A leader of the Oxford University group, one of the furthest ahead with human trials, admits the reality is paradoxical, even "bizarre," but said the declining numbers of new infections this summer could be one of the big hurdles vaccine developers face in the global race to beat down the virus.
Even as new cases are growing worldwide, transmission rates are falling in Britain, China and many of the hardest-hit regions in the United States — the three countries that have experimental vaccines ready to move into large-scale human testing in June, July and August.
The shrinking number of new infections in former hot spots is good news, of course. But vaccine developers need sufficient numbers of infected people, with and without symptoms, circulating in the general population — in the streets, workplaces, clinics — to test whether the vaccine protects volunteers when they are exposed.
If there's not much chance of volunteers running into someone with the virus, researchers will have to expand their efforts and potentially chase down outbreaks in other countries, delaying the prospect of a successful vaccine.
Pascal Soriot, chief executive of AstraZeneca — a British-Swedish firm that has partnered with the University of Oxford group and gotten an infusion of $1.2 billion from the U.S. government to develop its vaccine — said in a recent briefing that the trajectory of transmissions added a new sort of time pressure.
"Now the problem we will all have, I think, is we are running against time a little bit, because we see already the disease in Europe is declining," Soriot said. "Pretty soon, the disease's intensity will be low and it will become difficult" to gauge efficacy in a vaccine trial.
Adrian Hill, director of the Jenner Institute at Oxford, told the Sunday Telegraph newspaper that his team was in "a race against the virus disappearing."
Hill, who is a co-leader of the Oxford effort, said, "We're in the bizarre position of wanting covid to stay, at least for a little while. But cases are declining."
The Oxford group earlier boasted that it had an 80 percent chance of developing an effective vaccine by September. Hill said the difficulty of testing the vaccine in Britain may mean there's only a 50 percent chance of success within that time frame now.
In the United States, the Trump administration has pledged to pursue a vaccine at "warp speed," plugging the possibility of having something ready by the end of the year. That would be an unprecedented feat, as vaccines in the past have taken years or decades to bring to market.
Getting approval for use in the United States will require large-scale trials conducted over several months — long enough for researchers to observe whether people randomly assigned to receive the experimental vaccine are getting sick significantly less often than people who get a placebo.
Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said the trials will involve 30,000 volunteers, and, to assess how well a vaccine is working, scientists will need to see at least 100 of those volunteers get sick. If there's not much virus around, hitting that target might be tough.
"I hope — I don't want to see a lot of infections in the United States. I wouldn't want people to get infected and suffer and die," Fauci said.
"Hopefully, by mid- to late fall, we get an idea of whether or not it works. I'm cautiously optimistic, but no guarantee, that we will have an answer and the possibility of a deployable vaccine by end of the calendar year," Fauci said.
Tal Zaks, chief medical officer at Moderna, a Massachusetts biotech company that is partnering with Fauci's institute and will launch late-stage clinical trials in early July, told investors last month that one of the biggest challenges is vaccinating people who are really at risk of getting infected.
"If I vaccinate a whole bunch of people, it doesn't matter how many. If there is no circulating virus in the places that I chose to vaccinate, then we won't have the cases and it will be a long time before we know" if it works, Zaks said.
The United States has activated large clinical-trial networks that typically focus on testing vaccines or treatments for HIV, influenza or other infectious diseases. The trials most likely will take place in states or cities where the number of infections is highest.
Britain has the highest coronavirus death toll in Europe, but new infections here are rapidly tapering off. John McCauley, director of the Worldwide Influenza Center at the Francis Crick Institute in London, imagined that healthy volunteers left to wander London might not encounter many infected individuals. The capital has been reporting several hundred new cases a day, but that's in a city of almost 9 million.
And so the Oxford trial is focusing its volunteer recruitment effort on British health-care workers, "as they have the highest rates of virus infections," said Sarah Gilbert, a leader of the group.
David Heymann, an infectious-disease specialist at the London School of Hygiene and Tropical Medicine, noted that vaccine trials are especially hard when people are in lockdown. Volunteers given a vaccine dose in Britain, for example, would be required — like everyone else — to wear masks on public transport, continue social distancing, work from home if possible and avoid gatherings of more than six people.
