As more Covid-19 vaccines are authorized, scientists are exploring whether different vaccines can be safely and effectively mixed and matched, Carl Zimmer reports for the New York Times—an approach that if proven successful could not only overcome supply setbacks, but may also improve the efficacy of the vaccines.

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Ongoing trials for mixing vaccines

Scientists have long explored the concept of vaccinating people with two different vaccines for the same disease, an approach known as a heterologous prime-boost. The theory is that, because each vaccine trains the immune system to respond in slightly different ways, two different vaccines in combination may produce more robust immunity than two doses of the same vaccine.

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However, because of the logistical difficulties and expense in conducting studies of multiple vaccines that may be manufactured by different companies, the real-world efficacy of the approach has rarely been studied in clinical trials.

That changed amid the Ebola outbreak a few years ago, when researchers finally had the opportunity to conduct such resource-intensive work, Zimmer explains.

According to Zimmer, the Gamaleya Research Institute in Russia in 2017 developed a two-dose viral vector Ebola vaccine. For this kind of vaccine, an underlying virus that isn't risky to humans is modified to produce surface proteins characteristic of a dangerous virus—in this case, Ebola.

The researchers used an adenovirus for the first dose of their regimen and a vesicular stomatitis virus for the second. That approach, Zimmer writes, ensured that recipients wouldn't develop immunity to the viral vector after the first dose, which could have made the second dose ineffective; instead, both doses would be perceived as new by the immune system.

When Covid-19 hit, the researchers at Gamaleya started developing a two-dose coronavirus vaccine using a similar approach. According to Zimmer, that vaccine, known as Sputnik V, was shown to have a 91.6% efficacy in clinical trials and is being used in 57 countries.

Now, researchers at Gamaleya are partnering with AstraZeneca to determine whether one of the doses used in Sputnik V can pair with AstraZeneca's Covid-19 vaccine, which uses a chimpanzee adenovirus as its vector. According to a spokesperson for AstraZeneca, a clinical trial for the two shots is underway in Azerbaijan, while another in Russia is currently under review by the ministry of health.

And the research isn't limited to viral vector vaccines, Zimmer writes. Adam Wheatley, an immunologist at the University of Melbourne, and colleagues are testing a Covid-19 vaccine that uses various parts of the coronavirus' spike protein—as opposed to genetic instructions for the protein—in its two shots. Specifically, the vaccine involves injecting the full spike protein in the first shot and then, for the second dose, just the tip of the spike protein, known as the receptor-binding domain (RBD).

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After injecting the mixture into mice, Wheatley and his team found the mixture worked better than injecting two shots of the spike protein or two shots of the RBD, Zimmer reports. Wheatley and colleagues hypothesize that the first dose produces a wide range of antibodies that stick to various spots along the spike protein, while the second delivers a large supply of strong antibodies to the tip of the spike protein.

"You're able to basically take that initial immunity that was elicited to that spike vaccine, and then really focus it down onto that RBD," Wheatley said.

And other trials are blending two different types of vaccines, rather than variations of the same kind. For instance, in an ongoing trial called Com-Cov, researchers at the University of Oxford are testing to see if the Pfizer/BioNTech vaccine, which uses mRNA to create spike proteins, can be effectively paired with AstraZeneca's adenovirus-based vaccine, Zimmer reports.

In that trial, participants either receive the Pfizer vaccine first followed by the AstraZeneca vaccine or vice versa, and both groups will be compared with volunteers who receive the standard two-dose version of each vaccines. Later this month, researchers will use blood samples from the participants to assess their antibodies and immune system response to determine whether the mixed vaccines create an immune response as strong as the vaccines do on their own.

Why studying vaccine mixing is important

Not only could mixing vaccines reduce supply chain bottlenecks, but some experts believe two different vaccines mixed together could work better than two doses of the same vaccine, Zimmer reports.

Jakob Cramer, head of clinical development at CEPI, a vaccine development organization, said some combinations of vaccines could produce an immune response more effective than a single vaccine. "Immunologically, there are several arguments in favor of exploring heterologous priming," he said.

However, John Moore, a virologist at Weill Cornell Medicine, cautioned there's no guarantee that mixing vaccines will work, noting that researchers tried mixing viral vectors and protein boosts in the search for an HIV vaccine and never succeeded. However, the case might be different for Covid-19 vaccines, Moore said.

"I'd like to see these studies done," he said. "Doing it in the Covid space is completely rational, but may not be necessary."

Getting vaccine manufacturers to work together on clinical trials could also present a challenge, Zimmer reports, especially as the number of authorized vaccines grow and more companies get involved. "You're requiring quite large pharmaceutical companies to play nice together," Wheatley said.

But Bernard Moss, a virologist at the National Institute of Allergy and Infectious Diseases, said he believes many drugmakers will be willing to work together on mixing Covid-19 vaccines. "It's always better to be a part of something that is going to be used than to wholly own something that isn't," he said (Zimmer, New York Times, 3/30).