A primer on what we know about mixing and matching Covid vaccines

Later this week an expert committee that advises the Centers for Disease Control and Prevention will hear about the results of a clinical trial that could influence how Covid vaccines are used in this country at some point in the future. The trial, conducted by the National Institute of Allergy and Infectious Diseases, is a so-called mix-and-match trial, testing the Covid vaccines authorized in the U.S. in combinations with each other.

The goal of the trial was to see whether using a different vaccine as a booster shot improves protection. So does getting a dose of Pfizer vaccine after getting a single dose of Johnson & Johnson’s vaccine trigger production of more antibodies than a second dose of the J&J would? Are the messenger RNA vaccines made by Pfizer and Moderna virtually interchangeable, or does switching even there produce a broader set of immune responses?

This isn’t theoretical. The booster shot most vaccinated Americans are in the process of getting or booking may not be the last needed. Figuring out how to optimize use of the current generation of Covid vaccines is critical, a number of experts have told STAT.

Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy, said we need to realize that many questions remain to be answered about use of these vaccines. We don’t know the optimal dose. We don’t know the most effective interval between doses. We don’t know how many doses we’re going to need and we don’t know whether we would get more durable protection if we mix up the vaccines each person receives, he said.

In terms of how we use Covid vaccines, we’re in the very early days, Osterholm said, adding that now that we have effective vaccines, we need to start figuring out how best to use them. “We have to start adopting a public health mindset for decision making,” he said.

What follows is a primer on what we know about mixing Covid vaccines.

Let’s start with the terminology

If you get a booster jab that is of the same brand as your previous jab or jabs, you are getting a homologous booster. In the United States, most people who have been vaccinated have had homologous vaccine series and homologous boosters.

There may be some exceptions. Earlier in the vaccine rollout, when supplies were scarce, the CDC advised that people could be given a second shot of whatever vaccine was on hand if they were due for their second shot of vaccine and no supplies of the brand they were due to get were available.

If your original series of vaccines or the booster were from different manufacturers, you have what’s called a heterologous vaccine series or a heterologous boost.

A few vaccines are actually designed to capture the benefits of heterologous boosting. For instance, Johnson & Johnson’s Ebola vaccine uses two different types of vaccines — one of which is made using a similar design to the company’s Covid vaccine. Likewise, the Sputnik V vaccine is made up of two doses of similar but not identical vaccines, each made using a different adenovirus that has been modified to carry genetic material from the SARS-CoV-2 virus. In both cases, the goal was to ensure that the immune response the first dose generated didn’t prevent the second shot from taking effect.

Necessity is the mother of invention

As mentioned above, most immunized people in the United States were vaccinated with a homologous series of vaccines. But elsewhere heterologous regimens were used for a couple of different reasons.

In the early days of the vaccine rollout, some countries opted to use heterologous boosts because they didn’t have adequate supply to be able to give people a matching shot when they were due for their second dose. And after the AstraZeneca vaccine was seen to cause serious clotting problems in some people who received it (a problem later seen with the J&J vaccine too), some countries stopped using it or limited its use to older adults, for whom the risk of a clotting event after vaccination appeared to be lower. Younger adults were offered one of the mRNA vaccines as their second dose instead.

Kathryn Edwards, a vaccines researcher at Vanderbilt University, suggested the United States should probably look at whether specific brands of booster doses should be targeted at certain populations — or more specifically, if certain people should be steered away from certain vaccines when it comes time for them to get boosters. With concerns about myocarditis in young males associated with mRNA vaccines and clotting problems reported mainly with younger women who got one of the viral vectored vaccines, such as the J&J, maybe it’s time to think about who gets which type of Covid vaccine, Edwards said.

A natural experiment turns into a border barrier

Countries like the United Kingdom, Canada, France, and Germany that used heterologous vaccine approaches have created a travel conundrum for their citizens.

A number of countries — the United States among them — do not consider people who received two different brands of vaccines fully vaccinated, even if the person’s home country does. This means someone who got an mRNA vaccine as a second dose after receiving an AstraZeneca shot as a priming dose is not deemed fully vaccinated and is not eligible to travel to the U.S. or other countries with the same rule.