Gilbert suggested that as lockdown measures are eased, transmission in Britain may rise again, providing more opportunity to test the vaccine as people move around in their day-to-day lives. But other countries in Europe have so far seen no spikes since loosening their lockdowns.
If case infections continue to decline, the Oxford scientists are also looking beyond Britain and Europe for trial sites. They got approval last week from the health regulator of Brazil, where the virus continues to surge, to conduct a trial there involving 2,000 volunteers.
"I think you're going to have go with where the dynamics of the outbreak are, and that changes. You really have to be mobile and flexible," Fauci said.
In China, where at least five groups are developing vaccines, a dwindling number of reported infections has similarly prompted researchers to move ahead with plans to test their vaccines in the Philippines and elsewhere.
One Chinese company, Sinovac, told Sky News that the biggest challenge the company faces is also the low number of cases in China. In the original epicenter of Wuhan, there are hardly any. A Sinovac executive said the company is in discussion with European countries to perhaps test the vaccine there — though trials in Europe may run into the same problem.
CanSino Biologics, which was founded by Chinese-Canadian scientists, has forged an agreement with the National Research Council of Canada to work together on coronavirus vaccine research, paving the way for potential clinical trials in Canada.
Zhu Tao, co-founder of CanSino Biologics, told reporters last month that regulators in the target countries and China would have to unanimously agree on the parameters for the trials.
It's not unusual for drugs to undergo some trials overseas. A 2010 report from the Office of Inspector General in the U.S. Department of Health and Human Services found that more than half of clinical-trial sites were located outside the United States, a shift that helped companies recruit volunteers and reduce research costs. Trials in developing countries — where diseases of poverty, such as malaria, persist and diseases like the Zika virus and Ebola are emergent — also may help secure approval for drugs that would specifically benefit those populations.
But overseas trials can present ethical issues and questions about oversight. It may be harder to get true informed consent from volunteers, especially where literacy is low or translation is required. It may be difficult to monitor whether remote trial sites are adhering to research protocols. There's also debate among ethicists about whether communities where trials were conducted should expect priority access once vaccines have been demonstrated to be safe and effective.
In the case of a meningitis vaccine trial, the World Health Organization determined afterward that only the study participants who hadn't been inoculated should get early access to the vaccine, not their broader community.
Given that countries around the world want access to a coronavirus vaccine, questions about who gets it first and how to share it fairly are already front and center. Drug companies wanting to test in Brazil or the Philippines, for example, may have to promise those countries that their citizens would get some degree of priority.
And working with those countries in particular may present challenges. Brazilian President Jair Bolsonaro has been accused of allowing the virus to spread while playing down the threat, and his government has been criticized for withholding coronavirus data. In the Philippines, President Rodrigo Duterte similarly dismissed the danger, saying "fools, don't believe it," just days before he imposed a lockdown on March 15. He has also restricted communication during the pandemic by shutting down the country's largest broadcasting network.
Another option for researchers would be "human challenge trials," where healthy volunteers are given a vaccine and intentionally "challenged" with the coronavirus. Protocols for such experiments are being written.
Human challenge trials have been used to test vaccines against diseases such malaria and influenza, in which subjects are isolated and monitored to see whether they develop immunity. But covid-19, the disease caused by the novel coronavirus, currently has no cure or surefire treatment. So what happens if a human subject becomes sick or dies?
Bioethicist George Annas of the Boston University School of Public Health told the Journal of the American Medical Association that he wondered "how volunteers in such studies could truly provide informed consent," given how little is known about outcomes for covid-19.
Others say it might be worth a try. In an article in the journal Vaccine, Stanley A. Plotkin of the University of Pennsylvania and Arthur L. Caplan of New York University wrote that deliberately causing disease in humans "is normally abhorrent, but asking volunteers to take risks without pressure or coercion is not exploitation but benefiting from altruism."
It's not only unusual, it's normal. Common flu vaccines used in the West have been tested in China for the last few decades (for example ones produced by Sanofi Pasteur).