Many of us undertook some daring mix-and-match during the pandemic – office clothes on top, for example a pair of pajama bottoms at the bottom – and there was nothing worse than that.
Imagine doing the same with COVID-19 vaccines, and perhaps linking a first dose of the AstraZeneca product to a second dose provided by Novavax. Will the consequences of such mixing be any greater?
This is hardly an idle question. According to experts, it is accidental or design, inevitable.
Two vaccines are currently being rolled out in the United States, and a third is expected to join next week and two more are likely to arrive in the coming months. All but one are designed to deliver as two-dose regimens.
Another 69 vaccines are in clinical development around the world, and nearly two-thirds of them are designed to bring about immunity with two or more doses.
But making sure people get the right vaccine at the right time seems to be a bigger logistical challenge than initially expected. What’s more, the unexpectedly rapid emergence of looming coronavirus variants has made it necessary to get shots in the arms as quickly as possible.
Health officials in the UK have proposed a radical solution to both problems: postponing the second doses to 12 weeks so that more people can get at least some protection. Later, the government acknowledged that in exceptional circumstances, people arriving for their second dose could not give corresponding doses and discovered that the vaccine they had originally had was not available.
This seems ridiculous, especially considering that none of these protocols have been evaluated in clinical trials. If they do not work, the precious vaccine will be wasted at a time when there is nothing to spare.
“I will not change anything if you have good data,” says dr. Anthony Fauci, director of the American National Institute of Allergy and Infectious Diseases. “I do not think you mix and match without the results being very effective and safe.”
Now British researchers are trying to do just that.
This month, a team of vaccinators from Oxford University began recruiting 800 people aged around 50 or older for a complex study to see if vaccine switching could work.
Using an eight-arm clinical trial, they will test the vaccines using different combinations and intervals of the two vaccines currently being distributed in the UK: one made by Pfizer and BioNTech, and one developed by Oxford and AstraZeneca. .
In announcing the mix-and-match vaccine trial, dr. Matthew Snape experiments cited in mice in which combinations of the Pfizer and AstraZeneca vaccines promote immunity better than two doses of one alone. Maybe it will work with people too.
Both vaccines direct the immune system to target the coronavirus’ ear protein, which plays an important role in the infection process. But they come in at different parts of the peak, and they deliver their payloads in two different ways.
The AstraZeneca one uses a modified cold virus to present the ear protein in the immune system, while the Pfizer hands over genetic instructions to make the ear protein and relies on human cells to produce it.
Additional COVID-19 vaccines made by Novavax and Johnson & Johnson also focus on the peak proteins on the virus’ surface, and researchers expect to add them to the trial as it continues. (J & J’s vaccine candidate is designed to be administered as a single dose, but the company is testing whether a second dose, delivered 57 days after the first, will provide a higher level of immunity).
The British trial is expected to announce its findings in June.
The mouse study cited by Snape encouraged scientists’ belief that the combination of vaccines would kick the body’s immune system into a higher gear. By pushing it in different ways and training it to recognize new and different parts of the virus, these mismatched regimens could not only generate neutralizing antibodies, but also increase the production of a special immune cell called CD8 + T cells.
The neutralizing antibodies produced in response to most vaccines specialize in hunting and killing free-floating viral particles while circulating in the bloodstream. If you also deploy an army of CD8 + T cells, it will enable the immune system to find and kill already infected cells and convert them into virus copiers. This would terminate an infection faster and more completely.
These T cells also have long and specific memories of what the SARS-CoV-2 virus looks like. This means that immunity can last longer if these host immune cells are used heavily.
Although the mixing and corresponding vaccines have awakened these T cells in mice, the same reaction has not yet been unequivocally shown in humans. There are also no studies that have confirmed the hope of scientists that millions of healthy people can safely fit with vaccines.
A potential advantage of non-matching vaccines is that the immune system is willing to face a wider range of threats if the two samples target different sets of proteins. It can preserve or enhance the immunity induced as new variants of the virus emerge.
The emergence of a new tension in South Africa emphasized the importance of such a backup. After evidence surfaced that the variant was less susceptible to the Astra-Zeneca vaccination, Moderna began work on a modified shot specifically adapted to protect against it. The doses of the scheme vaccine were sent to the National Institutes of Health this week for testing, and a new clinical trial will investigate whether it increases the immunity of people who have already been vaccinated against COVID-19.
But there is recent precedent for the combination of vaccines that different vehicles use to deliver their immunological charge.
The two doses of Russian Sputnik V COVID vaccine, for example, use two types of viruses to carry the genetic instructions that tell the immune system what the coronavirus proteins need to look for. The first is a harmless cold virus. For the second shot, which comes 21 days later, scientists have designed another harmless cold virus to transport the cargo.
This way, there is no chance that the immune system will accidentally attack the harmless cold virus when it’s time for the second dose. With a new ride, the genetic wage of the vaccine could slip undisputedly.
The Russian Gamaleya Research Institute, which designed Sputnik V, followed 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 manufactured by Pfizer-BioNTech and Moderna use the same mRNA “platform” that asks cells to construct harmless ear proteins that will recognize the immune system. However, they contain their instructions in 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 the Moderna reaction, although both are very low). ).
At the end of January, the U.S. Centers for Disease Control and Prevention told medical professionals that they could offer a maladaptive second-dose mRNA vaccine “in exceptional situations where the first-dose vaccine product could not be determined or was no longer available.”
But there is a reason for every multi-dose vaccine on the US market – from the hepatitis B shots that start just after birth to the shingles vaccine range for adults in their 50s – to come up with a recommendation for all doses of to get the same manufacturer: their safety and effectiveness have been tested as an established pairing. Do not mix-and-match combinations.
The problem with testing the safety and effectiveness of mix-and-match combinations is exacerbated by the complexity of the immune system.
“What we know to measure is only half the story,” said Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic in Rochester, Minn., Said. The UK mix-and-match test will measure the amount of antibodies in the bloodstream, but real immunity is more complicated than that. Immunity induced by neutralization of antibodies and immunity induced by CD8 + cells complement each other in mysterious ways.
“If you change one component of it, you no longer know if you have the same efficiency and safety,” Poland said.
But this level of caution can be a luxury we cannot afford in an emergency for public health.
In the midst of a pandemic, a natural experiment in mixing and adaptation may be inevitable. Problems in the production and distribution of vaccines are likely to occur, impeding the guaranteed timely access to a second dose corresponding to the first.
People looking for their second shot may not even remember what they first got. And many may be willing to take whatever they can get.
“There is the ideal and there are the necessary practical things,” Poland said. ‘Absent clinical trials do you fleeting. But you want to study. ”
This story originally appeared in the Los Angeles Times.