Multiple Covid-19 vaccine candidates are now in Phase I or Phase II human trials. Soon a decision will have to be made as to what type of testing to perform next. Two significant ethical questions must be answered before the next phase of vaccine testing.

1. Is it ethical to use a placebo vaccine as a control?

I don’t consider this procedure to be ethical for Covid-19 as there is substantial risk from the virus of death as well as substantial suffering in the short- and long-term. The benefits of such a procedure must be weighed against the alternative, which is a retrospective arm as a control. A retrospective control uses past cases, in this case matched to the patients receiving the real vaccine, for comparison. The results using a placebo control are more certain, but a well-designed retrospective arm has sufficient usefulness that it would not be worth the additional suffering and deaths to use a placebo instead.

Ethically, we cannot simply weigh the benefits to society against the detriments to willing volunteers. It is not moral for society or medicine to sacrifice the lives of individuals for the good of society, when an alternative course of action has nearly the same benefits and greatly reduced harm to individuals.

2. Is it ethical to challenge vaccinated volunteers by deliberate infection with Covid-19?

This type of vaccine trial is sometimes used for diseases which have a known effective treatment and which do not often cause death. However, its use for Covid-19 is a substantially different ethical situation. Covid-19 has no highly-effective treatments; current treatments do not remove the risk of death. Treated patients nevertheless end up on a ventilator or in an ICU for many days. Covid-19 can result in death, even in healthy young adults.

Again, the ethical questioned is answered, not by comparing risks to benefits, but by comparing this approach (challenging vaccinated subjects with the virus) to other approaches aimed at the same goal — to assess the efficacy of the vaccine. The alternative is vaccination without challenge. The trial subjects can then ethically be given a placebo or the vaccine. A placebo becomes ethical here because they are at no increased risk by participating in the trial than if they did not participate (as no vaccine is currently available). Then the researchers wait to see if there is a difference in the two groups.

Ordinarily, this approach would be unquestionably ethical. However, the waiting is what introduces an ethical dilemma. While we wait for the vaccinated group to be confronted with possible infection, people are dying. And one trial might not be enough to establish safety and effectiveness. Is it ethical to take the safest course for testing the vaccine? Perhaps the riskier path is morally required, so as to save hundreds of thousands of lives by bringing the vaccine to the world sooner.

The World Health Organization has suggested that a human challenge study, i.e. deliberately infecting vaccinated volunteers with Covid-19, can be moral, if certain conditions are met: Key criteria for the ethical acceptability of COVID-19 human challenge studies.

My opinion is that a challenge vaccine trial can be ethical, if the reasonably anticipated good consequences morally outweigh the reasonably anticipated bad consequences. But we cannot weigh the good for society against the bad for the individuals being vaccinated and “challenged”. Society cannot sacrifice its members for the good of the whole. An individual might choose such a sacrifice, morally. But this type of decision tests the limits of informed consent. Such volunteers would need to be chosen very carefully, so that they are making a decision fully aware of the risks to themselves of death or of long-lasting health complications.

The possible benefits to this type of challenge trial are immense, or at least they can be, if the vaccine works. Many months are taken off of the time to bring a vaccine to widespread use, saving many thousands of lives. But then the number of lives saved depends on the degree of efficacy and how many people can be vaccinated in the short-term. We can’t sacrifice lives based on a rosy scenario of a highly effective vaccine that would be given out very rapidly to very many persons. So the evaluation of the benefits must be tempered by realism.

Suppose the vaccine fails. The volunteers challenged with the virus will become ill, and a certain number will die. The suffering imposed on the volunteers is burdensome. The benefit is merely identifying that the vaccine does not work. We can limit the suffering by choosing healthy young adults to test the vaccine. They are at lowest risk for a severe case and for death from Covid-19. However, this leaves the vaccine untested in the elderly and those with co-morbidities, which is where the vaccine is most needed.

Eventually, any vaccine becomes tested by being given to millions of persons. That is also a type of trial. You can’t really be sure about a vaccine until millions of persons have been given the vaccine, and we see the results over many years. So the idea of a challenge trial is not so different from a large-scale vaccination of the population.

I favor the idea of a challenge vaccine trial, if it is done according to WHO guidelines. But the volunteers must be particularly well-informed and be given every possible protection and benefit.

More Reading:
* WHO: Key criteria for the ethical acceptability of COVID-19 human challenge studies (6 May 2020)
* Science Mag article: Speed coronavirus vaccine testing by deliberately infecting volunteers? Not so fast, some scientists warn
* Ethics and Human Research article: Why Challenge Trials of SARS-CoV-2 Vaccines Could Be Ethical Despite Risk of Severe Adverse Events.
* Should scientists infect healthy people with the coronavirus to test vaccines?

Ronald L. Conte Jr.

Take a look at my Covid-19 website: Covid.us.org