Around the globe, labs and factories are racing to test and produce more than a billion doses of coronavirus vaccine.
To shrink a 10-year marathon into a 10-month sprint, they are merging institutional knowledge with novel bioscience methods.
"This first round of vaccines is certainly using more of what we would call experimental platforms — things that don't have a lot of track record yet," said Deepta Bhattacharya, a cell biologist and immunologist at the University of Arizona.
"Now, that's not to say that it won't work. And to be honest, all of the early data that I'm seeing so far, it looks really quite promising."
Lines Of Attack
Of more than 165 vaccine candidates, around 30 are in clinical trials and a handful have begun large-scale human testing.
The various vaccine types use different means to achieve the same end.
"It's just different ways to get the viral protein made so that you can make an immune response to it," said Bhattacharya.
In short, vaccines give the body's cellular cops something to put in their molecular mug books — the distinguishing marks, or antigens, of various invaders.
For SARS-CoV-2, the coronavirus that causes COVID-19, that's a distinctive crown of spike proteins by which it invades cells and reproduces.
"Then the human immune system is going to recognize the viral spike protein and start to produce antibodies," said Jun Wang of the University of Arizona College of Pharmacy.
Different vaccine types employ different training methods.
DNA and RNA vaccines teach the body's own genetic machinery to make the antigen themselves. It's a bit like a police station printing wanted posters. One example, the mRNA vaccine by Moderna Therapeutics now in widespread human trials, produces enough antibodies to halt virus replication.
But gene-based vaccines remain largely untried.
"The problem is that right now there's no FDA-approved DNA and RNA vaccines," said Wang.
Recombinant protein vaccines inject the target protein into the body, giving the immune system's bloodhounds a molecular "scent" to sniff out.
The viral factor vaccines made by Russia, China, AstraZeneca and Johnson & Johnson dress up a harmless virus in the target protein. These are sometimes called adenovirus vaccines after one of the most commonly used delivery viruses.
"They then use that virus basically as a vaccine and let the immune system produce antibodies and long-term immune response," said Wang.
Approval-Seeking Behavior
Whatever their lines of attack, all vaccines go through a four-phase approval process.
Phase 1 tests safety and tolerance in 20 to 100 people.
"That's also a time where investigators look at the proper dose of the vaccine," said Dr. William Moss, executive director of the International Vaccine Access Center at Johns Hopkins University in Baltimore.
If successful, the vaccine enters Phase 2.
"You're looking for larger groups of people to see if there's any adverse events, see how well it's tolerated and, at the same time, you're checking for some of the usual correlates as to how well the vaccine might work," said Bhattacharya.
"You're looking for larger groups of people to see if there's any adverse events, see how well it's tolerated and, at the same time, you're checking for some of the usual correlates as to how well the vaccine might work." — Deepta Bhattacharya, UA cell biologist and immunologist
Phase 3 enrolls tens of thousands of people to gauge efficacy and to seek out less common reactions. So far, most vaccines report mild side-effects.
"With some of the current COVID-19 vaccines there's tenderness perhaps at the site of injection and perhaps some fever in some individuals," said Moss.
That said, Pfizer and BioNTech switched to their second vaccine candidate after they found participants tolerated it better.
One pack-leading partnership, AstraZeneca and the University of Oxford, paused its global trial after a United Kingdom participant reportedly developed severe neurological symptoms. It has since resumed trials following regulatory approval.
Such events illustrate the purpose of large human trials, said Bhattacharya.
"As we start to expand out the numbers into tens of thousands of people, will we start to see some rare events, and what is the risk-reward proposition once you start to see that data?" he said.
Moss says many vaccine candidates historically drop out during this process.
Companies with vaccines that survive the first three phases scale up manufacturing and enter the regulatory and licensure processes.
Then begins the quieter fourth phase begins, in which scientists watch for even scarcer reactions and ensure antibodies don't worsen the illness.
"It's very important to evaluate vaccines even after they have been licensed and used more widely," said Moss.
Altogether, it's a long gauntlet to run, as Moss explained.
"Historically this path for vaccine licensure has taken years, you know, on the order of four years, ten years, sometimes even longer than ten years," he said.
The mumps vaccine holds the current speed record — at a brisk four years.
Still, Bhattacharya remains optimistic.
"I'm very much a glass-half-full person when it comes to this. I'm really quite confident that more than one of them are going to be effective," he said.
Even so, experts agree COVID-19 is here to stay and may well require several vaccines, each with its own supply chain and distribution challenges.
The vaccine campaign's success might ultimately hinge on whether scientific, corporate and government institutions can earn people's trust.
"This is happening obviously at a time in the United States where there's mistrust of science, mistrust of government, a tradition of mistrust in vaccines," said Moss.
But other, less obvious hurdles remain.
The Hidden Hurdles
Progress toward coronavirus vaccines inspires cautious optimism while raising social and commercial concerns.
With pressure building and opportunity knocking, companies are merging trial phases, an approach pioneered during the West African Ebola outbreak.
Bhattacharya sees little danger in the approach.
