Scientists are serious about mixing and matching COVID-19 vaccines | National

It’s almost not a lazy question. According to experts, dose discrepancies are inevitable, either by chance or by design.

Currently, two vaccines are being rolled out nationwide, a third joining them this week, and two likely to grow further in the coming months. All but one were designed to be offered as a double dose regimen.

Another 69 vaccines are in clinical development worldwide, and nearly two-thirds of them are designed to generate immunity with two or more doses.

However, enabling people to get the right vaccine at the right time turned out to be a bigger logistical challenge than initially expected. In addition, the menacing coronavirus variants emerged unexpectedly quickly, making it essential to shoot the gun as soon as possible.

UK health authorities have proposed fundamental solutions to both problems. Delay the second dose by up to 12 weeks so that more people can receive at least some protection. The government then acknowledged that, in exceptional circumstances, inconsistent vaccinations could be given to those who arrived for a second vaccination and found that their original vaccine was not available. It was.

It seemed ridiculous, especially considering that neither of these protocols was evaluated in clinical trials. If they don’t work, valuable vaccines are wasted when they can’t afford it.

“I won’t make any changes unless you have good data,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. “I don’t think you can mix and match without results that show that it’s very effective and safe.”

Now, British researchers are about to do just that.

This month, a team of vaccinologists at Oxford University began recruiting around 800 people over the age of 50 for a complex study to see if vaccine switching actually works. ..

They use 8-arm clinical trials to test vaccine regimens using different combinations and intervals of the two vaccines currently being dispensed in the United Kingdom. One manufactured by Pfizer and BioNTech and the other developed by Oxford and AstraZeneca.

In the announcement of the mixed-and-match vaccine trial, Dr. Matthew Snape quoted in mice an experiment in which a combination of Pfizer and AstraZeneca vaccines boosts immunity over two doses of either alone. Perhaps it will work for humans as well.

Both vaccines stimulate the immune system to target coronavirus spelomers. It plays an important role in the infection process. However, they focus on different parts of the spike and deliver the payload in two very different ways.

AstraZeneca uses a modified cold virus to present a peer-to-peer protein to the immune system, and Pfizer passes genetic instructions to make the spike-protein and depends on human cells to produce it.

The additional COVID-19 vaccines created by Novavax and Johnson & Johnson also focus on the viral surface peplomeries, and researchers expect to add them to the trial as they progress. (J & J’s vaccine candidates are designed to be given as a single dose, but the company tests whether a second dose, given 57 days after the first dose, provides a higher level of immunity. doing).

The UK trial will announce its findings in June.

The mouse study, quoted by Snape, encouraged scientists’ belief that the combination of vaccines kicks the body’s immune system into higher gear. By fine-tuning it by various means and training it to recognize different new parts of the virus, these mismatched regimens not only produce neutralizing antibodies, but also a special called CD8 + T cells. It can stimulate the production of class immune cells.

Neutralizing antibodies produced in response to most vaccines specialize in hunting down and killing airborne viral particles that circulate in the bloodstream. Defending an army of CD8 + T cells will empower the immune system to find and kill cells that have already been infected and turned into virus copy factories. It will end the infection faster and more completely.

These T cells also have a long and concrete memory of what the SARS-CoV-2 virus looks like. In other words, if this army of immune cells is strongly mobilized, immunity can last longer.

Vaccine mixing and matching awakened these T cells in mice, but the same response has not yet been conclusively demonstrated in humans. Nor is there any study supporting scientists’ hope that a mismatched vaccine can be safely administered to millions of healthy people.

One of the potential benefits of a mismatched vaccine is that the immune system is ready to face a wider range of threats if the two jabs target different sets of proteins on the surface of the virus. This may maintain or improve vaccine immunity when new variants of the virus emerge.

The emergence of new strains in South Africa underscores the importance of having such a backup. After evidence surfaced that the variants were less susceptible to the AstraZeneca vaccine, Moderna began working on modified shots that were specially tuned to protect against it. Booster vaccine doses were sent to the National Institutes of Health for testing this week, and a new clinical trial investigates whether it enhances immunity in people already vaccinated against COVID-19. I will.

However, there are recent precedents for combining vaccines that use different media to deliver immunological payloads.

For example, a double dose of the Russian Sputnik V COVID vaccine uses two viruses to convey genetic instructions to the immune system to tell which coronavirus surface protein to look for. The first is a harmless cold virus. In the second shot, 21 days later, scientists designed another harmless cold virus to carry the cargo.

Thus, when it’s time for the second dose, the immune system can’t inadvertently attack the harmless cold virus. With the new vehicle, the genetic payload of the vaccine can glide without challenge.

The Russian Gamalaya Institute, which designed Sputnik V, took a similar approach to the first and second doses of the Ebola vaccine. Several HIV vaccines are also testing this approach.

The COVID-19 vaccine produced by Pfizer-BioNTech and Moderna uses the same mRNA “platform” that encourages cells to build harmless peplomer proteins that the immune system learns to recognize. However, the instructions are encapsulated in very different packages (which explains why the risk of a severe allergic reaction called anaphylaxis is more than four times higher with the Pfizer-BioNTech vaccine than with the Moderna vaccine. It’s possible, but both are very low).

In late January, the US Centers for Disease Control and Prevention told healthcare professionals that it could offer a second inconsistent mRNA vaccine “in exceptional circumstances where the first vaccine product could not be determined or was unavailable.” ..

However, from hepatitis B injections that begin shortly after birth to the shingles vaccine series for adults in their 50s, all multiple dose vaccines on the U.S. market are recommended to receive all vaccinations from the same manufacturer. There is a reason to be. Safety and effectiveness have been tested as an established pairing. Mix and match combos are not.

The problem of testing the safety and effectiveness of mix-and-match combinations is exacerbated by the complexity of the immune system.

“Only half of the story is known to measure,” said Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic in Rochester, Minnesota. The UK mix-and-match study measures the amount of antibodies in the bloodstream, but the actual immunity is more complex. The immunity provided by neutralizing antibodies and, for example, CD8 + cells, complement each other in a mysterious way.

“I don’t know if changing that one component will have the same effectiveness and security,” says Poland.

However, this level of attention may be a luxury that cannot be afforded in a public health emergency.

In the midst of a pandemic, natural experiments of mixing and matching may be unavoidable. Vaccine production and distribution humming always occurs, ensuring on-time access to a second dose that matches the first dose.

If you’re looking for a second shot, you may not even remember what you got in the first place. And many may be willing to take whatever they can get.

“There must be an ideal and it must be born of practice,” Poland said. “If you don’t have a clinical trial, you do the research on the spot. But you want to do the research.”

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