The extraordinary speed with which mRNA technology has delivered what appear to be safe and highly efficacious vaccines for preventing COVID-19 herald the start of a “golden age of vaccinology,” according to C. Buddy Creech, director of the vaccine research program at Vanderbilt University in Nashville and principal investigator on the phase III trial of Moderna Inc.’s mRNA-1273 COVID-19 vaccine.
Creech, who is also principal investigator on a phase III trial of Johnson & Johnson’s recombinant adenovirus-26(Ad26-)-based vaccine, JNJ-78436735, said expectations for mRNA-based COVID-19 vaccines at the outset were “hopeful” because of promising preliminary data from vaccines directed against other pathogens, but there were still so many unknowns about the virus, the immune response to it and about the technology itself.
“I would say when the first data came out there was excitement, and when subsequent data corroborated that, I think there was just abject giddiness that we’d gotten this target right and this technology worked,” he said, during a media briefing hosted by the Infectious Diseases Society of America. “This has major implications for Ebola outbreaks, for other emerging infectious diseases that may occur across the globe and even for other pathogens that thus far have eluded us,” he said. “It doesn’t make everything simple, but it certainly unlocks a new way for us to tackle other pathogens, with maybe the same type of speed.”
The conditional approval, which the U.K.’s MHRA granted this week to BNT-162b2, the mRNA vaccine that Biontech SE and Pfizer Inc. are co-developing, has further raised already heightened expectations that the FDA and the EMA will approve both it and the Moderna vaccine in the coming weeks. At this point, at least, neither program has raised safety concerns that could prevent their approval. “We’re not seeing any signals for safety in the short term. It’s important to remember that most vaccine side effects do occur in the short term,” said Kathleen Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland, Baltimore. She is co-principal investigator on the COVID-19 prevention trials network, which the U.S. National Institute of Allergy and Infectious Diseases established to coordinate phase III trials of vaccine candidates. The ongoing trials will continue to monitor participants for safety – the protocols stipulate two years of follow-up. “That safety monitor does not stop at FDA approval – it continues,” Neuzil said.
The existing institutional and federal infrastructures that routinely monitor vaccine safety are now stepping up to include COVID-19 vaccine monitoring as part of their missions. “It’s as big a lift as doing the clinical trials, because we want to do it well,” Creech said.
At the same time, preparations are also underway to broaden recruitment onto clinical trials, to include those who were excluded initially, including pregnant women and pediatric populations. “We really won’t have a vaccine for everyone until we have a vaccine for pregnant women,” Neuzil said. Vaccine manufacturers have been waiting on data from DART – development and reproductive toxicology – studies in animals before embarking on that phase of clinical development. “Most companies now are nearing the end of those studies, and we are in very active planning stages to move into pregnant women,” she said.
The ethics of further placebo-controlled trials
Thoughts are already turning to how the vaccines will be rolled out, to ensure that those who need them most will receive priority access. Strategies are being developed at national and state levels and differences may emerge between differing regions. “This is going to be a moving target over the next few weeks, but it’s a great problem to have,” Creech said.
The rapid trajectory of mRNA vaccine development raises questions about whether it is appropriate to continue placebo-controlled trials of other vaccines that are still in development – an issue that was also explored in a commentary published on Dec. 3 in Science. The authors, David Wendler and colleagues at the U.S. NIH’s Department of Ethics and at the Fogarty International Center, noted that FDA guidance states that “in the event that a COVID-19 vaccine candidate is judged to be ‘safe and effective,’ discussion may be necessary ‘to address ethical arguments to break the blind and offer vaccine to placebo recipients.’”
They argue that it is important to maintain a distinction between the obligations clinicians have toward their patients and those that clinical researchers have toward trial participants. The social value of a particular study must be weighed against the potential harm to which those in the placebo arm may be exposed. If the risk is low, “it can be ethically acceptable to continue a placebo-controlled trial for a short period after the vaccine candidate has been found to be safe and efficacious, even when participants might be able to access the vaccine candidate outside the trial,” they note.
How long that period may be is under active consideration. “I do think clinical trials get harder over time, if we have vaccines that are rolling out,” Creech said. “The design of those clinical trials might have to be modified over time.” They could involve head-to-head comparisons between approved and investigational vaccines, for example, or studies involving subgroups who have not been previously enrolled onto vaccine trials.
“Our immediate challenge is going to be supply, supply, supply,” Neuzil said. In that context, “we absolutely need” the additional vaccines, she said. Clinical trial recruitment is not an issue at present. “We have seen in the short term an uptake of interest in being in the ongoing clinical trials.” After approval and during early rollout, it would no longer be appropriate to recruit subjects from priority populations who are likely to receive the vaccine, but that will still leave a large population who could participate. Neuzil said she expects to see the present trials continuing “at least for the next month or two – and then there will have to be another reassessment.”