One Vaccine Is Good. How About Mixing Two?

In January, Britain Made a change Its vaccine guidelines shocked many health experts: if a second dose of a vaccine was not available, patients could be given a different one.

The New Testament was based on sheer presumption; At that time there was no scientific data to demonstrate that the mixture of the two coronavirus vaccines was safe and effective. But that may change soon.

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

As increasing numbers of vaccines are being authorized, researchers are testing other combinations. Some are in clinical trials, while others are being tested in animals.

Adding vaccines helps remove supply bottlenecks. Some researchers suspect that a pair of different vaccines may work better than two doses of the same.

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

The concept of mixing vaccines – sometimes called asymmetric growth – is not new to our epidemic era. For decades, researchers have investigated this approach, hoping to find powerful combinations against viruses such as influenza, HIV, and Ebola.

But scientists had little to do for all that research. It was fairly easy to demonstrate that two vaccines in a mouse can work well together. But running a full-blown clinical trial on a combination of vaccines is a tall order.

Dr. “For a single company to develop two parallel arms of a vaccine is double the cost,” said Wheatley.

The search for vaccines for Ebola found some early successes for hetero-dominant climates. Many researchers focused their efforts on introducing the immune system with proteins found on the surface of the Ebola virus.

The gene for that protein was inserted into a separate, harmless virus. When people received an injection of the vaccine, the harmless virus entered their cells; The cells then read the instructions in the Ebola gene and the mass-produced Ebola surface protein. The immune system encountered the Ebola protein and made antibodies against it. And those antibodies protected people with the vaccine if they became infected with the full-blown Ebola virus.

This type of vaccine, called the viral vector vaccine, has brought a major risk: recipients may develop immunity to the viral vector only after the first dose. When the second dose arrived, their immune system could rapidly erase the viral vector before it could deliver its payload.

Many vaccine manufacturers decided to address this potential threat by using different viruses for each dose. In this way, the viral vectors at the second dose will be as new to the immune system as before. In 2017, for example, researchers from the Gamale Research Institute in Russia was made An Ebola vaccine whose first dose contains a virus known as adenovirus. The second shot used another virus, known as vesicular stomatitis virus.

When the Kovid-19 pandemic began last year, Gamalay researchers used a similar strategy to create vaccines against the new coronovirus. The first dose used an adenovirus similar to their Ebola vaccine, called Ad5. The second dose contained a different human adenovirus, Ad26. Researches put a gene for the protein on the surface of the coronavirus in both viruses, called a spike.

Studies showed that the vaccine, now known as Sputnik V, provided a strong defense against Kovid-19. In clinical trials, researchers found that it had an efficacy 91.6 percent. Sputnik V is now in use in Russia and 56 other countries.

Recently, Gamaleya joined forces with the Institute AstraZeneca, which makes its Kovid-19 vaccine. AstraZeneca contains two doses of chimpanzee adenovirus known as ChAdOx1. Last week, the company reported that its vaccine efficacy was 76 percent.

The Gamale and AstraZeneca teams want to see how well their vaccines work together. They have registered a pair of clinical trials in which volunteers will receive a single dose of one of AstraZeneca’s ChAdOx1 and Sputnik V’s Ad26.

A spokesman for AstraZeneca said that a trial is underway in Azerbaijan, and another, in Russia, is still under review by the country’s Ministry of Health.

The head of clinical development at the Vaccine Development Organization CEPI, Dr. Jacob Kramer stated that vaccines that use viral vectors were not the only type that benefited from mixing. In fact, some types of combinations may provoke a different, more effective immune response than the same type of vaccine. Dr. “Immunologically, there are many arguments in favor of the discovery of heterogeneous priming,” Kramer said.

Another type of Kovid-19 vaccine is being tested that contains the actual spike protein rather than genetic instructions for it. Some of the vaccines contain complete protein; Others have a piece of it. Currently, there are 29 protein-based vaccines for Kovid-19 in clinical trials, although none have been authorized yet.

