Next-Gen COVID-19 Vaccine Trials Need an Active Comparator or Some Design Ingenuity

Approved vaccines and the diminishing numbers of unexposed individuals are making placebo-controlled trials for COVID-19 vaccines a thing of the past, so researchers will have to rely on active comparators to develop second-generation shots.

The problem is getting ahold of those doses, said Melanie Saville, director of vaccine research and development at the Coalition for Epidemic Preparedness Innovations (CEPI).

 “Unfortunately, lack of access to comparator vaccines is already stalling the development of promising vaccine candidates, and the potential impact on COVID-19 vaccine development and supply is huge,” Saville said in a letter published in the Sept. 7 issue of Nature.

Seven vaccines are currently approved by the World Health Organization. But all the stock is bound by contractual agreement that restricts its use to public health measures, eliminating the possibility of clinical research, Saville noted. “Thus far, vaccine manufacturers have been reluctant to change this arrangement, threatening to bring vital COVID-19 vaccine R&D to a standstill.”

She called on governments and vaccine manufacturers to release a stock of comparator vaccines for the research that must continue if prevention is to keep pace with rapidly evolving COVID strains.

Placebo-controlled studies are no longer practical or ethical, William Schaffner, a professor of infectious disease at Vanderbilt University Medical Center in Nashville, told FDAnews. The global combination of increasing vaccination and infection rates makes it increasingly difficult to find seronegative study populations. Additionally, “I can’t think of an institutional review board anywhere that would go for a placebo study when there’s an approved, effective vaccine,” Schaffner said.

Next-generation COVID-19 vaccines are a must, he agreed, adding that manufacturers of approved vaccines will probably take the lead using their own product as a comparator.  Potentially viable candidates will also arise from independent researchers, if they can put together well-designed trials with sufficient numbers. But even if a supply of comparator vaccines doesn’t materialize, these laboratories have other research options.

Immunobridging may be one.

“When we know that a trial is unlikely to be large enough or long enough to show an explicit difference in efficacy between two vaccines, we can demonstrate efficacy using immnunobridging. If the new vaccine produces a documented immune response that is comparable to, or better than, that which resulted in the licensure of an approved vaccine comparator, then the investigational vaccine can be licensed on that basis, as well as any new advantages.”

This approach has precedent, Schaffner said. Researchers used immnunobridging to advance the pneumococcal conjugate vaccine from a 7-valent to a 13-valent vaccine. The new vaccine demonstrated that it was at least as good as the original in the first seven serotypes and also induced comparable immunogenicity against the six new serotypes. “This kind of study could lead to the licensure of new COVID-19 vaccines as well.”

How about studies using historical controls as the comparator? It’s possible, he said, but not optimal.

“They are a fail-safe if you can’t use a prospective design. The strength of the evidence is not as solid as a prospective randomized trial, though. And it takes a whole lot of epidemiologic matching to make sure the historical controls are comparable in every way to the newly vaccinated group.”

The unifying message remains the same, he said: “Coping with COVID means staying on alert and implementing international surveillance programs that are always on the lookout for variants that could evade the protection offered by current vaccines. That’s the nightmare scenario, where we would have to, in effect, just start all over.”

Read the CEPI letter here: go.nature.com/3BKdZQK. — Michele G. Sullivan