an emergency authorization of a vaccine before the election, even if it hasn’t cleared efficacy and safety standards. Presumptive Democratic presidential nominee Joe Biden on Monday raised the specter of politics interfering in the quest for a vaccine.

Scientists and regulators are already stressing that safeguards aren’t being jettisoned. Public health experts say vaccine makers need to be transparent that while manufacturing and regulatory steps are being streamlined, safety checks aren’t being sacrificed.

In a call with reporters Monday, NIH Director Francis Collins, whom former President Obama first tapped for the position, defended the integrity of the decisions regulators will make. “Nothing is being done here to compromise the safety” of Covid-19 vaccine trials, he said, “nor will we compromise on an ultimate conclusion about whether the vaccine is effective. Those issues are going to be tested in the most rigorous way.”

The challenges ahead

Exactly what all this speed will translate into remains to be seen. The monthslong, final-stage clinical trials starting now will settle that.

The Moderna and Pfizer/BioNTech candidates respectively launched Phase 3 and Phase 2/3 trials this week, and the Oxford/AstraZeneca vaccine is in a Phase 2/3 trial. Others are entering pivotal studies soon. These involve enrolling thousands of people, injecting half with the candidate and half with a placebo or control, and then comparing whether people who received the vaccine are less likely to be infected than their counterparts.

Some vaccine candidates could very well fail — a normal part of the scientific pursuit, experts say. “I hope that doesn’t happen, but people need to accept when things don’t pan out the way they hope,” said Maria Elena Bottazzi, the co-director of Texas Children’s Hospital Center for Vaccine Development at Baylor.

It’s also not clear yet what a vaccine “working” will look like. A Covid-19 vaccine might be like the flu vaccine — only preventing infections in some people, or staving off serious disease but still leaving people contagious.

A vaccine that prevents even 50% of infections would be a massive lifeline. But experts worry there’s a disconnect between a public expecting vaccines to instantly reset their lives and what the first vaccines may actually allow. Successful vaccines will likely be restricted to frontline workers and vulnerable populations at first. It could take some time for enough vaccine to be made for everyone who wants a shot. Some vaccines might require two doses to confer protection.

“It might not be some magic bullet that’s going to stop the pandemic in its tracks, and people need to be prepared for that possibility,” said Columbia University virologist Angela Rasmussen about the first vaccines that reach people. “I really hate the term vaccine race. Because that implies there’s going to be a medal ceremony, and the pandemic is over.”