Scientists take COVID-19 vaccine mix-and-match seriously


A dose of the COVID-19 vaccine manufactured by Pfizer and BioNTech is prepared at the Royal Victoria Infirmary in Newcastle, England. (Owen Humphreys / Pool via Associated Press)

Many of us have engaged in some bold combinations during the pandemic (office attire on top, pajama bottoms, for example) and we haven’t been worse.

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

It is not a useless question. Whether by accident or by design, improper dosing is inevitable, experts say.

Two vaccines are currently being rolled out in the United States, with a third expected to join them next week with two more likely to arrive in the coming months. All but one were designed to be administered as two-dose regimens.

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

But ensuring that people receive the right vaccine at the right time has proven to be a greater logistical challenge than initially expected. What’s more, the unexpectedly rapid emergence of threatening coronavirus variants has made it imperative to shoot arms as quickly as possible.

Britain’s health officials proposed a radical solution to both problems: delay second doses for up to 12 weeks so that more people could get at least some protection. The government later acknowledged that, in exceptional circumstances, mismatched doses can be given to people who arrive for their second dose and find that the vaccine they originally had is not available.

It seemed ridiculous, especially considering that none of these protocols were tested in clinical trials. If they don’t work, the precious vaccine will be wasted at a time when there is nothing to spare.

“I wouldn’t make any changes unless I have good data,” said Dr. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases. 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 800 people aged 50 and over for a complex study to see if the vaccine switch could really work.

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

A researcher works on the coronavirus vaccine developed by AstraZeneca and the University of Oxford.

A researcher works on the coronavirus vaccine developed by AstraZeneca and the University of Oxford. (John Cairns / University of Oxford via Associated Press)

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

Both vaccines prepare the immune system to attack the coronavirus spike protein, which plays a critical role in the infection process. But they focus on different parts of the peak and deliver their payloads by two very different means.

The AstraZeneca uses a modified cold virus to present the spike protein to the immune system, while the Pfizer provides genetic instructions for producing the spike protein and relies on human cells to produce it.

Additional COVID-19 vaccines made by Novavax and Johnson & Johnson also target the spike proteins on the surface of the virus, and the researchers hope to add them to the trial as it progresses. (J & J’s candidate vaccine 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 British trial is expected to publish its findings in June.

That mouse study cited by Snape has encouraged scientists to believe that combining vaccines will boost the body’s immune system. By pushing it through different mediums and training it to recognize new and different parts of the virus, these incompatible regimens could not only generate neutralizing antibodies, but also boost 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 hunting down and killing free-floating viral particles as they circulate in the bloodstream. The deployment of 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. That would kill an infection more quickly and completely.

These T cells also have long and specific memories of what the SARS-CoV-2 virus looks like. That means immunity could last longer when this army of immune cells is strongly recruited.

An atomic resolution three-dimensional model of the SARS-CoV-2 coronavirus.

An atomic resolution three-dimensional model of the SARS-CoV-2 coronavirus, surrounded by antibodies that try to bind to spike proteins and prevent the virus from attaching to a cell. (Visual science)

Although the combination and combination of vaccines aroused these T cells in mice, the same response has not yet been conclusively demonstrated in humans. Studies have also not confirmed scientists’ hope that mismatched vaccines can be safely administered to millions of healthy people.

One potential benefit of mismatched vaccines is that if the two jabs target different sets of proteins on the surface of the virus, the immune system would be primed to face a wider range of threats. That could preserve or enhance vaccine-induced immunity as new variants of the virus emerge.

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

But there is a recent precedent for combining vaccines using different vehicles to deliver their immune payloads.

The two doses of Russia’s Sputnik V COVID vaccine, for example, use two types of viruses to carry the 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 that comes 21 days later, scientists engineered another harmless cold virus to carry the load.

In this way, there is no chance that the immune system will inadvertently attack the harmless cold virus when it is time for the second dose. With a new trip, the genetic load of the vaccine can go unnoticed.

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 drives 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 severe allergic reaction called anaphylaxis is more than four times higher for the Pfizer-BioNTech vaccine than for the Moderna, although both are extremely low).

In late January, the US Centers for Disease Control and Prevention told medical professionals that they could offer a second dose of mismatched mRNA vaccine “in rare situations where the vaccine product from first dose cannot be determined or is no longer available. “

But there is a reason why all multidose vaccines on the U.S. market, from hepatitis B vaccines that start right after birth to the herpes zoster vaccine series for adults over 50, come with a recommendation to get all doses from the same manufacturer – safety and efficacy have been tested as an established combination. Mix and match combos have not.

The problem of proving 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, a vaccine researcher at the Mayo Clinic in Rochester, Minnesota. The British mix-and-match assay will measure the amount of antibodies in the bloodstream, but actual immunity is more complicated than that. Immunity elicited by neutralizing antibodies and immunity elicited, for example, by CD8 + cells complement each other in mysterious ways.

“If you modify a component of that, you no longer know if it has the same efficacy and safety,” Poland said.

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

Older adults wait in a long line to receive the COVID-19 vaccine

Seniors wait in line for appointments to receive a dose of the COVID-19 vaccine at the Balboa Sports Complex in Encino. (Mel Melcon / Los Angeles Times)

In the midst of a pandemic, a natural mix-and-match experiment may be unavoidable. Problems are likely to occur in vaccine production and distribution, jeopardizing guaranteed timely access to a second dose to match the first.

People looking for their second chance may not even remember what they got the first time. And many may be willing to take all they can.

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

This story originally appeared in the Los Angeles Times.

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