“Only one rule in medical ethics need concern you – that action on your part which best conserves the interests of your patient.” — Martin H. Fischer (1897-1962)
My mother, who I give complete credit for my abilities to manipulate the English language to craft these editorials, recently sent me an article by Julie Steenhuysen (Reuters, Aug. 14, 2020) entitled, “U.S. to make coronavirus strain for possible human challenge trials.” Mom, who is not one to mince words, included the email comment, “OMG! Crazy … ” I believe my mother’s remark was able to convey the meaning behind this month’s quote by Dr. Martin H. Fischer, but she managed to do so with just 12 characters. Although my mother is not a healthcare professional, she understands a foundational medical ethics concept of which I, Dr. Fischer, and all healthcare providers are familiar with—primum non nocere.
The news article was describing an effort to bioengineer a novel strain of the coronavirus—COVID-19 is a strain of coronavirus—that can be used in a human challenge trial. Challenge trials are quite different from the current COVID-19 Phase 3 human vaccine trials. In Phase 3 experiments, a vaccine that has been determined to be safe for human injection is given to a large number of volunteers, half of whom receive a placebo. The two large cohorts are then followed for several months to determine whether there is a difference in infection rates or side effects. These studies are cumbersome to say the least, take a long time to complete and are beset by numerous experimental variables that researchers cannot control. Perhaps the most damning issue in these trails is the fact that a participant exposed to the actual vaccine might never actually encounter the virus the vaccination was designed for. On the other hand, this approach offers the least possible risk for the study volunteers.
A challenge trial requires far fewer participants because it involves vaccinating the volunteers and then intentionally infecting them with the virus to determine the effectiveness of the vaccine. You do not have to be a physician, as my mother makes so abundantly clear, to understand this approach is saddled with murky ethics at best.
It might be a surprise for some to learn that challenge trials have played a role in some of the most significant medical advances in the 20th century. One of the most celebrated examples involved a U.S. Army physician, Major Walter Reed, who had been dispatched with a team of researchers to determine a cause for Yellow Fever that was plaguing the American occupying force in Cuba following the Spanish-American War in 1900. One must remember that physicians of the time had no real understanding of viruses or any of the genetic technology that we take for granted today. Despite this significant handicap, Reed and his team intentionally exposed volunteers to infected mosquitos or blood from infected patients. Through these efforts Reed’s team confirmed that Yellow Fever is transmitted by the Aedes aegypti mosquito and not through direct contact. Akhil Mehra, MD, in the AMA Journal of Ethics article, “Politics of Participation: Walter Reed’s Yellow-Fever Experiments,” provides an excellent review of Reed’s experiments and the questionable ethics issues involved.1 In short, a number of “volunteers” in these experiments lost their lives to Yellow Fever. I use quotations regarding the volunteers in the previous sentence because participant understanding or motivations for consenting to the experiments were dubious. There was considerable fatalism regarding the disease in 1900, and some volunteers might have seen the experiments as an opportunity to get the possibility of the disease behind them while enjoying the best care the Army could provide at the time. Others might have been enticed by payments of as much as $20,000 to participate in the risky experiments. Certainly, others could have been motivated by a sheer sense of duty. Notwithstanding the questionable ethical standards employed, the fact remains that the experiments provided the knowledge needed to control Yellow Fever outbreaks through control of the mosquito vector.
On a personal note, I recall during my tour as a flight surgeon in Panama visiting the Corozal American Cemetery and Memorial just west of Panama City, on the Atlantic side of the canal. The memorial recognizes the many American servicemembers who lost their lives during the construction of the Panama Canal. Many likely succumbed to Yellow Fever. Walter Reed’s efforts in understanding how the disease was transmitted resulted in vector control efforts in the canal zone that allowed the canal’s completion. Do the ends justify the means?
I would not be so bold, as I gaze through the lens of my “retrospectroscope,” to judge Reed and his team. They were the actors of their era, and modern physician researchers should only learn gratefully from their example without judgment. These past lessons are certainly worth another look as we grapple with a similar decision during the COVID-19 pandemic. It is likely that an effective vaccine could be developed and available far more expediently with challenge trials. This would likely save a significant number of human lives worldwide. Still, after a career in conducting human research, the ethical issues in intentionally infecting another human with a potentially deadly disease is beyond distasteful. “Logic clearly dictates that the needs of the many outweigh the needs of the few,” according to Mr. Spock from the “Star Trek” series (great episode and, yes, I am a nerd if you have not already figured that out). I am not sure the answer is so logical or cut-and-dried as Spock would have us believe. Is the cost to our humanity in potential abuse of the less economically or socially privileged among us who might volunteer for such a project justify the lives that might be saved?
I do not know the answers to the questions I have posed, although I am sure we had better start having this conversation. COVID-19 certainly has not been the world’s first pandemic, nor will it be the last. I predict more frequent disease outbreaks as population and climate change pressures create ever more fertile ground for viral outbreaks. We should not miss this opportunity to learn from our current missteps in managing COVID-19 and begin designing our plan of actions for the next assault by mother nature, which is surely moving our way.
- Virtual Mentor. 2009;11(4):326-330. doi: 10.1001/virtualmentor.2009.11.4.mhst1-0904.