Because of unpredictable supply and some concerns about an exceedingly rare but serious clotting risk from the
vaccine, public health officials in some parts of the world that have relied heavily on that shot have recently issued new guidance on mixing and matching different Covid-19 vaccines.
Recently, for example, Canada’s National Advisory Committee on Immunization updated its guidance to say that people who received the AstraZeneca vaccine as their first dose can receive that same vaccine as their second dose or get a follow-up shot of Pfizer-BioNTech or Moderna instead. The committee also said that it was possible to receive the Pfizer-BioNTech and Moderna vaccines interchangeably as first and second doses. Countries ranging from France to Finland to China to Bahrain have also outlined possible scenarios for combining different vaccines. Even the Centers for Disease Control and Prevention has interim guidance saying this is acceptable in “exceptional situations,” such as if the same vaccine is not available.
While this guidance may seem confusing, especially when the initial vaccine guidance told people to get the same shot for both doses, it does provide an opportunity to understand the safety of using mismatched vaccines, and to measure whether mismatched vaccines offer any advantage.
One recent small and not yet peer-reviewed study of 26 people who received the AstraZeneca shot followed by one from Pfizer-BioNTech suggested, based on blood tests, that those with mismatched vaccines had at least as strong an immune response as people who got both Pfizer shots. The National Institutes of Health recently began a clinical trial that will examine the effects of different combinations of Covid-19 vaccines.
In Britain, a trial of this kind is already underway for the AstraZeneca and Pfizer-BioNTech vaccines, and the scientists behind it have released early data on side effects. They found more reports of feverishness, chills, fatigue and headache among people who received a dose that was different from their original shot compared with people who received identical shots. Scientists want to know whether that indicates that the immune system was more stimulated by the different vaccine, and could develop added protection. It’s still too soon to say, but more results from the trial are expected this month.
This is not the first time scientists have investigated what seems like an unconventional way of vaccine dosing, and it’s not necessarily something to fear. It may be our best hope against certain pathogens.
In the last two decades, as new vaccine technologies have emerged, the idea of using different kinds of vaccines against the same pathogen has gained momentum. The approach — known among scientists as “heterologous prime-boost” — has been explored in rodent experiments to develop vaccines against Ebola (now authorized for use by European regulators), tuberculosis and even cancers associated with the Epstein-Barr virus. Mouse experiments of this approach have even been tested for other coronaviruses in the past, such as the original SARS virus and the coronavirus that causes Middle East Respiratory Syndrome.
More recently, in March 2021, scientists in China published a study in mice that looked at different combinations of four different kinds of Covid-19 vaccines, including one made from mRNA and one viral vector vaccine, which — like the AstraZeneca and Johnson & Johnson coronavirus vaccines — uses an inactivated cold virus to trigger an immune response to Covid.
Why mix-and-match at all? Part of the thinking among scientists is that by administering different vaccines that expose the immune system to different parts of a pathogen, one after the other, the body becomes trained to recognize different parts of the invader and becomes more effective at defending against it.
Another line of reasoning is that using different kinds of vaccines jump-starts different elements of the immune system. Viral vector vaccines, for example, are well-equipped to stimulate a part of the immune response that helps generate an army of what are called “killer T cells” to protect the body against an invading virus. Other kinds of vaccines are thought to skew more heavily toward prompting the creation of antibodies to combat the virus. Both immune system responses are helpful, and scientists’ theory is that combining them could be more potent than either of them alone.
One area where the mix-and-match approach stirs the most hope is in the fight against H.I.V., where vaccine researchers have been investigating it for decades. In what might have been the first human trial of this method, the immunologist Dr. Daniel Zagury of the Pierre and Marie Curie University in Paris received two different experimental H.I.V. shots in 1987. First, a version of a virus that was engineered to produce an H.I.V. protein in the body, and later booster shots of the protein directly (rather than the engineered virus). Dr. Zagury and his colleagues reported that his immune system showed signs of responding, including producing antibodies.
Although attempts at making a successful H.I.V. vaccine have faltered since then, there is still enthusiasm for the mix-and-match approach. A trial called RV144, done more than a decade ago, followed the mix-and-match approach and was the only H.IV. vaccine trial to ever show protection against the virus among a handful of other experimental H.I.V. vaccines. More trials of this kind are underway, and the hope is that finding the right pairing of vaccines will prove successful.
It’s clear that many Covid-19 vaccines are mightily effective on their own and don’t need to be paired with other versions. But scientists should keep a close eye on the results of the mix-and-match trials underway to see if large, well-controlled studies show any signal of better protection.
The findings could inform vaccine development for other pathogens. This is especially true for viruses that mutate even more rapidly than SARS-CoV-2, like H.I.V. In an era of multiplying vaccine technologies, it might be the case that vaccines, like people, prove more effective when they work together.