In January, the UK made a change to its vaccination guidelines that shocked many health professionals: if the second dose of a vaccine were not available, patients could get another.

The new rule was based on mere guesswork; At the time, there was no scientific data to show that mixing two coronavirus vaccines was safe and effective. But that could change soon.

In February, researchers at Oxford University began a study in which volunteers were given a dose of the Pfizer BioNTech vaccine followed by a dose of the AstraZeneca formulation, or vice versa. This month, researchers will begin analyzing the subjects’ blood to see how well the mix-and-match approach works.

As more vaccines become approved, researchers are testing other combinations. Some are in clinical trials while others are currently being tested on animals.

Mixing vaccines can do more than just help overcome supply shortages. Some researchers suggest that a pair of different vaccines might work better than two doses of the same.

“I think we are about to get some interesting data,” said Adam Wheatley, an immunologist at the University of Melbourne in Australia.

The concept of vaccine mixing – sometimes referred to as heterologous prime boost – is not new in our pandemic era. For decades, researchers have studied the approach in the hope of finding effective combinations against a range of viruses such as influenza, HIV, and Ebola.

But scientists had little to show for all of this research. It was easy enough to show that two vaccines can work well together in a mouse. However, it is a huge task to conduct comprehensive clinical studies with a combination of vaccines.

“For a single company, developing two parallel arms of a vaccine is twice as difficult and twice as expensive,” said Dr. Wheatley.

Some of the early successes for heterologous prime boosts were in finding vaccines for Ebola. Many researchers focused their efforts on presenting the immune system with a protein found on the surface of the Ebola virus.

The gene for this protein was inserted into another, harmless virus. When people were given an injection of the vaccine, the harmless virus entered their cells; The cells then read the instructions in the Ebola gene and mass-produce Ebola surface protein. The immune system encountered the Ebola protein and made antibodies against it. And these antibodies protected the vaccinated people when they were infected with a full-blown Ebola virus.

This type of vaccine, known as the viral vector vaccine, was fraught with great risk: recipients could develop immunity to the viral vector after just the first dose. When the second dose arrived, her immune system was able to quickly wipe out the viral vector before releasing its payload.

A number of vaccine manufacturers have chosen to circumvent this potential threat by using different viruses for each dose. In this way, the viral vectors in the second dose would be just as new to the immune system as the first. For example, in 2017, researchers at the Gamaleya Research Institute in Russia developed an Ebola vaccine, the first dose of which contained a virus called adenovirus. The second shot used another virus, the vesicular stomatitis virus.

When the Covid-19 pandemic began last year, Gamaleya researchers used a similar strategy to develop vaccines against the new coronavirus. The first dose used the same adenovirus as in their Ebola vaccine called Ad5. The second dose contained another human adenovirus, Ad26. The research inserted a gene into both viruses for the protein on the surface of the coronavirus called a spike.

Studies showed that the vaccine now known as Sputnik V offers a strong defense against Covid-19. In clinical studies, the researchers found an effectiveness of 91.6 percent. Sputnik V is currently used in Russia and 56 other countries.

Recently, the Gamaleya Institute partnered with AstraZeneca, which makes its own Covid-19 vaccine. AstraZenecas consists of two doses of a chimpanzee adenovirus called ChAdOx1. Last week, the company reported that its vaccine was 76 percent effective.

Teams Gamaleya and AstraZeneca want to see how well their vaccines work together. They registered two clinical trials where volunteers received one dose of AstraZeneca’s ChAdOx1 and another one of Sputnik Vs Ad26.

Updated

March 30, 2021, 11:18 p.m. ET

An AstraZeneca spokesman said one process was ongoing in Azerbaijan and a second in Russia was still under review by the country’s health ministry.

Dr. Jakob Cramer, head of clinical development at CEPI, a vaccine development organization, said vaccines that use viral vectors aren’t the only kind that could benefit from mixing. In fact, certain combinations can produce a different, more effective immune response than a single type of vaccine. “Immunologically, there are several arguments in favor of research into heterologous primer,” said Dr. Chandler.

