This is a recurring column on clinical research in the early stages of development, what is referred to as phase 1. These are treatments being used for the first time in a small number of human patients to determine safety, dosing and general pharmacological activity.
There are many differences between the unprecedented COVID-19 pandemic and the Ebola outbreak that began in 2014, but at least one common thread emerges: Vaccine development is never straightforward, despite the best intentions.
Merck & Co. Inc.'s Ervebo was approved in both Europe and the U.S. near the end of 2019, following decades of research. One of the minds behind this Ebola vaccine was Gary Kobinger, who helped usher the vaccine into clinical trials during his time at the National Microbiology Laboratory in Manitoba, Canada.
Kobinger is now director of infectious disease research at Université Laval in Quebec, where he is working with laboratories across North America, Asia, Europe and Africa on vaccine candidates for SARS-CoV-2, the strain of coronavirus that causes the COVID-19 infection and has resulted in a global pandemic that has claimed more than 430,000 lives around the world as of June 17.
Vaccines for the novel coronavirus have entered human trials at a speed never before seen in infectious diseases — huge players in the biopharma space, such as Moderna Inc., Johnson & Johnson, Pfizer Inc., GlaxoSmithKline PLC and Sanofi, were quick to begin or announce plans for phase 1 trials in 2020.
This "great moment" in vaccine development can be attributed to a worldwide effort and an urgent need propelling the science forward, Kobinger told S&P Global Market Intelligence.
Director of Université Laval's Infectious Disease Research Center Gary Kobinger
Source: World Health Organization
"I can't think of another moment in vaccination when we had over 100 vaccine candidates advancing to solve an infectious disease problem," he said. "The fastest to enter phase 1 before was just under seven months ... from the design of a vaccine on the computer to starting enrollment."
"This has been completely shattered: the first phase 1 was just under three months [ago], so that's phenomenal," said Kobinger, who remains realistic about expectations for a globally available vaccine.
"When people talk about a vaccine in the fall, I don't believe it personally," he said. "We'll be lucky if we have one next summer, June 2021, and that's a vaccine that makes a difference and that's available to even a portion of the population."
Picking the right patients
Entering human trials for a vaccine is a very different process than for other drugs — participating patients are from a healthy population, as opposed to a subset that a particular therapy is designed to treat — making enrollment and trial design tricky and often controversial.
Patients in early-stage vaccine trials are screened to ensure they are the healthiest, with no other worrisome conditions. Small side effects like pain at the injection site are bound to arise as patient populations are increased, and more serious reactions — especially disease worsening — need to be addressed, Kobinger said.
"It's very hard to draw conclusions from phase 1 data," Kobinger said. "It's a good sign when you have good safety and acceptability, but that's definitely just the first step — this is why it takes so long."
There are many different approaches to vaccine trials at the early stages. For Ebola, this involved a process called ring vaccination, in which the population consisted of patients who were contacts of confirmed cases. This strategy requires thorough case investigation but can be successful.
Another option is the double-blind, classical control, randomized trials, which are open to any patients within a broad group — for example, adults aged 18 to 55, Kobinger said. Though widely accepted, this strategy can be less useful in a rapidly evolving outbreak environment.
"Every concept has its pluses and minuses, but you have to see what is more advantageous in terms of speed, safety and collecting the right data."
Beyond phase 1, trials get bigger and bigger in an effort to determine the efficacy and safety of the vaccine in large populations even after approval. France's Sanofi was forced to pull its dengue fever vaccine from the Philippines market as the company allegedly missed post-marketing requirements.
"For COVID-19, I expect the dynamic of the immune response with regards to vaccination is going to be complex, and that is what could turn out to be a much more important challenge that we anticipate in vaccine development," Kobinger said.
Lessons from Ebola
There were many challenges in developing the Ebola vaccine, Kobinger said, one of which was that no version of it had been licensed anywhere in the world. This led to a four-year gap from final clinical trial data to regulatory approval, partially because of manufacturing logistics.
"Merck is one of the top three vaccine producers and knew the business very well, and it still took four years," Kobinger said of Ervebo. As it relates to COVID-19, manufacturing could play a similar role this time around, Kobinger and other experts have said.
"Right now, depending on [the] vaccine platform, I think we can safely expect many to cross the line to phase 3 clinical trials, but ... it's possible that manufacturing may be challenging."
However, the global demand may overcome some of those hurdles faced when attempting a vaccine for Ebola, which was a less widespread outbreak.
"In 2014, we had to start from scratch and no one had the clinical prep for a vaccine ready," Kobinger said. "So that's the big difference — things are moving much faster than they did in 2014 because this is a global problem with global contributions."