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Scientists are serious about mixing and matching COVID-19 vaccines



During the pandemic, many of us did some bold mashups. For example, we wore office attire and pajamas underneath, and the situation was not bad.

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

This is hardly a complicated problem. Experts say that no matter by accident or by design, there will inevitably be a dose mismatch.

Currently, two vaccines are being promoted across the United States, and the third vaccine is expected to be added next week, and the other two may be available in the next few months. With the exception of one drug, all drugs are designed to be administered on a two-dose schedule.

There are also 69 vaccines in clinical development worldwide, and nearly two-thirds of them are designed to produce two or more doses of immunity.

However, to ensure that people get the right vaccine at the right time, the logistics challenge is greater than originally anticipated. Moreover, the unexpected and rapid emergence of threatening coronavirus variants is imperative and must be shot down as soon as possible.

British health officials have proposed a fundamental solution to these two problems: delay the second dose of the drug for up to 1

2 weeks so that more people can get at least some protection. Later, the government admitted that under special circumstances, people who arrived at the second dose might find a mismatched dose, and found that the vaccine they had originally had was unavailable.

It seems ridiculous, especially considering that none of these options have been evaluated in clinical trials. If they do not work, then precious vaccines will be wasted when there is no room left.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said: “Unless I have enough data, I will not make any changes.” “I think there are no results that show that it is very effective and safe. , You will not mix and match.”

Now British researchers are trying to do this.

This month, a team of vaccinologists from the University of Oxford began recruiting about 800 people aged 50 or over to conduct complex studies to see if the vaccine switch is really effective.

They will use eight-arm clinical trials to test vaccine protocols using various combinations and intervals of two vaccines currently distributed in the UK: one manufactured by Pfizer and BioNTech, and the other developed by Oxford and AstraZeneca.

A researcher studied the coronavirus vaccine developed by AstraZeneca and Oxford University.

A researcher studied the coronavirus vaccine developed by AstraZeneca and Oxford University.

(John Keynes/University of Oxford, via The Associated Press)

When announcing the mixed-and-match vaccine trial, Dr. Matthew Snape cited experiments conducted in mice, in which the combination of Pfizer and AstraZeneca vaccines is more effective in enhancing immunity than using two doses alone. . Maybe it will also be effective for humans.

Both vaccines allow the immune system to target the spike protein of the coronavirus, thus playing an important role in the infection process. But they reside in different parts of the peak, and they deliver the payload in two distinct ways.

AstraZeneca uses a modified cold virus to present the spike protein to the immune system, while Pfizer passes the genetic instructions to the production of the spike protein and relies on human cells to produce it.

Novavax and other COVID-19 vaccines produced by Johnson & Johnson also focus on the spike protein on the surface of the virus, and the researchers hope to add it to the trial as they proceed. (J&J’s vaccine candidate is designed to be administered as a single dose, but the company is testing whether the second dose delivered 57 days after the first dose will provide higher immunity).

The British trial is expected to announce its findings in June.

The mouse study cited by Snape encouraged scientists to believe that a combination of vaccines would make the body’s immune system more effective. By tapping it in different ways and training it to recognize new and different viral fragments, these mismatched schemes can not only produce neutralizing antibodies, but also promote the production of a special type of immune cell called CD8 + T cells .

The neutralizing antibodies produced in response to most vaccines are specifically designed to hunt down and kill free-floating virus particles circulating in the blood. Deploying an army of CD8 + T cells will also enable the immune system to detect and kill cells that have been infected and become virus replication factories. This can end the infection faster and more thoroughly.

These T cells also have the long and specific memory of the SARS-CoV-2 virus. This means that when a large number of these immune cells are absorbed, the immunity may last longer.

Atomic resolution 3-D model of SARS-CoV-2 coronavirus.

The atomic resolution 3-D model of the SARS-CoV-2 coronavirus is surrounded by antibodies that try to bind to the spike protein and prevent the virus from docking with the cell.

(Visual Science)

Although mixed and paired vaccines awakened these T cells in mice, the same response has not yet been finally confirmed in humans. There is also no research to prove that scientists hope that mismatched vaccines can be safely vaccinated among millions of healthy people.

The potential benefit of a mismatched vaccine is that if the two needles target different protein groups on the surface of the virus, the immune system will be prepared to face a wider range of threats. With the emergence of new variants of the virus, this may preserve or improve vaccine-induced immunity.

A new virus has emerged in South Africa, which highlights the importance of such backups. After there was evidence that the variant was not very sensitive to AstraZeneca’s vaccine, Moderna began to develop an improved vaccine specifically designed for this variant. The dose of the booster vaccine was sent to the National Institutes of Health for testing this week, and a new clinical trial will explore whether the vaccine can expand the immunity of people who have been vaccinated against COVID-19.

However, there are recent precedents of vaccines that combine different vehicles to deliver their immune payloads.

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

In this way, the immune system will not inadvertently attack the harmless cold virus during the second injection. With new experience, the genetic payload of the vaccine can slip off without challenge.

The Gamaleya Institute in Russia, which designed Sputnik V, used a similar method to formulate its first and second doses of Ebola vaccine. Several experimental HIV vaccines are also testing this method.

The COVID-19 vaccines produced by Pfizer-BioNTech and Moderna use the same mRNA “platform” to encourage cells to build harmless spike proteins that the immune system will learn to recognize. However, they will state that they are packaged in very different packaging (this may explain why the risk of severe allergic reactions (called allergic reactions) with the Pfizer-BioNTech vaccine is more than four times higher than that of the Moderna vaccine, although both are very low).

In late January, the US Centers for Disease Control and Prevention told medical experts that they might provide a second dose of a mismatched mRNA vaccine, “under special circumstances where the first dose of vaccine product cannot be determined or is no longer available.”

However, every multi-dose vaccine on the US market has a reason. From the hepatitis B vaccine just after birth to the series of adult shingles vaccines in their 50s, it is recommended to obtain all doses from the same manufacturer. Vaccines: Their safety efficacy has been tested as an established pair. No mix and match combos.

The complexity of the immune system exacerbates the problem of testing the safety and effectiveness of mixed-match combinations.

Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic in Rochester, Minnesota, said: “What we want to measure is only half of the story.” The UK mix and match test will measure the amount of antibodies in the blood, but the actual immunity is complicated. many. The immunity produced by neutralizing antibodies and the immunity produced by CD8 + cells complement each other in mysterious ways.

Poland said: “If you change one of the components, you will no longer know whether you have the same efficacy and safety.”

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

Seniors waiting in line for COVID-19 vaccine

Elderly people are waiting in line at the Balboa Stadium in Encino for an appointment to get the CovID-19 vaccine.

(Melmelkang/Los Angeles Times)

In a pandemic, natural experiments of mixing and matching are inevitable. The rant during the production and sales of the vaccine is bound to occur, which will result in no guarantee that he will receive a second dose that matches his first dose on time.

The person looking for the second shot may not even remember what they encountered the first time. And many people may be happy to accept everything they can get.

Poland said: “Practice is both ideal and necessary.” “Without clinical trials, you can conduct research immediately. But you want to learn.”

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