Another type of Covid-19 vaccine tested contains the actual spike protein and no genetic instructions for it. Some of the vaccines contain all of the protein; others contain only a fragment of it. There are currently 29 protein-based vaccines for Covid-19 in clinical trials, although none have been approved.

Dr. Wheatley and colleagues tested protein-based vaccines on mice. They injected the animals with the full spike protein as the first dose. For the second dose, they only injected the tip of the spike, a region known as the receptor binding domain, or RBD

Dr. Wheatley and colleagues found that the mixture worked better than two cans of the Spike or the RBD

The researchers suspect that the first dose produces a wide range of antibodies that can adhere to spots along the length of the spike protein, and that the second dose delivers a large supply of particularly potent antibodies to the tip of the spike. Together, the range of antibodies can better stop the coronavirus.

“You can basically take the initial immunity that was created for that spike vaccine and then really focus it on that RBD,” said Dr. Wheatley.

Other combinations of vaccines may have their own benefits. Some vaccines, especially protein-based vaccines, do a good job at generating antibodies. Others, such as B. viral vectors, immune cells can train better. A viral vector followed by a protein boost could be the best of both worlds.

John Moore, a virologist at Weill Cornell Medicine, warned that there is no guarantee that clinical trials would show any benefit for vaccine mixing. In the search for an HIV vaccine, the researchers tried unsuccessfully to combine viral vectors and protein boost. Still, said Dr. Moore, the story could be different for coronavirus vaccines.

“I would like to see these studies done,” he said. “It is completely rational but may not be necessary to do this in the Covid room.”

Some researchers are studying heterologous vaccines not to find a superior mix, but simply to open up more opportunities for countries desperate to vaccinate their populations. Last week India held back vaccine exports to other countries as it struggled with a surge in Covid-19. For countries that are counting on these vaccines, a safe alternative to second doses could save lives.

After the UK was criticized in January for blending vaccines, researchers at Oxford University set out to put the idea to a formal test. In a study called Com-Cov, they recruited 830 volunteers to test the two UK government-approved vaccines: the adenovirus-based vaccine from AstraZeneca and the vaccine from Pfizer-BioNTech.

Pfizer-BioNTech’s vaccine uses a fundamentally different technology to produce spike proteins in the body. It contains tiny bubbles with genetic molecules called RNA. Once the bubbles fuse with the cells, the cells use the RNA to make spike proteins.

One group of volunteers will receive a Pfizer BioNTech shot followed by AstraZeneca while another group will receive them in reverse order. The other volunteers receive the standard two-dose version of the vaccines.

Later this month, the Oxford team will draw blood from the volunteers and examine their antibodies and immune cells to see if the heterologous prime boost elicits an immune response roughly as strong as two doses of any of the approved vaccines.

If more vaccines are approved in the UK, the Com-Cov team can add them to the study. Dr. Matthew Snape, who leads the Com-COV study, hopes it will be useful not only for his own country, but also for others who will try to vaccinate their citizens over the next few years.

“It could be that this flexibility will actually become essential in the future,” he said.

Dr. Cramer said CEPI plans to support additional prime-boost heterologous studies. There are many possible studies that need to be done. 13 vaccines against Covid-19 are currently being used worldwide, and 67 others are in clinical studies.

“In the current situation, we are in a pretty luxurious position to have so many advanced, effective vaccines,” said Dr. Wheatley.

As the number of approved vaccines increases, the possible combinations in which they can be used are exploding. Recently, researchers at China’s National Institutes for Food and Drug Control expanded their research on heterologous prime boosts by trying four different vaccines that were either approved in China or are in late-stage clinical trials – adenovirus-based vaccines, Proteins, RNA, and coronaviruses that have been inactivated with chemicals.

The researchers injected mice with a first dose of one vaccine and then a second dose of another. Some of the combinations caused the mice to produce stronger immune responses than mice that received the same vaccine for both doses.

Whether scientists conduct more experiments with other vaccines depends on the willingness of vaccine manufacturers. “You need pretty big drug companies to play well together,” said Dr. Wheatley.

Dr. Bernard Moss, a virologist at the National Institute for Allergies and Infectious Diseases, suspects a number of companies will be ready to have their vaccines tested in combinations. “It is always better to be part of something that is used,” he said, “than to own something that is not used.”