Can you mix and match Covid-19 vaccines?

As Covid-19 vaccine rollouts continue across the globe, people are being administered two-doses: a ‘prime’ first dose, followed by a ‘boost’ second dose some weeks later.

Thirteen vaccines are currently in use against the virus and an additional 67 are in clinical development around the world, with nearly two-thirds designed to generate immunity with two or more doses.

But with supply scarcity and distribution of certain vaccines an ongoing issue and many hunting for leftovers, a question is starting to cross people’s minds: what happens if you get two different vaccine doses? What if you were to pair a first dose of the AstraZeneca vaccine with a second dose supplied by Moderna?

And, most importantly, would it be safe?

It could be possible that greater immunity is generated if different vaccines are used one after the other, in what is known as “heterologous prime boosting”.

Both the Pfizer and AstraZeneca vaccines prime the immune system to target the coronavirus’ spike protein, which plays an instrumental role in the infection process.

But they hone in on different parts of the spike and deliver their payloads by two different means. Pfizer hands over genetic instructions for making the spike protein and relies on human cells to produce it, while AstraZeneca uses a modified cold virus to present the spike protein to the immune system.

Moderna also uses the same mRNA platform that Pfizer does.

“We’re not sure why a mix-and-match approach can be more potent. But it’s possible combining two different vaccines – which give the same antigen target but stimulate the immune system in different ways – could better focus our immune cells’ attention on the right target,” wrote Dr Kylie Quinn, a Vice-Chancellor’s Research Fellow at the School of Health and Biomedical Sciences at RMIT University.

According to the Centers for Disease Control and Prevention (CDC) in the US, while more research is needed on the subject, there should be no side effects to mixing. The CDC maintains that medical professionals administering vaccinations should do their best to ensure patients receive two of the same shots if they’re administering the Pfizer or Moderna vaccine.

However, in an “exceptional situation” where a second shot of the first vaccine type isn’t available, “any available mRNA Covid-19 vaccine may be administered at a minimum interval of 28 days between doses to complete the mRNA Covid-19 vaccination series.”

Dr Bulent Sekerel, Director of Hacettepe University’s Faculty of Medicine, is skeptical about mixing and matching until there is clear scientific backing.

“As far as I know neither of these protocols have been evaluated in clinical trials. We need to have evidence to discuss it with the public or suggest it as a treatment alternative,” he told TRT World.

TRT World reached out to BioNTech and AstraZeneca for comment, but both declined until conclusive studies on vaccine mixing were available. Other experts were also reluctant to discuss it until evidence from trials emerged.

For the moment, experiments in mice have shown promising results, in which combinations of the Pfizer and AstraZeneca vaccines boosted immunity better than two doses on their own.

But there is no evidence that it works in humans – at least, not as of yet.

Significance of the UK’s mix-and-match trial

As of last month, Oxford University has begun conducting a clinical trial to test whether it’s safe to mix vaccination types after the UK government gave medical professionals the go ahead to mix shots in January.

The trial, referred to as the Covid-19 Heterologous Prime Boost study or ‘Com-Cov’ study, will recruit over 800 volunteers aged 50 and above. Using an eight-armed clinical trial, it will evaluate the four different combinations of prime and booster vaccinations: volunteers will either receive one dose of the Pfizer vaccine followed by one dose of the AstraZeneca vaccine, the reverse, or two regular doses of each vaccine type.

Volunteers will then be evaluated at two different dosing schedules: a four-week interval for early interim data and a twelve-week interval. Using blood samples, the study will monitor the impact of different dosing regimens on participant’s immune responses.

Overall, the study will last for thirteen months.

“As we roll out vaccination in the UK, we have the opportunity to look at how to get the most out of the vaccines available to us. This innovative study looks at whether using different combinations of two currently approved vaccines is a good alternative to the standard schedule. We will also be looking at the impact of the interval between doses on immune responses,” Dr Maheshi Ramasamy, Senior Clinical Researcher and Investigator on the trial, said in a statement.

If the results are positive, it could help ease supply chain issues and help boost a more robust immune response in recipients.

Professor Jonathan Van-Tam, Deputy Chief Medical Officer and Senior Responsible Officer for the study, said: “Given the inevitable challenges of immunising large numbers of the population against COVID-19 and potential global supply constraints, there are definite advantages to having data that could support a more flexible immunization programme, if needed and if approved by the medicines regulator.”

“It is also even possible that by combining vaccines, the immune response could be enhanced giving even higher antibody levels that last longer; unless this is evaluated in a clinical trial we just won’t know.”

New strains in South Africa for example, underscore the importance of having an immunisation strategy that preserves or improves vaccine-induced immunity as novel variants of the virus emerge.

There is also precedent for combining vaccines that use different vehicles to deliver their payloads. Two doses of Russia’s Sputnik V vaccine use two kinds of viruses to transport the genetic instructions that tell the immune system which coronavirus surface proteins to look for.

In clinical trials, research revealed that Sputnik V had an efficacy of 91.6 percent and is now in use in Russia and 56 other countries.

Russia’s Gamaleya Research Institute, which designed Sputnik V, took a similar approach to formulating the first and second doses of its Ebola vaccine. Several experimental HIV vaccines are being tested using the same approach too.

Recently, Gamaleya and AstraZeneca have teamed up to register a pair of clinical trials – one in Azerbaijan and the other in Russia – to see how well their vaccines work in tandem.

But the problem with testing the safety of mixing vaccine combinations is ultimately compounded by the complexity of immunity itself.

“What we know to measure is only half the story,” said Dr Gregory Poland, a vaccine researcher at the Mayo Clinic in Minnesota. While the British trial will measure the antibodies in the bloodstream, it’s not clear if immunity can be achieved through neutralising antibodies alone.

“If you alter one component of that, you no longer know if you have the same efficacy and safety,” said Poland.

But in the midst of a global pandemic that level of caution might be a luxury – and mixing vaccines may end up being inevitable.