Many of us engaged in some daring mix and match during the pandemic – office attire on top, pajama pants on the bottom, for example – and we didn’t get any worse with that.
Imagine doing the same with the COVID-19 vaccines, perhaps combining a first dose of the AstraZeneca product with a second dose provided by Novavax. Will the consequences of this mixture be more severe?
It is not an idle question. Whether by accident or on purpose, some incompatible dosages are inevitable, experts say.
Two vaccines are being launched in the United States, with a third scheduled to join them next week and two more are likely to come in the coming months. All but one were designed to be administered in two-dose regimens.
Another 69 vaccines are in clinical development worldwide, and nearly two-thirds of them have been designed to generate immunity with two or more doses.
But ensuring that people get the right vaccine at the right time turned out to be a bigger logistical challenge than initially expected. Furthermore, the unexpectedly rapid emergence of threatening variants of the coronavirus has made it imperative to obtain vaccines in arms as quickly as possible.
Health officials in Britain have proposed a radical solution to both problems: postponing second doses for up to 12 weeks so that more people can get at least some protection. The government later recognized that, in exceptional circumstances, incompatible doses can be administered to people who arrive for the second dose and discover that the vaccine they originally had is not available.
It seemed absurd, especially considering that none of these protocols have been evaluated in clinical trials. If they don’t work, the precious vaccine will have been lost at a time when there is nothing left to spare.
“I wouldn’t make any changes unless you had good data,” said Dr. Anthony Fauci, director of the United States’ National Institute of Allergy and Infectious Diseases. “I don’t think you mix and match without results showing that it is very effective and safe.”
British researchers are now trying to do just that.
This month, a team of vaccinologists at the University of Oxford began recruiting 800 or more people aged 50 and over for a complex study to see if vaccine switching could really work.
Using an eight-arm clinical trial, they will test vaccine regimens using various combinations and ranges of the two vaccines currently being distributed in Britain: one made by Pfizer and BioNTech, and the other developed by Oxford and AstraZeneca.
In announcing the combined vaccine trial, Dr. Matthew Snape cited experiments in mice in which the combinations of the Pfizer and AstraZeneca vaccines increased immunity better than two doses of either vaccine alone. Maybe it worked on humans too.
Both vaccines prepare the immune system to target the coronavirus spiny protein, which plays a key role in the infection process. But they concentrate on different parts of the peak and deliver their cargo by two very different means.
AstraZeneca uses a modified cold virus to present the spike protein to the immune system, while Pfizer delivers genetic instructions for making the spike protein and relies on human cells to produce it.
The additional COVID-19 vaccines made by Novavax and Johnson & Johnson also focus on the peak proteins on the virus’s surface, and the researchers hope to add them to the assay as it progresses. (The J&J vaccine candidate was designed to be administered in a single dose, but the company is testing whether a second dose, administered 57 days after the first, would provide a higher level of immunity).
The British trial is expected to release its findings in June.
The mouse study cited by Snape encouraged scientists’ belief that the combination of vaccines will put the body’s immune system in a higher gear. By nudging it by different means and training it to recognize new and different parts of the virus, these incompatible regimes could not only generate neutralizing antibodies, but also increase 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 and killing floating viral particles as they circulate in the bloodstream. Fielding an army of CD8 + T cells would also enable the immune system to find and kill cells that have already been infected and turned into virus copy factories. This would end an infection more quickly and completely.
These T cells also have long, specific memories of the appearance of the SARS-CoV-2 virus. This means that immunity can last longer when this army of immune cells is heavily recruited.
Although mixing and matching vaccines has aroused these T cells in mice, the same response has yet to be conclusively demonstrated in humans. Nor have the studies confirmed scientists’ hope that incompatible vaccines can be safely administered to millions of healthy people.
A potential benefit of incompatible vaccines is that if the two jabs target different sets of proteins on the virus’s surface, the immune system will be prepared to face a wider range of threats. This can preserve or improve vaccine-induced immunity as new variants of the virus emerge.
The emergence of a new strain in South Africa underscored the importance of having such a reserve. After evidence emerged that the variant was less susceptible to the Astra-Zeneca vaccine, Moderna began work on a modified injection specifically to protect it. The 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 expands the immunity of people who have already been vaccinated against COVID-19.
But there are recent precedents for combining vaccines that use different vehicles to deliver their immune loads.
The two doses of the Russian 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 injection, 21 days later, the scientists created another innocuous cold virus to carry the cargo.
Thus, there is no chance that the immune system will inadvertently attack the harmless virus of the cold when it is time for the second dose. With a new tour, the genetic load of the vaccine may 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 leads cells to build harmless peak proteins that the immune system will learn to recognize. However, they wrap their instructions in very different packaging (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 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 incompatible dose of mRNA vaccine “in exceptional situations where the first dose vaccine cannot be determined or is no longer available. “.
But there is a reason why every multi-dose vaccine on the United States market – from hepatitis B vaccines that start right after birth to the herpes zoster vaccine series for adults in their 50s – comes with a recommendation for obtain all doses from the same manufacturer: their safety and effectiveness have been tested as an established match. Mix-and-match combos, no.
The problem of testing the safety and effectiveness of mixed and combined 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 combination assay will measure the amount of antibodies in the bloodstream, but real immunity is more complicated than that. The immunity produced by neutralizing antibodies and the immunity produced by, say, CD8 + cells complement each other in mysterious ways.
“If you change a component of this, you will no longer know if it has the same effectiveness and safety,” said Poland.
But that level of caution can be a luxury that we cannot afford in a public health emergency.
In the midst of a pandemic, a natural experience of matching and matching may be inevitable. Problems in the production and distribution of vaccines are about to happen, putting guaranteed access to a second dose that corresponds to the first at risk.
People looking for their second chance may not even remember what they achieved the first time. And many may be willing to do what they can.
“There is the ideal and there is the necessary support for the practice,” said Poland. “In the absence of clinical trials, you do studies dynamically. But you would like to have studies. “
This story originally appeared in the Los Angeles Times.