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

Dr. Wheatley and his colleagues found it This mixture worked better than two doses of Spike or RBD.

Researchers suspect that the first dose produces a wide range of antibodies that can cling to spots along the length of the spike protein, and the second dose provides a large supply of particularly potent antibodies to the tip of the spike. Together, the classification of antibodies does a better job of inhibiting coronaviruses.

“You’re basically able to take that initial vaccine that was related to that spike vaccine, and then really focus on that RBD,” Dr. Wheatley said.

Other combinations of vaccines can bring their own benefits. Some vaccines, particularly protein-based, do a good job of making antibodies. Others, such as viral vectors, are better at training immune cells. A viral vector that is followed by a protein boost can offer the best of both worlds.

John Moore, a virologist at Weill Cornell Medicine, cautioned that there was no guarantee that clinical trials would reveal the benefits of mixing the vaccines. In the discovery of an HIV vaccine, researchers attempted to combine viral vectors and protein boosts without success, he notes. Nevertheless, Drs. The story may be different for coronovirus vaccines, Moore said.

“I want to see these studies,” he said. “It is perfectly logical to do this in the Kovid space, but it may not be necessary.”

Some researchers are investigating heterogeneous vaccines not to find a better mix, but to open up more options for countries desperate to vaccinate their populations. Last week, India Exports of vaccines held back As in other countries it is grappling with the growth of Kovid-19. For countries that count those vaccines, a safer alternative to a second dose can save lives.

After criticism from Britain in January to suggest that vaccines could be mixed, researchers at the University of Oxford put the idea up for formal testing. Named test Com-cove, They recruited 830 volunteers to test two vaccines authorized by the British government: the Adenovirus-based vaccine of AstraZeneca and the vaccine by Pfizer-BioNotech.

The Pfizer-BioNotech vaccine uses a fundamentally different technique to produce spike proteins in the body. It consists of small bubbles with genetic molecules called RNA. Once the bubbles fuse into the cells, the cells use RNA to make spike proteins.

A group of volunteers are receiving a Pfizer-BioNotech shot chased by AstraZeneca, while another will receive them in reverse order. Other volunteers are receiving standard two-dose versions of vaccines.

Later this month, the Oxford team will draw blood from volunteers, examine their antibodies and immune cells to see if heterologous total-growth potentiates nearly an immune response in the form of two doses of each authorized vaccine.

If more vaccines are authorized in the UK, the Com-Cove team can add them for testing. Dr. Matthew Snape, who is leading the Com-COV trial, hopes it will be useful not only for his country but for others who will try to get their citizens vaccinated in the next few years.

“It may be that this flexibility actually becomes necessary in the future,” he said.

Dr. Cramer said CEPI plans to support additional heterogeneous prime-boost studies. There are a lot of possible studies to run. Worldwide, 13 vaccines are now in use against Kovid-19, with 67 more in clinical trials.

“In the present case, we have a wonderful position to have such advanced, effective vaccines,” Dr. Wheatley said.

As the number of authorized vaccines increases, possible combinations in which they can be used will explode. Recently, researchers at China’s National Institute for Food and Drug Control have exaggerated their research by trying four different vaccines that are either authorized in China or in late-stage clinical trials Are – adenoviruses, protein-based vaccines, RNA and coronaviruses that have been inactivated with chemicals.

Researchers injected mice with the first dose of a vaccine, then the second dose of the second. Some combinations led to the production of mice Strong immune response Compared to mice received the same vaccine for both doses.

Whether scientists do more experiments on other vaccines or not will depend on the willingness of the vaccine manufacturers. Dr. “You need big enough pharmaceutical companies to play together,” said Wheatley.

Dr. Bernard Moss, a virologist at the National Institute of Allergy and Infectious Diseases, suspects that many companies will be ready to test their vaccines in combination. “It is always better to use something,” he said, “to use whatever is not, to its fullest.”

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