Support is growing around the world for initiatives that involve deliberate infection of healthy young people with the coronavirus to test the effectiveness of experimental vaccines. An organization called 1 Day Sooner has already enlisted more than 3,400 people from 52 countries, who have volunteered to be vaccinated in this controversial approach, also known as human challenge trials (HCT). The initiative is not linked to any companies or research groups that are currently working to develop a vaccine, but it exemplifies the mounting interest in smart ways to find an effective vaccine sooner than predicted.
One reason for the lengthy time frame needed to develop a new vaccine is the standard structure what is typically the last stage of testing: efficacy testing, or phase III trials. Usually, a vaccine is initially developed in a lab.
Then its efficacy is tested in vitro and in animals. After these trials show that the vaccine prevents infection of animals that were exposed to the virus, researchers move to the first clinical stage – testing the safety of the vaccine for use in humans. At this stage, it is given to a small group of healthy subjects, and researchers check to see whether there are any negative side effects.
After safety testing is complete, complete, and there are some demonstrated effects on recipients’ immune systems, comes efficacy testing. Development teams give the vaccine to a large group of volunteers, and a placebo vaccine to control groups. Both are monitored over time to see if there is any difference in the rate of infection or high viral load in those who received the vaccine and the control group.
The advantage of HCT is that by deliberately exposing subjects to the virus, which is not done in standard trials, a clear answer concerning the vaccine’s efficacy can be obtained more quickly.
In an article published in late March in The Journal of Infectious Diseases, Nir Eyal of Rutgers University, Mark Lipsitch of Harvard University and Peter G. Smith of the School of Hygiene & Tropical Medicine in London, laid out the advantages of HCT. “Vaccines are our ticket out of the crisis,” says Prof. Eyal. “If we have a vaccine a few months sooner, we’ll be able to save millions of people from dying from the coronavirus, other diseases and of famine ‘on a biblical scale’ (as per the UN).”
This isn’t the first time that the idea of human challenge testing has been considered by the international scientific community. Edward Jenner, the physician who developed the world’s first vaccine, against smallpox, exposed his gardener’s son, eight-year-old James Phipps, to cowpox after he discovered that milkmaids who developed this disease displayed immunity to smallpox. A few weeks later, he exposed the child to smallpox, and saw that the boy did not develop the disease. Based on this experiment, Jenner produced the world’s first vaccine in 1796.
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But even today, when scientists and physicians must follow strict rules of ethics and cannot expose poor children to serious diseases, human challenge testing is being done – though mostly for relatively mild illnesses.
In recent years, researchers have been testing the efficacy of a number of flu vaccines versus various strains of the flu virus. In previous decades, the development of vaccines for cholera and malaria also relied in part on human challenge testing. More recently, various groups around the world have conducted human testing trials for vaccines against weakened versions of the viruses that cause dengue fever and typhoid.
Regulatory standards for HCT vary widely among different countries. In Britain, the authorities are more inclined to permit such testing than those in the U.S. In 2016, a research group at Oxford University used HCT in a trial where subjects who had received an experimental vaccine were exposed to the abdominal typhus bacterium and then sent home (despite a concern that they could infect others).
Regulations for this type of testing are stricter in the United States. A few years ago, the U.S. considered HCT for a vaccine against the Zika virus, but ultimately decided to avoid the risk.
In the current pandemic, there is pressure to change the U.S. approach. Thirty-five members of Congress recently signed a statement calling on the Food and Drug Adminsitration, as well as the Department of Health and Human Services, to approve HCT for vaccine trials for the novel coronavirus – citing the article by Eyal and his colleagues. In the past, regulatory authorities saw human challenge trials as an initial filter before moving on to wide-scale testing. But given the intensity of the current medical, economic and social crisis, “We think the regulator should deviate from its habits.” Eyal told Haaretz.
Opponents of the approach say there are still too many unknowns about how the novel coronavirus works. Human challenge trials require the controlled breeding of the virus and determination of the optimal dosage for exposure. Another problem is that certain vaccines may actually exacerbate the illness rather than prevent the infection. This increases the risk – and thus the ethical concerns – of deliberately exposing healthy subjects to the virus.
Eyal says HCT also has significant advantages for the subjects. First, the number of participants in a trial is low (between 100 and 200), so it is possible to ensure access to intensive care for them if necessary, which could be vital if the subjects are recruited, as he recommends, from areas where there is a high rate of infection and ICUs are not accepting new patients. Second, the risk of complications due to the vaccine is reduced with HCT, since the subjects are kept in isolation under constant medical supervision, unlike the thousands of participants in ordinary vaccine trials. And third, with HCT, the subjects know there is no risk that they will infect their family members.
“People may conclude that they have a high risk of getting infected and so they would rather do it in a supervised way under safe conditions,” Eyal says. The Rutgers University researcher adds that, because of the need to first breed the virus in a controlled fashion and to determine the correct dosage, preliminary studies for HCT should already begin and suitable research facilities should be prepared, so if the go-ahead for these trials is given, no time will be wasted.
Some say, however, that the controversial approach is not needed in the current crisis. Myron Levine, an infectious disease specialist from the University of Maryland who has been conducting human challenge trials for other vaccines for over 40 years, told the news website of Science magazine that he believes standard vaccine testing will be much faster than many people think. Because of the high rates of infection occurring in many places, standard trials will be able to draw conclusions about the vaccines’ efficacy within a similar time frame to that of HCT, he says.
For example, the Chinese company Sinovac Biotech, which began clinical trials of a COVID-19 vaccine last week, announced that it hopes to complete the first two phases of testing by the end of June. If the trials are successful, the company hopes to apply for regulatory approval to conduct the third phase of testing on at-risk populations such as medical personnel, which is an alternative way to accelerate the efficacy testing of the vaccine without seeking volunteers to be deliberately infected.
On the other hand, says Eyal, regular vaccine studies can take a long time, and sometimes they are never completed – as with a study of an experimental vaccine for Ebola that was suspended because the epidemic abated in the place where the trial was being conducted. “In China the disease is on the decline, and it’s unclear if there will be enough doctors who are candidates to get the vaccine. In HCT, results are promised within a limited time frame.”