Canada has roughly 4 million people who were vaccinated on a heterologous schedule. The U.S. and its northern neighbor share the world’s longest border and in pre-Covid times, travel across it was brisk. Now many Canadians are in limbo, unsure if or when they will be allowed to cross into the U.S.

Figuring out how to deal with a range of vaccines used in a variety of ways around the world is going to be a challenge that the Biden administration and other governments will have to grapple with as international travel increases.

All combos may not be created equal

Is it possible that any combination of vaccine types or brands will work as well — or better — than if the shots were all of a single brand? That’s not yet clear, but it’s possible — even likely — that the combinations and the order in which the vaccines are given will matter.

“A followed by B may not be the same as B followed by A,” explained Bruce Gellin, chief of global public health strategy for the Rockefeller Foundation’s pandemic prevention institute.

A number of small studies done in Europe have shown that following up AstraZeneca’s adenovirus-vectored vaccine with a Pfizer or a Moderna mRNA booster elicits a greater immune response than what is seen from two doses of the AstraZeneca alone. But an ongoing research effort at Britain’s University of Oxford comparing Covid vaccine combinations called the Com-CoV trials suggests that the inverse may not be true.

Scientists conducting the original Com-CoV trial gave volunteers two doses apiece of either AstraZeneca or Pfizer, comparing the antibody levels those regimens elicited to AstraZeneca followed by Pfizer or Pfizer followed by AstraZeneca. Pfizer after AstraZeneca generated higher antibody levels than two doses of AstraZeneca alone; but AstraZeneca after Pfizer was not better than two doses of Pfizer.

“The priming event is really important,” said Barney Graham, who was deputy director of the National Institutes of Health’s Vaccine Research Center until the end of August and who played a critical role in the design of the Moderna and other vaccine prototypes.

Graham explained that the kind of immune response one gets from Covid vaccines is determined by the first dose. “And so it kind of locks you into a repertoire and a pattern of antibody, T-cell balances that carry on through subsequent boosters,” he said.

Much remains to be learned about how to effectively mix Covid vaccines — and it will take time to answer these questions, Graham said. “Those are the kind of things that happen over a 12-year development program. We didn’t do that this time.”

Mixed vaccines carry a punch

In general, Covid vaccines are what’s known as reactogenic; they can carry a wallop. Fevers, sore arms, fatigue, and malaise — a lot of people report feeling kind of crappy in the hours or even day or two after getting a Covid shot.

Complaints about reactogenicity were even greater among people who got mixed vaccine brands, the Com-CoV trial reported. So, potentially more post-vaccination side effects, but nothing unmanageable. “It is reassuring that all reactogenicity symptoms were short lived,” the Com-CoV researchers said in a short study published in late May in The Lancet.

The challenge ahead

If evidence continues to amass suggesting that mixing vaccine brands would be of benefit, how do those data get translated into public policy? That won’t be easy, experts warn.

Typically, regulators like the Food and Drug Administration act on requests from companies. They review data provided by a manufacturer and decide yes, this vaccine or drug can be given to these people or no, it should not be.

But when you are talking about a plan that involves combining products from two different companies, things become much more complex. None of these companies have asked to have a rival’s vaccine used as a booster for their Covid shot — and they’re not likely to.

“Normally the manufacturer puts in an application to do something,” said Glen Nowak, director of the Center for Health and Risk Communication at Grady College of Journalism and Mass Communication. “Who then has that responsibility to bring forward a recommendation to mix and match? I think it’s a very good question.”

The CDC could address the issue, said Norman Baylor, president and CEO of Biologics Consulting and a former head of the FDA’s Office of Vaccines. Its advisory panel, ACIP, could evaluate the data and, if it supports using heterologous boosts, recommend that this is the way the vaccines could be used. Such advice could take the form of what is known as preferential recommendations — effectively not saying that vaccine B must be used after vaccine A, but noting it would be advisable to do so.

Could that happen? Possibly. But if it does happen, it will likely affect the way Covid vaccines are used in the future — in people who haven’t yet started to be vaccinated, or if and when people in the country need a fourth dose of Covid vaccine. Because by the time there are enough data to move forward with this type of policy, most Americans who are currently due for a booster jab will likely have had one.