Speeding coronavirus vaccine development with challenge trials

Matthew Yglesias

The value of getting a coronavirus vaccine quickly is so high that we should let volunteers risk their lives for the cause, and the US should be willing to “waste” billions on manufacturing candidate vaccines that turn out not to work.

Scientists all around the world are racing to develop a vaccine with financial support from philanthropists and governments, but we need to be thinking much bigger. This is an unprecedented situation that demands far bigger sums of money and bolder approaches to testing and licensing.

Covid-19 is currently killing thousands of people a day. The vast majority of the world’s population has no acquired immunity to the disease. And the economy is grinding to a halt to curb its spread. Given the dire situation, the value of even marginally speeding the widespread availability of a vaccine is incredibly high and warrants much more attention and more extreme measures.

The federal government should do two things immediately: Throw huge sums of money at mass production of candidate vaccines that may not pan out, and explicitly authorize “human challenge” trials in lieu of the conventional FDA approval process.

To be clear: Doing these things with the correct amount of urgency will waste billions of dollars on producing ineffective medicine and almost inevitably get some people killed. But the world does not currently have options that don’t involve substantial losses of both money and lives. The cost of an all-out race to a vaccine is high, but the benefits in terms of lives and money saved would be much higher.

The conventional road to a vaccine is long. We can try to speed it up.

NIH official Anthony Fauci has repeatedly cited a timeline of 12 to 18 months for creating a vaccine, which is frustratingly slow to the bulk of the public. But experts say it is extremely optimistic relative to past vaccine work.

It’s not possible to know what scientific breakthroughs will or won’t happen in the future or on what timeline. But the reason insiders are confident that vaccine development will be slow is that the normal process takes a long time even once you’ve developed the vaccine that works. That’s because there’s a multi-step process that’s inherently time-consuming:


First you do trials in animals to test your candidate with minimal risk to humans.
Then come Phase I trials in a small group of humans designed to ensure the vaccine is safe.
Then you do Phase II trials, also with a small group, focused on checking that people who get it really do develop antibodies like you were hoping.
Next is a Phase III trial in which you give the vaccine to a bunch of people and give other people a placebo. Then you need to follow the whole group for a long time as they go about their lives. That lets you see whether the vaccinated group is less likely to get sick than the placebo group in a statistically meaningful way.

Then if your Phase III trials go well enough to get licensed, it’s time to start actually setting up factories, making vaccines, and shipping them places.

The fastest that this has ever been done is four years, but experts in the US government and World Health Organization think that given the urgency of the situation, a conventional process could be undertaken in something like 18 months. That’s still not very fast because the Phase III trial, in particular, is inherently slow.

On any given day any particular person’s odds of getting sick are relatively low whether or not they have a vaccine. Obtaining statistically meaningful information about whether or not the vaccine is working requires a large-scale study and a lot of time.

Making vaccines is also slow. The US is going to want to immunize 200 million or more Americans. And of course there will be global demand for a vaccine. It’s a humanitarian imperative to push a workable coronavirus vaccine out globally, and it’s in the self-interest of the United States and other countries doing vaccine research to curb spread of Covid-19 in poorer countries.

But we can try to speed the process up.

Challenge trials can greatly speed our knowledge

The easiest way to get around the inherently time-consuming nature of a Phase III trial is to do a “human challenge” trial.

Just like in a regular Phase III trial, you give some of your subjects the vaccine and some others a placebo. But instead of just having them go about their daily lives (daily lives that these days would involve social distancing and other steps designed to minimize the risk of infection), you deliberately expose them to the disease. The downside is that some test subjects are going to get sick. The vaccine may not work, after all, and even if it does, many in the trial were deliberately given a placebo. And if people get sick, some of them may die.

This is anathema to conventional medical ethics (“first do no harm”), which holds that you should not do something deliberately injurious like give someone a fake vaccine and then expose them to a deadly virus for which there is no cure. Human challenges are used sometimes for malaria vaccine candidates. But doctors consider that acceptable because high quality malaria treatment is very effective, while that’s not the case for Covid-19 so far.

Experts advocating human challenge trials — like Nir Eyal, Marc Lipsitch, and Peter G. Smith in an influential article in the Journal of Infectious Diseases — note that it’s possible to minimize the risk. If you only allow young people with no known major risk factors to volunteer based on everything we currently know about Covid-19, the risk of death is very low. Volunteers should also be segregated from the general population, in comfortable conditions, and assured of absolutely top-notch care. To further assuage ethical concerns, volunteers could be drawn from high-risk geographical areas or professions.

Real world ethics trumps medical ethics

Contemporary medical ethics is haunted by the legacy of the Tuskegee syphilis experiment. A group of marginalized African American men were deceived by researchers into participating in a study where their syphilis infections went untreated despite the availability of effective treatment. The goal was primarily to satisfy researchers’ curiosity about what would happen.

