Which COVID-19 vaccine candidates will be successful? Canadian experts warn it may be hard to tell

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The varying nature of the COVID-19 pandemic and uncertainties about immunity levels in different populations could complicate efforts to determine which vaccine candidates currently being tested will be successful, a group of Canadian experts has warned.

While multiple groups around the world are developing and testing vaccines at a blinding pace, those efforts must still take into account additional factors that are unique to COVID-19.

“Failure to do so could lead to setbacks in getting vaccines approved by regulators and delay their deployment,” said Bahaa Abu Raya, a pediatric infectious diseases specialist with the BC Children’s Hospital Research Institute in Vancouver.

Dr. Abu Raya is the lead author of a paper published last week in the Canadian Medical Association Journal that makes clear just how difficult the process of assessing COVID-19 vaccines could be. The report has emerged amid a flurry of new developments related to some of the leading vaccine candidates.

An overview document released Wednesday by the World Health Organization lists 23 candidates undergoing clinical trials around the world, including one developed by Quebec-based Medicago, which on Monday launched the first COVID-19 human trial in Canada.

Almost all of the 23 are still in earlier-stage trials involving relatively small numbers of participants, primarily to determine safety rather than efficacy. Two candidates – one developed by the University of Oxford in partnership with pharmaceutical giant AstraZeneca and another by Beijing-based Sinovac – are in Phase 3 trials. These involve thousands of participants – enough to provide meaningful data on how well the vaccines perform.

A third candidate, developed by Massachusetts-based Moderna Inc., is heading to a Phase 3 trial at the end of this month, the company announced Tuesday, after positive results from an early trial, involving 45 individuals, were published in the New England Journal of Medicine.

The WHO document lists an additional 140 candidates in preclinical evaluation – laboratory and animal studies that can help determine if a candidate is likely to succeed in humans.

While the process of vaccine testing and approval is well established, what makes it so challenging in the context of COVID-19 is that the presence of the virus among different populations and regions is not very well known.

Someone working on a vaccine for influenza or another virus that is endemic to the human population can estimate with some confidence how many people are likely to be infected over a given period of time. Individuals who receive the vaccine in a clinical trial can then be compared to the background infection rate to see if they fare any better. The rate is crucial in determining what size of clinical trial is needed to demonstrate that a vaccine is working.

“We typically have a good idea of how many people are likely to get sick in a given season, so we have a clear idea of how many people need to be in the study,” Dr. Abu Raya said.

When it comes to COVID-19, however, the background infection rate is not constant over time and differs from place to place. In general it would be better to test a vaccine where there is a high likelihood of many infections; otherwise too many subjects will be required to show if the vaccine is having a real effect.

John Lewis, a University of Alberta researcher who is leading the development of a COVID-19 vaccine, said the ever-shifting infection rate “is definitely something we are paying attention to.”

He added that because infection rates are climbing significantly in some parts of the United States, “it is likely that we will be incorporating a number of U.S. sites” in upcoming clinical trials of the group’s vaccine candidate.

However, going to where the disease is surging also presents complications because of the likelihood of high numbers of unreported or asymptomatic cases, which may raise immunity levels in the population and make a vaccine seem more effective than it really is.

Another factor is that different subpopulations – including children, the elderly and pregnant women – are either not equally susceptible to the disease or their susceptibility is not well understood.

In their paper, Dr. Abu Raya and his colleagues recommend a flexible clinical trial design that can accommodate the state of the pandemic in different places and groups. They also recommend thorough testing of participants in vaccine trials for antibodies that would indicate prior exposure to the virus.

The study does not delve into the issue of human challenge trials, which would involve deliberately exposing subjects to COVID-19 after vaccination in order to more directly test vaccine efficacy. In addition to the ethical problem of infecting individuals with a disease that cannot always be treated successfully, some experts have pointed out that such trials are unlikely to provide data that is relevant to those who are most vulnerable to the disease. No human challenge trials are currently being considered in Canada.

Assuming that at least some vaccines are shown to be effective, Dr. Abu Raya said there is one final challenge he is less concerned about: persuading people to get the vaccine.

Resistance to vaccines, spurred by social media, is a public health threat that predates the pandemic. However, Dr. Abu Raya said the phenomenon has typically involved vaccines for diseases that most people have had little experience with, thanks – ironically – to widespread vaccination.

When it comes to public uptake of a vaccine for COVID-19, he said, “I expect it to be high because we are all seeing the devastating consequences of the disease, both on health and the economy.”

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