"Those protocols are all run through the FDA ahead of time. And a lot of the things that you're looking for in a Phase 1 and a Phase 2 are the same," he said.
Still, Moss and other experts worry the public will be wary of rushed vaccines — safe or not.
"Perhaps a bigger factor that might affect our ability to get to a herd immunity threshold is going to be the vaccine acceptance," said Moss.
Mistrust And Blind Spots
An August Gallup Poll showed one-third of Americans would not take a free coronavirus vaccine, even one approved by the Food and Drug Administration.
Experts also fear public trust could erode if the FDA sanctions unapproved vaccines for emergency use. Historically, anthrax remains the only vaccine to receive such approval, which was due to its potential as a biological weapon.
Mistrust could deepen if a vaccine appears unreliable due to natural variability.
"Everybody's immune system is different. So it's almost for sure that, if you give the same vaccine to different people, they will have different reactions," said Wang.
"Everybody's immune system is different. So it's almost for sure that, if you give the same vaccine to different people, they will have different reactions." — Jun Wang of the University of Arizona College of Pharmacy
Scientists don't yet know how high antibody levels must climb to confer protection, how solid a defense they will offer or how long they will last.
"We will learn this hopefully through these Phase 3 trials of vaccines, as well as by following individuals who've had COVID-19," said Moss.
Other blind spots could hamper vaccine safety and efficacy, including a lack of data on Black patients, children, and women who are pregnant or breastfeeding.
Some scientists have begun reaching out to communities of color, but such efforts face deep-seated mistrust rooted in historical mistreatment by governments and researchers alike.
"Those are communities where there's a lot of mistrust of the government. If they were prioritized, would they feel that this is an experiment, and further mistrust?" said Moss.
An Associated Press poll in May found Black and Latinx Americans — both groups disproportionately harmed by the pandemic — are more skeptical about coronavirus vaccines than white Americans.
Those factors — and the possibility some vaccines will work better or worse in different populations, such as the elderly — underscore the importance of effective communication and planning during any vaccine rollout.
Messaging must also make clear vaccines probably won't confer total immunity.
"We're going to accept a vaccine that perhaps doesn't have as high efficacy as some of our other vaccines. And people have talked about a threshold of even 50% protective or 60% protective," said Moss.
The less effective the vaccine, the larger the percentage that must receive it to confer herd immunity.
"It would really be great to have many different vaccines hit the market, all of which are effective, so we can shut this pandemic down," said Bhattacharya.
Supply Chains And Cold Chains
The body makes antibodies differently when it first battles a virus than in later bouts.
"After the first shot, what we've seen from these vaccines so far is you make some antibodies, probably not at a level that would be protective, that would actually keep you from getting infected," said Bhattacharya.
After the first immunization, the initial immune response by plasma cells gives way to antibody-producing factories called memory B cells.
"They can respond very, very quickly to new infections or vaccines. And when they get going, they make a ton of antibodies," he said.
But that means some vaccines, including RNA and DNA candidates, will take more than one shot to work.
"And that actually poses some logistical challenges, because it means that you need twice as many doses for it," said Bhattacharya.
Also unclear: how long it will take to make the hundreds of millions or billions of doses needed. Some contenders boast strong vaccine track records, but scaling-up will likely involve massive knowledge transfer and inventing novel methods.
And pressures to succeed — and quickly — could shift priorities.
"We've had to go through some of these experimental platforms where the consideration is almost how quickly can you manufacture it more than anything else," said Bhattacharya.
It's easier to produce large amounts of novel-but-promising DNA or RNA vaccines than to gin up the vast quantities of spike protein needed for more tried-and-true methods.
But easier does not mean easy.
"No one has any experience manufacturing an RNA vaccine at that scale," said Moss.
And RNA reacts badly to heat. Such vaccines will require an extensive "cold chain" that could test the limits of delivery and storage capacity.
Such considerations also cast doubt on whether firms like Novavax, Pfizer, GlaxoSmithKline and Sanofi Pasteur can fulfill their government contracts.
"It's rather more just a bunch of wishful thinking and saying like, 'Hey, we're going to get 600 million doses from Pfizer and then another a hundred million doses from here or there,' without maybe stepping back and being just a little bit more realistic as to what's really going to be available," said Bhattacharya.
Thumbs On The Scales
Those government dollars can speed the process by funding "at-risk manufacturing," a gamble in which companies increase production before they complete testing and licensing.
But key supplies like glass vials and syringes still could run short.
Some experts worry, too, that governments might hoard supplies or vaccines as they did medications and ventilators.
"There's no doubt in the beginning that there will be insufficient volume of vaccines for everyone who wants it," said Moss.
If shortages arise, who gets dibs, and who decides? The answers remain unclear and, given the Trump administration's track record, likely subject to change.
"I think that we would agree that health care workers and people who are most likely to be exposed to the virus should really be first in line, but I've never actually seen that articulated into a policy," said Bhattacharya.
If successful, the coronavirus vaccine moonshot will go down as one of the fastest and most consequential inoculation campaigns in history.
But who it helps or doesn't help, and who it includes or leaves out, may prove as much a social and administrative question as a scientific one.