As more COVID-19 vaccines become available, researchers are testing the impact of pairing different products that require two injections.
Beata Zawrzel / NurPhoto via Getty Images
By Jon Cohen
Science‘s COVID-19 reports are supported by the Heising-Simons Foundation.
With nine vaccines showing that they can prevent serious illness and death from COVID-19 – and missing vaccines – researchers are reflecting on an issue that, even a few months ago, was only hypothetical: people should mix and match vaccines that require two shots ?
If some combinations work, they can provide the necessary flexibility whenever vaccine production fails, as it usually does. And there is even a chance that mixing doses of two different vaccines could increase protection against COVID-19.
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A mixed vaccine trial is already underway: it is examining the combination of a dose of the Sputnik V vaccine produced by the Russian Epidemiology and Microbiology Research Institute, Gamaleya, with a booster dose of a similar vaccine made by AstraZeneca and the University from Oxford. A second trial, examining a combination of the AstraZeneca-Oxford and Pfizer-BioNTech vaccines, which mixes two different technologies, is just beginning, and others are under discussion.
Until these tests yield results, however, health officials are asking for caution. The United States Centers for Disease Control and Prevention discouraged people from mixing vaccines, unless there are “exceptional situations”, such as the shortage of the vaccine they received first due to production or distribution problems. In the United Kingdom, Public Health England took a similar position.
But the scarcity of COVID-19 vaccines – and the urgency to increase vaccination rates – is pushing the issue of combination and combination to the forefront. “As we have more products that are interchangeable, this will have major implications for conducting this mass vaccination campaign in an environment of uncertain supplies,” said Bruce Gellin, who directs global immunization for the nonprofit Sabin Vaccine Institute.
“There are definite advantages to having data that could support a more flexible immunization program, if needed and if approved by the drug regulator,” said Jonathan Van-Tam, UK deputy medical director, when announcing the trial combining AstraZeneca- Oxford and Pfizer-BioNTech vaccines.
The researchers have previous experience with combined vaccine trials. For more than 20 years, the HIV vaccine field, which has been struggling for a long time, has tried to combine different vaccine strategies to obtain more powerful immune responses, but none has been successful. Johnson & Johnson brought an Ebola vaccine to the European Union market that combines its preparation with one that uses a completely different formulation from Bavarian Nordic. Similarly, to trigger more robust protection in the elderly, an injection of a pneumococcal conjugate vaccine is reinforced by one that contains a pneumococcal polysaccharide. The inactivated polio vaccine, for safety reasons, was also administered before a vaccine made with live attenuated virus, which can sometimes cause the disease if the virus mutates. But there are few other examples of using two vaccines approved for the market in a double blow.
Mixing and matching COVID-19 vaccines raises several potential complications. One is regulatory: what if, say, only one is authorized for emergency use? Another is immunological: while some vaccines share the same underlying technology platforms – such as the messenger RNA technology used by the Pfizer-BioNTech and Moderna collaboration – others do not.
On the other hand, different platforms can activate different arms of the immune system. And the pairing of corresponding platforms can prevent unwanted immune responses. For example, the Gamaleya Sputnik V vaccine and the AstraZeneca-Oxford vaccine employ different adenovirus (Ad) vectors to deliver a key gene to human cells. Both require an initial shot followed by a reinforcement. The Lancet published efficacy data for each vaccine and received emergency use authorizations in several countries.
Gamaleya uses two different Ad vectors that contain the spike gene for its initiation and boost shots: Ad26 followed by Ad5. AstraZeneca and Oxford use the same chimpanzee adenovirus (ChAd) for both their primer and reinforcement. In theory, AstraZeneca’s use of the same vector for both injections means that the immune response triggered by the first injection can paralyze the booster. This potential problem could be avoided by combining the AstraZeneca injection with that of Sputnik V, probably in any order.
Gamaleya, in turn, could benefit from using the AstraZeneca-Oxford vaccine as a booster because the institute, according to a Bloomberg report, had trouble making the Ad5 vector. (Sputnik V representatives said Science they did not comment on the Bloomberg report, but said delays in supply to Latin America could occur as they update manufacturing facilities.) And many researchers criticized Gamaleya for choosing Ad5 because of disastrous testing in 2007 with a vaccine against Ad5-based HIV that somehow increased the risk of infection with the AIDS virus. Therefore, an Ad26-ChAd combination circumvents this concern.
Funders of Sputnik V also contacted CanSino Biologics, a Chinese company that makes a peak Ad5 vaccine that is used in a single injection, to discuss the pairing of their vaccines, said CEO Yu Xuefeng Science. But they have not yet negotiated a deal. CanSino has reported no efficacy data. (A health advisor to the Pakistani Prime Minister on February 8 tweeted that the CanSino candidate worked on a test there and in other countries. Yu said he could not confirm the report because the company did not see the data, but believes that are needed. )
The UK National Immunization Program Evaluation Consortium is moving forward with an elaborate combination study of the AstraZeneca-Oxford and Pfizer-BioNTech vaccines. It has eight different strategies that will involve administering the vaccines in different orders and at different intervals. Van-Tam hopes the test will produce “a broader view on how we can use vaccines to stay in control of this unpleasant disease”.
Gellin, for example, is frustrated that more mixed and combined tests are still not working. “It must be a priority for someone,” he says. But Gellin admits that regulatory issues are frightening. “This is something that companies should do and maybe they can do it,” he says. “But they will probably require more lawyers than volunteers.”