Could mixing COVID vaccines boost immune response?

Researchers in the United Kingdom have launched a study that will mix and match two COVID-19 vaccines in a bid to ease the daunting logistics of immunizing millions of people — and potentially boost immune responses in the process.

Most coronavirus vaccines are given as two injections: an initial ‘prime’ dose followed by a ‘boost’ to stimulate the immune system’s memory cells and amplify the immune response. The clinical trial will test participants’ immune responses to receiving one shot of a coronavirus vaccine produced by Oxford and drug firm AstraZeneca — which uses a harmless virus to carry a key coronavirus gene into cells — and one shot of the vaccine produced by drug company Pfizer, which uses RNA instructions to trigger an immune response. The trial, which is run by investigators at the University of Oxford, aims to begin enrolment on 4 February.

Vaccine developers often combine two vaccines to combat the same pathogen, and researchers are keen to deploy the strategy — known as a heterologous prime-boost — against the coronavirus. A heterologous prime-boost combination was approved last year by European regulators to protect against Ebola, and experimental HIV vaccines often rely on the strategy, says Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, Massachusetts. But it has yet to be tested using vaccines against COVID-19, which are typically given as a repeat injection of the same vaccine.

The ability to mix-and-match vaccines could make vaccination programmes more flexible: it would speed up the process and reduce the impact of any supply-chain disruptions. “It really makes the implementation much more simple,” said Mary Ramsay, head of immunization at Public Health England, at a press briefing on 3 February.

Oxford has said that it will also trial combinations of its COVID-19 vaccine with the Russian coronavirus vaccine, Sputnik V, which uses harmless viruses to shuttle components of the coronavirus into cells. Sputnik V, which this week was shown¹ to have greater than 90% efficacy against COVID-19, is itself a heterologous prime-boost vaccine, consisting of different viral components in the first and second doses.

T-cell focus

Some researchers also think that combining two vaccines could strengthen immune responses by harnessing the best features of each. That would be particularly desirable now that vaccine developers are combating coronavirus variants that seem to be partially resistant to certain immune responses, says Barouch. “It’s possible that responses might be better than what either vaccine can achieve on its own,” Barouch says. “But that remains to be proven experimentally for COVID-19.”

The Oxford trial aims to enrol 820 people, and it will test two dosing schedules: one with 4 weeks between the two injections, and another with a 12-week interval. The trial will not look directly at how well the combination protects against COVID-19 — such a study would need to be much larger and would take a long time to complete. Instead, the team will take regular blood samples to measure levels of antibodies and immune cells called T cells that participants produce against the coronavirus. It will also monitor for safety concerns.

T cells could be key to boosting immune response. RNA vaccines have generated powerful antibody responses to the SARS-CoV-2 coronavirus. But they have not proved to be as good as the AstraZeneca and Oxford vaccine at stimulating a class of T cells called CD8⁺ T cells, says Zhou Xing, an immunologist at McMaster University in Hamilton, Canada. These cells can strengthen an immune response by identifying and destroying cells infected with the virus.

Animal studies suggest that a strengthened immune response is possible: in a preprint published on bioRxiv on 29 January², researchers reported that a combination of an RNA coronavirus vaccine and the AstraZeneca vaccine roused CD8⁺ T cells in mice better than either vaccine alone.

Viral vectors

Other combinations could yield similar results. Immunologist Jae-Hwan Nam of the Catholic University of Korea in Bucheon is particularly keen to see trials of AstraZeneca’s vaccine together with a protein-based vaccine made by Novavax in Gaithersburg, Maryland. Protein vaccines provoke immune responses similar to RNA vaccines, he says, and Novavax’s vaccine might easier to make and distribute than the RNA vaccines.

Unlike the RNA vaccines, Sputnik V works by combining two vaccines that each tuck the DNA encoding a crucial coronavirus protein, called spike, into a harmless virus. The virus enters human cells, where the DNA is expressed. The immune system then mounts a response to the spike protein.

But if the same virus is used in subsequent shots, an immune response against the harmless virus itself could dampen the response to spike. Sputnik V addresses this problem by using two different shuttling viruses, one in each shot. AstraZeneca’s vaccine uses only one, making the heterologous prime-boost studies with Pfizer’s vaccine and Sputnik V particularly attractive.

If all goes well, the results from the trial arm testing the four-week regimen should be available by June, in time to inform the United Kingdom’s ongoing vaccination campaign, says Matthew Snape, a paediatrician at the University of Oxford and the trial’s chief investigator.

Snape says that the team hopes to add further vaccines to its study as they become available. Combination studies are possible thanks to the rapid development of multiple vaccine options against the coronavirus, says Xing. “We are in a strong position to go after the best immunologically considered strategies,” he says.