Mixing COVID-19 vaccines is proving to be a great way to give people the protection they need when faced with safety concerns and unpredictable deliveries. Most vaccines for SARS-CoV-2 must be given in two doses, but several studies are now backing the idea that mixing the Oxford-AstraZeneca vaccine and the Pfizer BioNTech vaccine produce an immune response similar to – or even stronger than – two Doses will trigger either vaccine.
Results announced on Monday 1 by a UK group suggest that the combination sometimes outperforms two shots of the same vaccine, and a similar picture emerges from German studies.
With the mix-and-match idea, you can now “feel a little more comfortable,” says immunologist Leif Erik Sander from the Berlin Charité.
The results also give the researchers confidence that the combination of other COVID-19 vaccines that have not yet been tested together could work as well. However, at least 16 vaccines have been approved for use in one or more countries, and mix-and-match studies have so far been small, so larger studies and long-term monitoring for side effects are urgently needed.
Strengthening the immune system
Mix-and-match studies were largely triggered by concerns about the safety of the vaccine, which was being developed by Oxford University and the Cambridge pharmaceutical company AstraZeneca, both in the UK. The vaccination has been linked to rare cases of blood clotting known as thrombosis with thrombocytopenia – and in March some European countries decided to discontinue use in some populations. As a result, many people were partially vaccinated unless they switched to a different brand for their second dose.
In May, researchers at the Carlos III Health Institute in Madrid announced the results of the CombiVacS study. The study found a strong immune response in people who were given the vaccine from pharmaceutical company Pfizer, based in New York City, and biotechnology company BioNTech in Mainz, Germany, 8-12 weeks after receiving a dose of the Oxford AstraZeneca vaccine.
There was no direct comparison with people who received two doses of the same vaccine, but the authors found in laboratory tests that those who received the combination produced 37 times more neutralizing SARS-CoV-2 antibodies and 4 times more SARS -CoV-2-specific immune cells, so-called T cells, as people who only had one dose of the Oxford AstraZeneca vaccine.
Further results showing a similar effect were available by the end of June.
Sander and colleagues studied 340 health care workers who received either two doses of the Pfizer BioNTech vaccine or an initial vaccination of the Oxford AstraZeneca vaccine followed by a dose of Pfizer BioNTech. Both therapies triggered an immune response that included neutralizing antibodies and T cells.
A third study by researchers at Saarland University in Homburg, Germany found that the mixed regimen elicited an immune response better than two Oxford-AstraZeneca syringes. It was as good or better than two shots of Pfizer-BioNTech, too.
And on June 25, the team behind the UK study – known as the Com-COV study – released a preprint online showing that regardless of the order in which the two vaccines were given, it produced a good immune response.
However, previous studies have been too small to test how effective combinations of vaccines are in preventing the development of COVID-19. “As long as there are no long-term or follow-up studies with efficacy calculations, it is difficult to say” how high or how long the protection is, says Martina Sester, immunologist and head of the Saarland study.
Another limitation of previous work is that there is no easy way to compare different combinations between studies. Large-scale efficacy studies are becoming more difficult, Sester says. This is because as infection rates decrease, the number of people in a study must increase to detect differences in infection and disease rates. Attempts to test mix-and-match vaccine sequences against a placebo control would also be unethical, she adds.
This is one of the reasons why efforts are being made to determine a “protective correlate” – a defined level of immune response that provides protection against infection and disease. “This is extremely urgent,” says Sander.
A nuanced picture
However, a nuanced picture is emerging of the extent and types of immune responses that vaccine mixing elicits. And these differences could be exploited to offer the best protection.
The Oxford-AstraZeneca vaccine uses a harmless virus called adenovirus to transport genetic material from SARS-CoV-2 into cells. Vaccines using this technology have a good track record of inducing strong T-cell responses, says Sander, while vaccines that use messenger RNA, such as Pfizer’s, have “exceptionally good” at inducing high levels of antibodies to have.
