What will COVID-19 vaccine candidate trials tell us? Not whether they will prevent deaths or serious illness, according to a new feature article in the BMJ.

As the world looks to pharmaceutical companies to forge a way out of the COVID-19 pandemic, vaccine development has never experienced such limelight.

With a significant number of COVID-19 vaccine candidates well into phase 3 clinical trials, you may be wondering what panacea to expect.

How quickly will these vaccines provide protection, how many lives will be spared, and will this allow us to return to our pre-pandemic lives?

But a recent feature in the BMJ may provide a sharp wake-up call to our post-pandemic dreams, highlighting precisely what these trials do and do not set out to answer.

Dr. Peter Doshi is an associate editor on the News and Views team at The BMJ. He is also an associate professor of pharmaceutical health services research at the University of Maryland School of Pharmacy in Baltimore.

In the feature, Dr. Doshi points to the dichotomy between how the world may perceive the purpose of the COVID-19 vaccine candidates and what the clinical trials that will put them to the test are designed to do.

“None of the trials currently underway are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths,” Dr. Doshi writes. “Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.”

This may come as a surprise. But what exactly are these trials investigating?

In his feature, Dr. Doshi provides a handy table that includes a number of the leading vaccine candidates from companies such as Moderna, Pfizer, AstraZeneca, and Janssen.

The table provides data on the number of volunteers each company will recruit, their age ranges, and what outcomes, or endpoints, the companies will analyze to find out whether their vaccine candidate works or not.

All of the vaccine candidates that Dr. Doshi discusses are in phase 3 clinical trial and involve tens of thousands of study participants.

Yet the trials mostly exclude children, people living with conditions that compromise their immune system, and pregnant or breastfeeding people. This, in itself, is not unusual.

While a vaccine candidate is under investigation in clinical trials, some of the short- and long-term risks remain, to some extent, unknown. Protecting vulnerable groups in this way is standard and ethical practice.

Dr. Doshi’s table also gives an insight into how each company will measure how well their vaccine candidate performs. The technical term for the main criteria under investigation in any clinical study is “the primary endpoints.”

For the leading vaccine candidates, the primary endpoints focus on preventing symptomatic COVID-19 in the study volunteers.

But there is a catch. While each company has its own definition of “symptomatic,” none of them are looking specifically at severe COVID-19.

To show that a vaccine candidate works, the companies will compare the number of volunteers in the treatment group who develop symptomatic COVID-19 with the number of those in the placebo group.

Why is this important? “In the trials, final efficacy analyses are planned after just 150 to 160 ‘events,’—that is, a positive indication of symptomatic [COVID-19], regardless of severity of the illness,” Dr. Doshi explains.

This means that the primary endpoints will not include any data on whether the vaccine candidates can prevent severe COVID-19, reduce the need for hospital admission, or lower the number of deaths.

Dr. Doshi does point out the challenges that running trials to pinpoint such things might present. These would need much larger numbers of volunteers.

Yet he criticizes the pharmaceutical companies for doing “little to dispel the notion that it was severe [COVID-19] that the trials were assessing.”

He suggests that it is “fair to say that most of the general public assumes that the whole point of the current trials, besides testing safety, is to see whether the vaccine can prevent bad outcomes.”

Dr. Doshi calls into question whether people who have a higher risk of severe COVID-19 and death are disproportionately underrepresented in these clinical trials.

“If frail elderly people, who are understood to die in disproportionate numbers from both influenza and [COVID-19], are not enrolled into vaccine trials in sufficient numbers to determine whether case numbers are reduced in this group, there can be little basis for assuming any benefit in terms of hospital admissions or mortality,” he writes.

“Whatever reduction in cases is seen in the overall study population (most of which may be among healthy adults), this benefit may not apply to the frail elderly subpopulation, and few lives may be saved.” – Dr. Peter Doshi

He also points to the lack of data about how likely the vaccine candidates are to reduce transmission of SARS-CoV-2 from person to person.

Again, it would be a mammoth task to study this, as every clinical trial volunteer would need to have a swab test on a regular basis.

No vaccine can provide a suit of armor that stops a pathogen from entering our bodies. But vaccines do train our immune systems to fight off infections and reduce the burden of disease.

How well COVID-19 vaccine candidates will be able to do this remains to be seen. There are many unanswered questions as the world and the pharmaceutical companies working on these much-needed vaccines at unprecedented speeds navigate through uncharted territory.

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