You do not need a special canon of medical ethics to see this as a moral failing, a deep betrayal of the patients who put themselves in the doctors’ care.

The medical community should recognize that the current situation involves some different risks. Allowing well-informed volunteers to put their lives on the line to help society in a crisis situation is not particularly out of the ordinary. This is the entire basis of fire departments, the military, and indeed the routine celebration of the health care workers who are on the front lines treating Covid-19 victims. To say that a doctor or nurse should be lauded for risking her life to help a handful of Covid-19 patients, but prohibited from risking their life to help end the pandemic entirely is hard to fathom.

The organization One Day Sooner which is trying to recruit volunteers for hypothetical challenge studies already has over 1,700 signups without much in the way of official encouragement. But allowing — and indeed encouraging — people to sign up is a no-brainer.

Congress and the Trump administration should act decisively to clarify that the FDA would welcome human challenge trial data as part of an accelerated vaccine licensing process. They should appropriate money to help recruit and inform potential volunteers, to establish suitable facilities, and to hail the volunteers as heroes much as they celebrate first responders, front-line medical workers, and soldiers during wartime.

Despite warnings from David Brooks and others that a coronavirus pandemic would likely kill human compassion, in practice the pandemic has brought forth a lot of positive social behavior. Unfortunately, the typical person without medical expertise simply can’t do that much to help beyond donating to charity and sewing cloth face masks. A relatively small number of challenge trial volunteers could have a huge impact on the world, and the government should encourage them to sign up if the risks are deemed acceptable.

We need redundant, wasteful vaccine manufacturing

A conventional business view is that no company is going to manufacture a vaccine at large scale until it’s been approved for use. Demand for a coronavirus vaccine would be off the charts, but it doesn’t make a ton of economic sense to invest in creating enough manufacturing capacity to meet the whole world’s vaccine demand in a short time frame and then be left with a bunch of idle factories. The economically rational approach, in other words, will lead to a situation where only a fraction of the needed vaccine is available at any point in time, with plenty of wrangling over prices paid and who exactly gets the medicine.

Bill Gates has a better idea, as Kelsey Piper has explained — just start manufacturing any promising candidate before it gets licensed:

Gates’s proposal is to build seven factories, for all the leading vaccine candidates, and manufacture lots of each of them. It will mean some wasted money, but it’ll be worth it to get a vaccine to patients sooner. He estimates this will cost billions. Though the foundation hasn’t disclosed how much it will personally be spending, a project of this magnitude will require other stakeholders — as have most of Gates’s public health projects.

“Billions” is a lot in the world of global poverty health philanthropy, which is normally dominated by earnest people helping poor people in developing countries. But we’re now living in a world where Congress is slapping together small-business support programs that cost hundreds of billions of dollars and are still inadequate to the size of the need. Spending extra money on accelerated vaccine manufacturing would be “waste” only if we ignore the genuinely crushing cost of not having a vaccine.

That burden is rightly calculated not only in terms of the (massive) economic cost of depressed business conditions, but also the seemingly large long-term harm to American children of prolonged school closures.

At the moment, interest rates on government bonds are less than the rate of inflation so anything with an economic benefit down the road is essentially free. It’s great that Gates is offering to kick in some of his own considerable personal fortune to help with this. But Congress should just pay whatever it takes, perhaps letting Gates save his charity money for work in developing countries that Congress is unlikely to fund.

Every week counts

The current debate over “opening up” the country is increasingly fantastical.

Even if limited reopening can be pulled off in a safe way (a big if), huge segments of the economy — mostly those directly related to travel and lodging, but also formal and informal supports for white-collar office work — will likely be offline, and children will likely remain out of school. “Vulnerable” populations, including senior citizens and significant swathes of the non-senior population, will have to remain in a state of isolation, even as things open up.

As far as best-case scenarios go, this is an extremely costly one. And yet the most realistic outcomes, which involve periodic surges in cases and renewed periods of near-total shutdown, are considerably grimmer than that. There are currently about 2,000 people dying per day, and while that number may be trending downward, the impulse in several large states to start lifting restrictions without any ability to do comprehensive contact tracing suggests it will rise again in the future.

The only real way out of this bind appears to be getting people vaccinated. Speeding this process up by a few months — or even a few weeks — would be an incredible boon to the country and the world. Ideas for how to do that are currently kicking around on a volunteer and philanthropic basis, but accelerating our way out of this disaster takes leadership from the federal government.

Doing what it takes to get to vaccination as fast as possible will have real costs, but every day of delay is unimaginably more costly than the price of speeding up.

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