Sester says high antibody levels after the second shot are an indicator that the combination approach is working. “Neutralizing antibodies are likely a good substitute for predicting effectiveness,” she says because they help prevent viral infections. But T cells, especially “killer” T cells that carry a protein called CD8, protect against serious illness by killing cells that are already infected.
In the Com-COV study, the highest antibody response was in people who received the two standard syringes Pfizer-BioNTech, but the response was almost as high in the combination Oxford-AstraZeneca followed by Pfizer-BioNTech. This combination also had the best T cell response – more than double that of the two Pfizer BioNTech doses.
Mixing an mRNA vaccine and an adenovirus-based vaccine could therefore offer “the best of both worlds,” explains Sander.
Sester and her colleagues found subtle differences in T cell populations depending on the vaccine administered. She says understanding these nuances could lead to individualized strategies. Combinations that produce good T-cell responses may be better for people who have had an organ transplant and are taking medication to suppress their immune system because their bodies have difficulty making antibodies. “There are many ways to use this knowledge strategically,” she says.
Security concerns remain
No mix-and-match studies have reported serious side effects to date. In the Com-COV study, mixing vaccines caused more side effects than giving two doses of the same vaccine, according to preliminary data released in May. However, this was not the case in the studies of the Charité and Saarland or CombiVacS, where the side effects were no worse than two injections of the same vaccine.
That’s likely due to the interval between doses, Sester says. Com-COV participants discussed in the latest study received their second syringe four weeks after the starting dose, while participants in the German studies had at least nine weeks between syringes. Some Com-COV participants received doses at longer intervals; their dates are expected in July.
Some safety concerns remain, says Sander. “They combine two different vaccines, both of which could have their own profile of adverse events and effects,” he says, which could exacerbate any problems.
The studies have so far only enrolled a few hundred people. This means they are too small to capture rare events like the coagulation disorders, which, according to current estimates, occur in about 1 in 50,000 people after the first Oxford-AstraZeneca vaccine dose and less than 1 in 1.7 million after the second . The disease has also been linked to an adenovirus vaccine made by the Johnson & Johnson pharmaceutical company of New Brunswick, New Jersey.
In small studies, “you don’t see your 1-in-1000 side-effect, let alone your 1-in-50,000 side-effect,” said Matthew Snape, an Oxford vaccine researcher who leads the Com-COV study, at a news conference on June 28th.
The new norm?
The persistent possibility of rare side effects is one reason why some researchers recommend people stick to the standard two shots of a single vaccine for the time being. “In my opinion, you’d better use the ones that we know work and that there are a known amount of when it comes to their safety,” says Snape.
However, as new variants of SARS-CoV-2 emerge, the results of mix-and-match studies could provide policy makers with the data they need to switch to more protective combinations. “It’s good to have this data to hand,” says Fiona Russell, a vaccine researcher at Murdoch Children’s Research Institute in Melbourne, Australia.
Mix-and-match vaccines could also be used to prevent rollouts from stalling due to supply issues. “If there is a global shortage of a particular vaccine, the vaccination program cannot be stopped, it can be continued,” says Russell.
“If either getting a mixed plan or not getting a second dose is an option, then definitely go for the mixed plan,” says Snape.
The Com-COV study has already started testing other vaccines in people who have received a first injection from Oxford-AstraZeneca or Pfizer-BioNTech. One combination includes the previously unapproved protein-based vaccine developed by pharmaceutical company Novavax in Gaithersburg, Maryland. Another uses the mRNA vaccine from Moderna in Cambridge, Massachusetts, which is approved in several countries.
A study is running in the Philippines until November 2022 in which the inactivated virus vaccine CoronaVac developed by the Sinovac company in Beijing is combined with the six other vaccines approved in the country. And a study by AstraZeneca and the Gamaleya Research Institute in Moscow will test combinations of the Oxford-AstraZeneca jab and Gamaleya’s adenovirus-based Sputnik-V shot.
This article is reproduced with permission and was first published on July 1, 2021.