COVID-19: Are mix-and-match vaccines the way forward?

Following its approval by the European Medicines Agency in January, the COVID-19 AstraZeneca vaccine was administered to all adults in Germany. After discovering that especially younger women who received the shot faced an increased risk of dangerous blood clots in the brain, Germany's Standing Committee on Vaccination (Stiko) in April recommended limiting the use of AstraZeneca to people aged over 60.

That meant quite a few people who had received their first dose of AstraZeneca had to then get BioNTech-Pfizer or Moderna for their second shot. Today, all adults in Germany, no matter their age, can be vaccinated with AstraZeneca again, if the patient and doctor have a conversation about the risks before the jab.

British study: Mix more effective than two AstraZeneca shots

But new studies show that combining two different vaccines could be more than just an emergency solution. Researchers at the University of Oxford have found that patients who received a dose of AstraZeneca followed by a dose of the BioNTech-Pfizer vaccine four weeks later developed a higher number of antibodies than those who had received two shots of AstraZeneca.

As part of their Com-COV trial, the Oxford researchers administered various vaccine combinations to 830 volunteers over the age of 50. Their results showed the highest number of antibodies was developed by people who had received two BioNTech jabs, followed by those who had gotten a shot of AstraZeneca first and BioNTech second. The reverse order still yielded more antibodies on average than two shots of AstraZeneca. 

Lead researcher Matthew Snape, an associate professor of paediatrics and vaccinology, told the BBC that the Com-COV findings didn't undermine the use of two AstraZeneca jabs in the fight against COVID. 

"We already know that both standard schedules are very effective against severe disease and hospitalizations, including against the Delta variant," he said.  

In the UK, the period between the two jabs is usually eight to 12 weeks, not four as in the Com-COV study. Results from trials with a period of 12 weeks between mixed doses will be available in July, Snape told the BBC.

German study: Mix-and-match more effective than two shots of any vaccine

Researchers at Saarland University in western Germany have found that people whose first shot was AstraZeneca and whose second shot was BioNTech-Pfizer showed an immune response stronger than that in patients who had received two doses of the same vaccine, be it AstraZeneca or BioNTech.

So, does that mean it's time to switch the world's immunization approach to a mix-and-match vaccination for everyone?

Not quite yet.

Preliminary results

The results from the Com-COV study have been published as a pre-print, meaning they haven't gone through the peer-review process yet, where independent scientists evaluate them. 

The findings coming out of Saarland University are also preliminary and have not yet been fully evaluated scientifically, the university emphasized in the press statement sharing the results. Before the researchers officially publish their findings, they will look into the role played by the age and gender of the patients, for example, and also delve deeper into which combinations can potentially trigger more severe side effects.

Even though a full data evaluation hasn't been completed yet, the team conducting the study was surprised by the clear results. 

"That's why we wanted to share our outcomes now and not wait for the scientific evaluation process to be completed," Martina Sester, professor for transplantation- and infection immunology at Saarland University, said in the press statement.

10 times the antibodies

There were more than 200 people that participated in the trial conducted at the University Hospital in Homburg, Saarland, over the last few months. Some of them received two AstraZeneca shots, some received two BioNTech-Pfizer shots and a third group received an AstraZeneca shot followed by one from BioNTech.

The researchers compared the strength of participants' immune responses two weeks after the second shot. "We didn't just look at the number of antibodies against the coronavirus [the participants] developed, but also how effective the so-called neutralizing antibodies were," Sester explained. "That tells us how good the antibodies are at preventing the virus from entering our cells."

In terms of antibody development, the double-BioNTech, as well as the combined AstraZeneca-BioNTech vaccination, was significantly more effective than the double-AstraZeneca alternative. Participants who had one of the first two combinations of shots produced around 10 times more antibodies than those with two AstraZeneca jabs. And looking at the neutralizing antibodies, results with the mix-and-match vaccine approach were "even slightly better" than those achieved with two BioNTech shots, Sester said.

For vaccines that require two jabs, health officials have typically recommended the second shot be the same as the first. 

'Remarkable' boost in antibody production

The Spanish CombivacS trial, conducted with 663 participants at the Carlos III Health Institute in Madrid, came to a similar conclusion. The study's preliminary results were reported in the scientific journal Nature. Like the results from Saarland University, they are not yet final ― the publication in Nature is an overview of what the researchers in Spain have found so far, and not a full, peer-reviewed article.

Two-thirds of participants received a shot of the BioNTech-Pfizer vaccine after their initial AstraZeneca jab. The last third had not received a second shot at the time the initial results were shared. Magdalena Campins, an investigator on the CombivacS study at the Vall d’Hebron University Hospital in Barcelona, reported that those who had received the full mix-and-match vaccine combination began producing much higher levels of antibodies after their second shot, and these antibodies were able to recognize and inactivate SARS-CoV-2 in laboratory tests. 

"It appears that the [BioNTech-]Pfizer vaccine boosted antibody responses remarkably in one-dose AstraZeneca vaccines," said Zhou Xing, an immunologist at McMaster University in Hamilton, Canada, who was not involved in the study, in the Nature article. Xing added that the boost appeared to be even more pronounced than the one in people who had received their second dose of the AstraZeneca vaccine.

However, aside from the fact that its results aren't yet finalized and peer-reviewed, one problem with this study out of Spain is that it doesn't include a control group of people who received two shots of the same vaccine — so no direct comparison between the two groups was possible.

Mix-and-match vaccination not always recognized

Even though initial results are promising, the World Health Organization (WHO) still advises against combining vaccines. As of yet, there is not sufficient data to assess whether this is a safe approach, says WHO spokeswoman Margaret Harris.

In Germany, however, someone is considered fully vaccinated if they have received two shots of the same vaccine, as well as if they have had a mix-and-match vaccination. The German government follows the guidelines of the Paul Ehrlich Institute (PEI).

That isn't the case for all countries, though. In Canada, for example, mix-and-match vaccination is approved, whereas in the US studies are still underway. And in the EU, it remains to be seen whether combined vaccines will be recognized by the digital vaccination pass, planned to come into effect in July.

Vaccine combination 'should be seriously considered'

If the initial results are anything to go by, the combination of AstraZeneca and BioNTech-Pfizer appears to be a promising way to immunize people against COVID.

That's not because the two vaccines are in any way similar, though. They represent two types of COVID vaccines currently on the market.

The AstraZeneca shot is a traditional vector vaccine. It uses a harmless version of a different virus to deliver instructions to human cells, which learn to build up antibodies against the coronavirus.

The BioNTech jab is an mRNA vaccine, a new kind of immunisation method. mRNA vaccines teach human cells how to make a protein that in turn triggers an immune response and the production of antibodies.

Researchers don't yet have enough information to know why the combination of these two vaccines can result in boosted immunity. Saarland University professor Sester said she was looking forward to seeing more research done on combining different types of vaccines and how they interact. "We believe that if other research teams reach conclusions similar to ours, the combination of vector- and mRNA vaccines should be seriously considered," she said.

(This article by author Carla Bleiker was originally published on Deutsche Welle.)