To have a vaccine by next summer will require both luck and cutting corners never cut before, putting once seemingly academic questions about vaccine testing suddenly front and center.

Vaccine trials can take decades. In the race against COVID-19, we don’t even have years.

To have a vaccine by next summer will require both luck and cutting corners never cut before, putting once seemingly academic questions about vaccine testing suddenly front and center.

Current rules are meant to protect volunteers from harm, but with the global death count from the coronavirus over 250,000, scientists are asking: Is it acceptable to deliberately infect healthy people with a disease that could kill them, and for which there is no cure?

It's called a challenge trial, and increasing scientists say the answer is yes.

The tried and true method would be to vaccinate tens of thousands of people, let them go about their daily, socially distanced lives and see who gets sick, knowing some small number would have anyway. That takes time. 

To speed up the process, some researchers are planning to give volunteers experimental vaccines and then infect them with SARS-CoV-2, the virus that causes COVID-19. 

“You’re weighing risks and benefit to the individual versus benefit to society as a whole,” said David Magnus, director of the Stanford Center for Biomedical Ethics at Stanford University.

The ethical quandary will be fast upon us. As of Tuesday, eight candidate vaccines were in clinical evaluation, four in China, one in Britain, one in the European Union and two in the United States, according to the World Health Organization. None are yet at Phase III trials, in which a vaccine is tested on large numbers of people to see if it works, is safe or has side effects.

Typically, such trials would be years away. Now, they could begin this year. Last week the Trump administration created Operation Warp Speed to cut development of a vaccine by at least eight months.

The Food and Drug Administration, which regulates vaccines, is looking hard at the scientific, ethical and feasibility questions raised by such a drastically shortened schedule.

"A formal determination about any specific human challenge trial proposal would be made by the FDA in the context of all the information that is available at that time," said spokesman Michael Felberbaum. 

Exactly when challenge trials will happen or what guidelines will be changed to make them possible have not been revealed.

One thing, however, is certain. To meet such a timeline, what happens next will be extraordinary.

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The usual vaccine timeline

The timeline for vaccines is usually measured in years. When Edward Jenner gave the first smallpox vaccine to the son of his gardener in 1796, he waited two years before he tried it again on anyone else.

The fastest a vaccine has ever been produced, for mumps, took four years. An Ebola vaccine took five.

The process is complex. First scientists must find a way to trigger the body to produce antibodies against the SARS-CoV-2 virus, then test it in cell cultures and in animals. This is known as the pre-clinical phase.

Human testing comes next. Phase I, to ensure the vaccine is safe, usually involves fewer than 100 people. Phase II employs several hundred volunteers and tests how their immune systems respond to the vaccine as well as  safety and side effects. 

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Phase III is pivotal. Tens of thousands of people are given the vaccine and compared with people who received a placebo. The large cohort is necessary to look for common, along with rare, side effects.

“Phase III trials are the primary source of data that helps us know whether we have a vaccine we can use at a broad scale,” said Jason Schwartz, a professor at the Yale University School of Public Health who studies vaccine policy. 

The clinical trials for the human papillomavirus vaccine, which protects against cervical cancer, included 30,000 subjects. The tests for the rotavirus vaccine, which protects against a common disease that causes severe diarrhea in children, included 70,000 research subjects, he said.

Only after Phase III is complete can a manufacturer apply for a license to market the vaccine for human use. 

COVID-19 challenge trials

Scientists hope to speed up the process for the coronavirus vaccine by running tests for each phase at the same time. In a normal scenario, each part of each phase of testing would be completed and carefully analyzed before the next one was begun. That’s partly for safety and effectiveness but also to save money by not continuing down paths that lead to dead ends.

This time, companies and nonprofits are pouring billions into the search. The rules also are being loosened. The FDA is working closely with companies that have SARS-CoV-2 vaccine trials underway to streamline the process as much as possible.

Phase III is the conundrum. Usually, researchers watch tens of thousands of volunteers as they go about their normal lives to see if they become infected. With COVID-19, because volunteers would still be following social distancing guidelines, few of them would even be exposed to the virus. That's partly why the group must be so large.

“Then we would use statistical techniques to see if there were fewer cases than we would expect there should have been among those vaccinated,” said Paul Root Wolpe, director of the Center for Ethics at Emory University.

In a challenge trial, volunteers are purposefully infected with the virus. The number could be much smaller because most would get sick. The time would be shorter because COVID-19 appears within two weeks.

It’s an ethical minefield. Some percentage of the volunteers, no matter how young and healthy, could die.

For that reason challenge trials are done only with diseases where there’s a 100% cure, said Susan Ellenberg,a professor of biostatistics, medical ethics and health policy at the University of Pennsylvania School of Medicine.

Even when there is a cure, taking part is no fun. When challenge trials were launched for malaria and cholera, participants got very sick.

“The volunteers had lots of diarrhea and vomiting, but they were standing by with IV fluids and antibiotics. so the people who took part were miserable but there was very low risk of actual permanent harm or death,” said Stanford’s Magnus.

With COVID-19, the death rates aren’t even known, and the one current potential treatment, remdesivir, appears only to lessen the duration of the illness.

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Is it ethical to infect someone with COVID-19?

In 2016, researchers wanted to infect volunteers with the Zika virus to test a possible vaccine. The National Institutes of Health said no.

COVID-19 may be different. Scientists have been debating the ethics of employing challenge studies – so-called because they “challenge” the immune system – in the fight against the pandemic since at least March. That's when three senior scientists published a paper in the Journal of Infectious Diseases suggesting the risks to volunteers must be weighed against deaths that will occur every week a vaccine is not available.

It can be ethical given very strict guidelines, said one of the authors, Nir Eyal, a professor of bioethics at Rutgers University.

Only young and healthy participants, whose risk of death from COVID-19 is real but low, should be selected, he said. They would need to be from areas of heavyinfection so the risk of getting sick is high anyway. And they would have to be isolated while infectious so they couldn’t pass it along.

Society allows others to decide to do dangerous things for the greater good, Eyal said.

“We rely on healthy volunteers to take on risks as organ donors, drug toxicity trial participants, and, in this crisis, emergency medical service volunteers,” he said.

Health care providers are probably the best choice for Phase III trials, said Dr. Machteld Wyss-van den Berg, a public health researcher who focuses on vaccine ethics with the Swiss Tropical and Public Health Institute in Basel, Switzerland.

“Their health literacy is high so they have the capacity to understand the risks and potential benefits,” she said.

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Decisions about how to conduct Phase III trials have not been made, or at least been made public, but political pressure to use rapid testing techniques is building.

A bipartisan group of 35 lawmakers on April 20 sent a letter to the heads of the U.S. Health and Human Services and the Food and Drug Administration calling for “a more rapid testing and approval process."

“Every week of delay in the deployment of a vaccine to the seven billion humans on Earth will cost thousands of lives,” the letter said. “Justifiable risks may be taken."

An ad hoc group has already set up a website – 1 Day Sooner – to gather volunteer names.

“We have to understand that this is a serious disease, the mortality and morbidity and the social consequences that are a result of this infection are enormous,” said Dr. Kathryn Edwards, scientific director of the Vanderbilt University Vaccine Research Program said in a call by the Infection Diseases Society of America.

“We have to figure out how to stop it, not to simply treat it,” she said. “This is a balancing act.”

Contributing: David Heath, USA TODAY

SEARCHABLE MAP: Coronavirus death rates and cases for every US county: https://interactives.courier-journal.com/projects/cv19/map/ 

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