On Tuesday, the European Medicines Agency (EMA) and European Centre for Disease Prevention and Control (ECDC) said combinations of viral-vector vaccines—ones that use modified versions of real viruses to deliver information to the body—and synthetic mRNA vaccines produce not only “good levels of antibodies” against SARS-CoV-2, but also a “higher T cell response” than when people receive doses of the same vaccines.

However, they noted, there was still no data to support giving immunosuppressed people boosters that are different from those given during their primary vaccination.

Some EU countries have already taken the mix-and-match route, more properly known as heterologous vaccination. In Germany, for example, the STIKO vaccine commission recommended in July that those who received a first dose of the Oxford-AstraZeneca vaccine (a viral-vector vaccine, like the Johnson & Johnson and Sputnik V jabs) should get an mRNA chaser from BioNTech/Pfizer or Moderna.

Tuesday’s recommendations and advice are partly intended to make the benefits of this approach clear for all national decision-makers, so citizens across the EU can get vaccinated as soon as possible.

“While research is ongoing to provide more evidence on long-term safety, duration of immunity, and effectiveness, the use of heterologous schedules may offer flexibility in terms of vaccination options, particularly to reduce the impact on the vaccine rollout should a vaccine not be available for any reason,” the agencies said in a statement.

T cell boost

Beyond logistical concerns, the recommendation also reflects how the scientific understanding of the mixing-doses issue is progressing.

When the U.S. Food and Drug Administration green-lit mix-and-match boosters a month and a half ago—for example allowing a J&J recipient to get Moderna as a booster—it said, “The known and potential benefits of the use of a single heterologous booster dose outweigh the known and potential risks of their use in eligible populations.”

That language is relatively cautious when compared with the EMA and ECDC’s words on Tuesday, especially regarding the benefit in T cell response. While people tend to think of antibodies (which are made by B cells) when envisioning people’s immune-system fightback against infection, T cells are also crucial, not least because they tend to hang around for longer, to help the body recognize and attack the virus against which it has been vaccinated.

However, the regulators also struck their own note of caution, with possible implications for the fight against the new Omicron variant: “While it would be expected that higher immune response will translate into increased protection against infection and disease, including from different variants of concern, due to the lack of established correlates of protections it cannot be precisely defined at this stage to what extent such an improved immunogenicity would translate into higher effectiveness.”

The European agencies said boosters could be safe and effective when given three to six months from completion of the primary vaccination, despite the fact that many current recommendations have six months as the minimum waiting period.

As for mixing doses during the primary vaccination, they said giving an mRNA vaccine as a second dose to someone who started with a vector vaccine provided “a positive impact on the achieved level of protection from infection and disease,” but doing things the other way round could provide less of a benefit—this option is less well studied.

There is not much evidence on mixing different mRNA vaccines either, they added, but that approach would be fine if it’s a logistical necessity.