Mixing vaccines with the same target could produce a stronger immune response.
British scientists on Thursday launched an unprecedented trial to find out if two doses of different COVID-19 vaccines yield an immune response that matches — or exceeds — the effect of two doses of the same vaccine.
The government-funded study will try to provide invaluable data on whether mixing brands is an effective strategy in the scramble to immunize the global population against the virus — all the more pressing now given unpredictable vaccine supplies and the need for a flexible system to reach all people. Researchers also want to test how well the mixed doses respond to the new virus variants.
Mixing brands has been shown to be effective against Ebola and in general practice — some people who require booster jabs later in life rarely receive the same brand of vaccine they were first given years ago. The seasonal flu jab also changes year on year.
A driving reason for this experiment, in the words of Matthew Snape, chief investigator of the trial, is to “create a safety net” that can offset any disruptions in supply. “It’s good to have that in the back pocket … if there was a problem,” he told journalists Wednesday.
This kind of insurance strategy couldn’t come at a better time: EU countries are already facing supply problems, with manufacturing failing to deliver at the anticipated pace. And many are opting to restrict the Oxford/AstraZeneca vaccine to younger adults, going against both the approved use by the EU and the U.K.
For now, Britain is alone as it goes full steam ahead in the clinical testing of vaccines and treatments — a discipline that it’s renowned for. After being the first Western country to approve a COVID-19 vaccine, and the first to roll out delayed dosing, it’s now the first to try mixing jabs.
The team said preliminary data will be available by early summer.
There is a small risk in that this approach has never before been tested in COVID-19. This approach assumes that vaccine makers are confident they have identified the right target on the virus to prevent disease, even as the virus mutates.
To date, all approved COVID-19 vaccines work in the same way, by training the immune system to recognize and attack a part of the virus called the spike protein. Generating a super immune response with two vaccines against this target might look good under the microscope, with high levels of antibodies and T-cells, but that’s only positive if attacking this target stops the illness, one immunologist warned.
But if it can work, it could have a significant impact around the world.
“This will have an impact on global vaccine policy,” said Mary Ramsay, head of immunization at Public Health England. “Other countries will continue to roll out vaccines at different rates around the world. So it’s important that we are able to provide data as to whether mixing schedules is a good alternative to using two standard doses.”
That potential has already attracted the interest of the World Health Organization’s COVID-19 vaccine program, COVAX, which met last week with Snape.
The trial
The trial is no simple exercise. Researchers will assess the body’s immune response after administering BioNTech/Pfizer’s jab first, followed by Oxford/AstraZeneca’s vaccine second; they also will test by swapping the order. These results will be compared with people receiving the standard regime of the same vaccine twice. And all arms of the trial will test both 28-day and 12-week dosing intervals, as per the U.K.’s current program.
That’s eight arms of the trial, and each will deliver immunogenicity results from these varying schedules.
The Oxford team is already in talks with other vaccine makers, including Johnson & Johnson and Novavax, about including their jabs. For now, it will only look at the two approved vaccines in the U.K., except Moderna’s jab, which is approved but not yet available until later in the year.
Once more jabs are approved, though, the permutations add up, Snape pointed out. Five approved vaccines mean “50 different arms of the study, and that quickly becomes not practical.”
Accordingly, the team will “prioritize combinations that were of most relevant to the U.K. schedule,” he added.
What’s also distinctive is that the trial isn’t looking at efficacy, since the vaccines in question are known to work, Snape noted. Rather, it’s about measuring the immune system’s response to these combinations, by assessing antibodies and T-cells in blood samples over a year. Namely, they want to find out whether mixing is better or worse, and whether it’s safe. The researchers will also store the blood samples to test them against future mutant strains that evolve.
The science
“The concept is a simple one,” said Al Edwards, associate professor in biomedical technology at Reading School of Pharmacy, in an interview. “You want an immune response to a particular target.”
“As soon as you know what the target is … you end up with a very powerful response to that one specific target, which is superior and more specific than if you use the same vaccine twice,” he explained.
So when scientists know what the target is, it’s “very attractive” to use two different vaccines, “because you get that extreme laser focus down on one thing,” he said.
Indeed, the original plan for the Oxford/AstraZeneca vaccine was to combine it with a different booster jab, noted Kate Bingham, the former chair of the Vaccine Taskforce, in a December journalists’ briefing.
“There’s nothing hugely rocket science about this,” she said. “Can you broaden, deepen and strengthen our response?”
AstraZeneca has already announced it’s testing its vaccine in a mix-and-match dosing trial with Russia’s Sputnik V jab. The two vaccines use the same adenovirus viral vector technology to enter the cells with instructions to make the spike protein, but Oxford uses a chimp virus while Sputnik uses two uncommon cold viruses. The theory goes that combining the two will generate a stronger immune response, since using a different adenovirus will prevent the body from attacking the vector in the second dose.
However, homing in on one target could also be the one risk, Edwards warned.
“It sounds compelling when you know what the target is,” he said, referring to the spike protein. “But if you’re wrong about the target … it could actually be not an advantage.”
If the trial produces a “most spectacular immune response … but the target isn’t helpful to protect against infection, all you’re doing is making a vaccine that looks like it works better but it doesn’t actually work any better,” he explained.
But as an immunologist, he thinks it’s a risk worth taking.
“It’s one of the great uncertainties in science and medicine: Until you get something that works, you might have a brilliant theory, but if your theory doesn’t pan out, it’s not proven until it’s proven,” Edwards said.
