One vaccine is good – how about mixing two?

In January, Britain changed its vaccine guidelines that shocked many health experts: If the second dose of a vaccine was not available, patients could receive another.

The new rule was based on simple guesswork; there was no scientific data at the time demonstrating that the mixture of two coronavirus vaccines was safe and effective. But that could change soon.

In February, researchers at the University of Oxford began a trial 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 start analyzing subjects’ blood to see how well the mix-and-match approach works.

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As more vaccines are licensed, researchers are testing other combinations. A few are in clinical trials, while others are currently being tested in animals.

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

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

The concept of mixing vaccines – sometimes referred to as heterologous prime-boost – is nothing new in the era of the pandemic. For decades, researchers have studied the approach, hoping to find potent 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 fairly easy to demonstrate that two vaccines can work well together in a mouse. But conducting full clinical trials on a combination of vaccines is a tall order.

“For a single company, developing two parallel arms of a vaccine is twice the work and double the cost,” said Wheatley.

Some of the early successes of heterologous prime-boosters came in Ebola vaccine research. Many researchers have focused their efforts on presenting a protein found on the surface of the Ebola virus to the immune system.

The gene for this protein was inserted into a different, harmless virus. When people were injected with the vaccine, the harmless virus entered their cells; the cells then read the instructions for the Ebola gene and the mass produced Ebola surface protein. The immune system encountered the Ebola protein and made antibodies against it. And these antibodies protected the vaccinated people if they became infected with a full-blown Ebola virus.

This type of vaccine, called a viral vector vaccine, presented a great risk: recipients could develop immunity to the viral vector after only the first dose. When the second dose arrived, their immune system could quickly eliminate the viral vector before it delivered its payload.

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

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

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Studies have found that the vaccine, now known as Sputnik V, offered strong defense against Covid-19. In clinical trials, researchers have found that it has 91.6% effectiveness. Sputnik V is now in use in Russia and 56 other countries.

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

The Gamaleya and AstraZeneca teams want to see how their vaccines work together. They recorded a pair of clinical trials in which volunteers will receive one dose of ChAdOx1 from AstraZeneca and another Ad26 from Sputnik V.

A spokesperson for AstraZeneca said that a trial in Azerbaijan is underway and a second one in Russia is still under review by the country’s health ministry.

Dr Jakob Cramer, head of clinical development at CEPI, a vaccine development organization, said vaccines using viral vectors weren’t the only ones benefiting from a mix. In fact, certain combinations can elicit a different and more effective immune response than a single type of vaccine. “Immunologically, there are several arguments in favor of exploring heterologous priming,” Kramer said.

Another type of Covid-19 vaccine tested contains the actual spike protein, rather than genetic instructions for it. Some vaccines contain the whole protein; others contain only a fragment. There are 29 protein-based vaccines for Covid-19 in clinical trials, although none have yet been licensed.

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

Wheatley and his colleagues found that the mixture worked better than two doses of spike or RBD.

Researchers suspect that the first dose produces a wide range of antibodies that can stick to spots along the length of the spike protein, and that the second dose delivers a large amount of particularly potent antibodies to the end of the point. Together, the assortment of antibodies does a better job of stopping the coronavirus.

“You are able to take that initial immunity that was elicited from this peak vaccine and then really focus on this RBD,” Wheatley said.

Other vaccine combinations may provide their own benefits. Some vaccines, especially protein-based ones, generate a good job of antibodies. Others, like viral vectors, are better able to train immune cells. A viral vector followed by a protein boost could offer the best of both worlds.

John Moore, a virus expert at Weill Cornell Medicine, warned that there was no guarantee that clinical trials would reveal any benefit to mixing vaccines. In the search for an HIV vaccine, researchers tried to combine viral vectors and a protein boost without success, he noted. Yet, Moore said, the story may turn out to be different for coronavirus vaccines.

“I would love to see these studies completed,” he said. “Doing it in the Covid space is completely rational, but may not be necessary.”

Some researchers are studying heterologous vaccines not to find a better mix, but simply to open up more options for countries that desperately want to vaccinate their populations. Last week, India curbed vaccine exports to other countries as it grappled with a Covid-19 outbreak. For countries that relied on these vaccines, a safe alternative to second doses could save lives.

After Britain came under fire in January for suggesting the vaccines could be mixed, researchers at the University of Oxford set out to test the idea. In a trial called Com-Cov, they recruited 830 volunteers to test the two vaccines authorized by the UK government: the AstraZeneca adenovirus vaccine and the Pfizer-BioNTech vaccine.

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

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

Later this month, the Oxford team will draw blood from the volunteers, examining their antibodies and immune cells to see if the heterologous prime-boost creates an immune response about as strong as two doses of each. authorized vaccines.

If other vaccines are licensed in Britain, the Com-Cov team can add them to the trial. Dr Matthew Snape, who is leading the Com-Cov trial, hopes it will be of use not only to his own country, but to others who try to vaccinate their citizens over the next few years.

“This flexibility may in fact become essential in the future,” he said.

Cramer said CEPI plans to support additional heterologous studies of primary stimulation. There are many possible studies that can be done. Globally, 13 vaccines are currently in use against Covid-19, with 67 more in clinical trials.

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

As the number of vaccines allowed increases, the possible combinations in which they can be used will explode. Recently, researchers at the Chinese National Institutes for Food and Drug Control stepped up their research on first-rate heterologous enhancers by trying four different vaccines that have been approved in China or are in advanced clinical trials there. low – vaccines based on adenoviruses, proteins. , RNA and coronavirus inactivated by chemicals.

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

Whether scientists conduct more experiments on other vaccines will depend on the willingness of the vaccine manufacturers. “You demand that the big pharmaceutical companies play well together,” said Wheatley.

Dr Bernard Moss, virus expert at the National Institute of Allergy and Infectious Diseases, suspects that a number of companies will be willing to let their vaccines be tested in combination. “It’s always better to be a part of something that’s going to be used,” he said, “than to fully own something that isn’t.”