As research continues to develop new and amended coronavirus vaccines, scientists across the world are also looking at what happens when individuals are immunised with more than one type of shot.
Administering different vaccines may offer stronger immunity against Covid-19, something that is especially valuable as new variants emerge.
But before such an approach becomes routine, more findings are needed to understand the effectiveness of using more than one vaccine – and to ensure there are no serious side effects.
“It seems an inherently good idea if you’re worried about the efficacy,” said Prof David Taylor, emeritus professor of pharmaceutical and public health policy at University College London.
“As the variants change, we’ll be introducing new antigens. It would be a sensible thing to do as and when a complementary vaccine becomes available.
"But we need data, we need trials.”
There are several reasons why it may be desirable to use different vaccines, including that it may lead to stronger immunity – something known as heterologous prime boosting.
When a person receives an adenovirus viral vector vaccine, such as the Oxford-AstraZeneca, there is a potential risk the immune system will react against the adenovirus. This is used as a vector to deliver coronavirus genetic material into human cells.
If this happens, when an individual is injected with the same vaccine again, some vaccine particles will be attacked by the recipient’s immune system, weakening the dose’s protective effect.
However, this will not affect mRNA vaccines – the technology behind those from Pfizer-BioNTech or Moderna.
Adenovirus viral vector vaccines use a weakened or inactivated virus to introduce coronavirus genetic material into cells, which then make coronavirus spike proteins, triggering an immune response.
The mRNA vaccines cause the body's cells to produce similar proteins, which again trigger an immune response.
Another reason to offer different doses is availability. If supplies of one vaccine dwindle, health authorities may welcome being able to give patients a different one for their second – or third – dose.
People who have had two doses of a vaccine with lower efficacy may want to have a booster of a different vaccine.
Also, concerns over rare blood clots caused by some viral vector vaccines may make it desirable to give individuals a different vaccine – such as an mRNA shot – for their subsequent shot.
This is why France announced in April that under 55s who had received the Oxford-AstraZeneca shot as their first dose would be given a Pfizer-BioNTech shot as their second, despite limited efficacy data being available. Other countries have introduced or are considering similar strategies.
Multiple trials involving giving people more than one Covid-19 vaccine are under way. Prof Zhou Xing, of the McMaster Immunology Research Centre at McMaster University, Canada, said results so far from studies in Germany and Spain are “very encouraging”.
“They indicate it’s not only safe, but also highly effective,” he said. “So far the evidence suggests that AZ/Pfizer mRNA is even more effective than AZ/AZ.”
A study published at the beginning of June looked at a cohort who received one dose of the Oxford-AstraZeneca vaccine followed eight weeks later by a Pfizer-BioNTech shot.
“We looked at neutralising antibody response: how the people that received the vaccinations responded with regards to antibodies in their blood or serum that actually neutralise virus,” said Ruediger Gross, of Ulm University Medical Centre in Germany, the first author of the study, which has yet to be peer reviewed.
Using blood sample extracts, they found that neutralisation of the Alpha variant was almost four times higher in people given the two different vaccines than it was in a group that had received two Pfizer-BioNTech doses.
"This doesn't necessarily mean that protection in the real world is fourfold higher, simply because protection for the double BioNTech vaccinated is already very high. But it indicates that it probably at least will be as good," he said.
Slight alterations in the coronavirus spike proteins generated by different vaccines may help to explain why using different shots is better than just one.
“It might help the immune system to simply see this protein from basically two different perspectives, to develop a better, broader immune response,” Mr Gross said.
Current studies involving more than one Covid-19 vaccine come with the caveat that results so far focus principally on laboratory tests.
“They show they produce good antibody response, which is important, but not the same as reducing hospitalisation and death,” said Dr Raghib Ali, director of the Public Health Research Centre at New York University Abu Dhabi.
He noted that at least one study has indicated a higher rate of side effects in people given different Covid-19 vaccines. Fever and headaches, for example, may be more common.
Giving several vaccines at once against different diseases is routine, with children receive as many as half a dozen in a single shot, but experience of giving an individual more than one vaccine against a single disease is limited, although there are precedents.
More than one vaccine has been employed against HIV, the virus that causes Aids, albeit with disappointing results.
Pharmaceutical company Johnson and Johnson created an effective two-dose vaccine against Ebola, the viral disease that has broken out several times in Africa in recent years.
The first dose uses an adenovirus viral vector, while the second employs a modified pox virus.
While more real-world efficacy data for Covid-19 vaccine combinations is awaited, Mr Gross said it may become more commonplace to give individuals more than one vaccine, particularly with third doses.
As coronavirus vaccines are largely being well tolerated, he suggests there are unlikely to be long-term side effects and he thinks it unlikely that third doses will be required to be of the same vaccine as the initial two shots.
Senior figures, such as Pfizer chief executive Albert Bourla, have suggested a third dose might be needed six to 12 months after the second, followed by annual vaccination.
However, some people who have received two doses of Covid-19 vaccines that appear to have lower efficacy may be keen to have a third shot of a different vaccine sooner than this.
In Abu Dhabi booster third vaccine doses are being made available six months after second shots.
Mr Gross said in principle there is no reason why an interval of several months is needed between second and third doses.
“I don’t think it necessarily needs to be half a year if your response to the first two vaccines was not great,” he said.
Indeed, in a study that announced findings this month, immunocompromised individuals who had reacted poorly to two doses of a vaccine were given a third shot as little as 24 days later.
In this research, one third of patients who had failed to develop antibodies after two doses did produce them after their third.
With multiple combinations of different vaccines being trialled, clinicians will be keeping a close eye on results to inform future Covid-19 vaccination strategies.
And the experiences gained during the pandemic in using more than one vaccine may offer wider benefits into the future, suggested Prof Xing.
“Since both adenoviral vector vaccines and mRNA-based vaccines are very new to us, going forward our experience in mixing them in the fight against Covid-19 certainly will lend to developing vaccines against other infectious diseases,” he said.