Scientists take COVID-19 vaccine mixing and pairing seriously

Many of us engaged in daring mixes during the pandemic – office attire on top, pajama pants on bottom, for example – and it hasn’t been worse.

Imagine doing the same with COVID-19 vaccines, perhaps combining a first dose of the AstraZeneca product with a second dose provided by Novavax. Will the consequences of such a mixture be more serious?

This is not an idle question. Whether by accident or by design, inadequate dosage is inevitable, experts say.

Two vaccines are currently being rolled out in the United States, a third is expected to join them next week, and two more are expected to be available in the coming months. All but one were designed to be given as two dose schedules.

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

But making sure people get the right vaccine at the right time has turned out to be a bigger logistical challenge than initially anticipated. In addition, the unexpectedly rapid emergence of threatening variants of the coronavirus has made it imperative to receive shots in the arms as quickly as possible.

Health officials in Britain have come up with a drastic solution to both of these problems: delaying second doses for up to 12 weeks so more people can get at least some protection. The government later acknowledged that in exceptional circumstances, inadequate doses may be given to people who arrive for their second dose and find that the vaccine they originally had is not available.

It seemed absurd, especially since none of these protocols have been evaluated in clinical trials. If they don’t work, the precious vaccine will have been wasted at a time when there is none to spare.

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

Now British researchers are trying to do just that.

This month, a team of vaccinologists from the University of Oxford began recruiting around 800 people aged 50 or older for a complex study to determine whether the vaccine change might actually work.

Using an eight-arm clinical trial, they will test vaccine regimens using various combinations and ranges of the two vaccines currently distributed in Britain: one made by Pfizer and BioNTech and another developed by Oxford and AstraZeneca .

In announcing the mix-and-match vaccine trial, Dr Matthew Snape cited experiments in mice in which combinations of the Pfizer and AstraZeneca vaccines boosted immunity better than two doses of either. alone. Maybe it would work in humans too.

Both vaccines prime the immune system to target the coronavirus spike protein, which is instrumental in the infection process. But they focus on different parts of the tip, and they deliver their payloads in two very different ways.

AstraZeneca’s uses a modified cold virus to present the spike protein to the immune system, while Pfizer’s transmits genetic instructions to make the spike protein and relies on human cells to make it.

Additional COVID-19 vaccines made by Novavax and Johnson & Johnson also focus on advanced proteins on the virus’s surface, and researchers expect to add them to the trial as it unfolds. . (J & J’s vaccine candidate is designed to be given as a single dose, but the company is testing whether a second dose, given 57 days after the first, would provide a higher level of immunity).

The UK trial is expected to release its findings in June.

This mouse study cited by Snape encouraged scientists to believe that the combination of vaccines will boost the body’s immune system to a higher speed. By pushing it through different means and training it to recognize new and different fragments of the virus, these maladaptive patterns could not only generate neutralizing antibodies, but stimulate the production of a specialized class of immune cells called CD8 + T cells. .

The neutralizing antibodies that are produced in response to most vaccines specialize in tracking down and destroying free-floating viral particles as they circulate in the bloodstream. Deploying an army of CD8 + T cells would also allow the immune system to find and kill cells that have already been infected and turned into virus copy factories. This would end an infection faster and more completely.

These T cells also have long, specific memories of what the SARS-CoV-2 virus looks like. This means that immunity can last longer when this army of immune cells is highly recruited.

Although mixing and pairing of vaccines awakened these T cells in mice, the same response has not yet been conclusively demonstrated in humans. The studies also did not support scientists’ hope that the wrong vaccines could be given safely to millions of healthy people.

One of the potential benefits of incompatible vaccines is that if the two injections target different sets of proteins on the surface of the virus, the immune system would be prepared to deal with a wider range of threats. This could preserve or improve the immunity induced by the vaccine as new variants of the virus appear.

The emergence of a new strain in South Africa underscored the importance of having such a backup. After evidence surfaced that the variant was less susceptible to Astra-Zeneca’s vaccine, Moderna began work on a modified shot specifically designed to protect against it. Doses of the booster vaccine were sent to the National Institutes of Health for testing this week, and a new clinical trial will explore whether it extends the immunity of people who have already been vaccinated against COVID-19.

But there is recent precedent for combining vaccines that use different vehicles to deliver their immunological payloads.

The two doses of the Russian Sputnik V COVID vaccine, for example, use two types of viruses to carry genetic instructions that tell the immune system which coronavirus surface proteins to look for. The first is a harmless cold virus. For the second shot, 21 days later, scientists engineered another harmless cold virus to carry the cargo.

This way there is no chance that the immune system will inadvertently attack the harmless cold virus by the time of the second dose. With a new spin, the genetic payload of the vaccine can unmistakably escape.

Russia’s Gamaleya Research Institute, which designed Sputnik V, took a similar approach to formulating the first and second doses of its Ebola vaccine. Several experimental HIV vaccines are also testing this approach.

The COVID-19 vaccines made by Pfizer-BioNTech and Moderna use the same mRNA “platform” that prompts cells to build harmless spike proteins that the immune system will learn to recognize. However, they encapsulate their instructions in very different packages (which may explain why the risk of a serious allergic reaction called anaphylaxis is more than four times higher for the Pfizer-BioNTech vaccine than for the Moderna vaccine, although both are extremely low).

At the end of January, the US Centers for Disease Control & Prevention told healthcare professionals that they could offer a second dose of unpaired mRNA vaccine “in exceptional situations where the first dose vaccine cannot. not be determined or no longer available ”.

But there’s a reason every multidose vaccine on the U.S. market – from hepatitis B vaccines that start right after birth to the shingles vaccine series for adults in their 50s – comes with a recommendation. aiming to obtain all doses from the same manufacturer: Their safety and efficacy have been tested as an established association. The mix-and-match combos don’t.

The problem with testing the safety and efficacy of mix-and-match combinations is compounded by the complexity of the immune system.

“What we know how to measure is only half the story,” said Dr. Gregory Poland, vaccine researcher at the Mayo Clinic in Rochester, Minnesota. The UK mix-and-match trial will measure the amount of antibodies in the bloodstream, but actual immunity is more complicated than that. The immunity elicited by neutralizing antibodies and the immunity elicited, for example, by CD8 + cells complement each other in mysterious ways.

“If you change a component of that, you just don’t know if you have the same efficiency and safety,” Poland said.

But that level of caution can be a luxury we can’t afford in a public health emergency.

In the midst of a pandemic, a natural experience of mixing and pairing can be inevitable. Difficulties in vaccine production and distribution are inevitable, jeopardizing guaranteed timely access to a second dose that matches the first.

People looking for their second shot may not even remember what they got the first time around. And many may be willing to take whatever they can get.

“There is the ideal and there is the necessary born of practice,” Poland said. “In the absence of clinical trials, you are doing studies on the fly. But you would like to have studies. “