Mixing different types of vaccines is known as heterologous prime boost vaccination. It started in the 1990s as a strategy that was tested by HIV researchers. Photo credit: Julia Koblitz / Unsplash
Amid the global introduction of vaccines, with nearly 1.2 billion doses currently being administered, some countries have recommended a mixed-dose approach where a first prime shot is followed by a second type of booster.
The measure was introduced by France and Germany for people who have received a first dose of the AstraZeneca vaccine but are in age groups for which this vaccine is no longer recommended in these countries due to rare cases of blood clotting (although the European Medicines Agency Agency (EMA) says the benefits still outweigh the risks).
However, a more widespread policy of mixing different vaccines could also help ease the pressure on vaccine supplies and even boost the immune response. While the World Health Organization has indicated that there is currently insufficient data on interchangeability, this approach is currently being evaluated in various studies.
Here are five things you should know about mixing coronavirus vaccines.
1. Mix and match is nothing new – it started with HIV research
Mixing different types of vaccines is known as heterologous prime boost vaccination. It started in the 1990s as a strategy that was being tested by HIV researchers, according to Dr. Pierre Meulien, Managing Director of the Innovative Medicines Initiative (IMI), a partnership between the EU and the European pharmaceutical industry. "Scientifically speaking, this is nothing new," he said.
HIV researchers knew that a classic vaccine would not induce the extremely complex immunological mechanisms required to possibly protect against HIV infection. "People were trying to understand how to induce both T and B cell immunity," said Dr. Meulien and referred to the critical cells in the adaptive immune system. "And that was the main driver for this work (mixing vaccines)."
HIV has also been the driver for scientists to develop new vaccine platforms to deliver their payload. These platforms include DNA, mRNA, and viral vectors such as adenovirus, the last two, both of which are used in approved COVID-19 vaccines. Thanks to the numerous new platforms developed over the past 30 years, coronavirus vaccines have been developed so quickly, says Dr. Frédéric Martinon, immunologist at the French National Institute for Health and Medical Research (INSERM).
Rodolphe Thiébaut, professor of public health at the French University of Bordeaux, says the idea behind mixing vaccines is that "you basically present the antigen (the recognizable part of the pathogen) to the immune system in a different way," which helps the immune system System get a better overview of the antigen and adjust its response.
A prime-boost regimen is the only vaccine that is ever effective, if not high enough, against HIV infection. In 2012, Phase 3 human trials showed that transmission could be reduced by about 30%. This has led to high expectations of the approach, says Prof. Thiébaut.
2. Mixing doses can help avoid immunity to a vaccine
Because some vaccines are released into the body with a modified virus, the immune system can attack the vaccine itself. Mixing the platforms for the booster could reduce the risk of immunity to a vector viral vaccine.
In COVID-19 vaccines, Russian products Sputnik V, Johnson & Johnson, CanSino Biologics, and AstraZeneca use a virus, an adenovirus – it usually causes a cold – that is modified to express the coronavirus spike protein against that activates the immune system. It is "replication deficit" so that after injection it cannot copy itself into the body and catch us cold, explains Pia Dosenovic, assistant professor of immunology at the Karolinska Institutet in Sweden, who researches vaccine development as part of the VIVA project.
However, it is possible that the immune system could develop a response against the adenovirus platform. This is not dangerous, says Prof. Dosenovic, but it could dampen the effect of the vaccine.
To avoid this potential risk, according to Prof. Dosenovic, Sputnik V uses a different adenovirus with each shot, and AstraZeneca uses one of chimpanzees our systems have never encountered.
Prof. Dosenovic says a third shot – which is possible when vaccines are updated to address variants – would not be optimal with a viral vector vaccine. From this perspective, it makes sense to switch platforms to mRNA or a protein-based platform such as Novavax.
3. Mixing vaccines may produce a stronger / longer lasting response than a single vaccination schedule
When it comes to viral vector-based vaccines, a mixed-dose approach can not only prevent the immune system from inhibiting a vaccine, but it can also provide stronger, longer-lasting protection.
"If you specify a vector, a vector, a vector or a vector, a vector or a protein, I would expect that the second approach would give you a stronger antibody response (to the encoded antigen)," said Prof. Dosenovic. "But to know that you'd have to do experiments."
Again, this is because we want to train the immune system to attack the virus causing the disease, not the one delivering the vaccine. "When you mix different types of vaccines, we can imagine that you are increasing the (immune) response against the common antigen, which is the antigen of interest, rather than the vector itself," said Dr. Martinon.
And there are precedents. The Ebola vaccine developed by Johnson & Johnson is an example of a mixed dose approach that has been specifically chosen because the immune response could be of long duration. The first shot uses the same adenovirus as the AstraZeneca coronavirus vaccine, and the second shot uses an MVA vector – a modified version of a smallpox virus – a type that is also being studied for future COVID-19 vaccines.
Prof. Thiébaut is the coordinator of EBOVAC2, a program to evaluate the safety and effectiveness of this vaccine. He says they got a "very good response" with that strategy and predict that the new burst will allow the protection to last longer than usual. "At least half of the cells that produce the antibodies will likely at least stay five years, "he said.
4. The safety and effectiveness of mixing coronavirus vaccines needs to be assessed
While experts do not consider the vaccine mixing approach dangerous, they say we do not have enough data on coronavirus vaccine mixing and that safety should be assessed as with any new vaccine strategy.
In particular, mixing mRNA vaccines with adenovirus-based vaccines and vice versa has been shown to be beneficial, according to Dr. Meulien has not yet been carried out as the first instance of mRNA vaccine technology approved for human use was COVID-19.
"I think you really have to start over," he said. "You have to follow dosing schedules and all the usual precautionary things you do. You have to do this with these new things as none of them have been tested together before."
Various studies are underway to test mixing coronavirus vaccines. One anticipated study is that of the Oxford Vaccine Group's Com-Cov study, which started after the UK approved a mixed-dose approach in January to look at immune responses and side effects from combinations of four vaccines: AstraZeneca, Pfizer / BioNTech, Moderna, and Novavax. "I hope we don't rule out any combinations," Senior Investigator Professor Matthew Snape told the BBC.
Regarding the research questions that need to be answered, Dr. Meulien: "I think the types of immune responses induced, the longevity of the response and then of course the safety profile would be the three things I would say would be very important."
Spain plans human trials of the effects of a dose of the AstraZeneca vaccine with a dose of the Pfizer / BioNTech vaccine. Countries that have already made decisions about mixing vaccines are considering, according to Dr. Meulien risks and benefits.
"This is not a brand new way of thinking," he said. "We have decades of pre-clinical and clinical (work) experience with these approaches, particularly with HIV. So it's not like we're putting the population at risk."
5. Mix-and-match could help us combat variants
For Dr. Meulias, the main incentive to mix vaccines is to potentially trigger a broader immune response. "I mean, expand to cover the variations that are popping up all over the place now," he said.
But there has to be real scientific and regulatory justification for it to mix, he says.
Dr. Martinon says vaccines are improving for different variants, such as those that emerged in the UK, Brazil, South Africa and most recently India, which is currently seeing a surge in cases and a new coronavirus mutation that may cause SARS. CoV-2 more contagious and able to re-infect.
The next generation of vaccines will likely target multiple coronavirus variants, with different vaccines targeting different variants. Mixing these vaccines would, according to Dr. Confer broad collective immunity on martinon and make variants difficult to spread or make new vaccines difficult to emerge.
Regular recordings will be required, he says, although it is unknown how much time there is between them, the hope is it will be years.
From a public health perspective, mixing vaccines could help overcome this pandemic by accelerating the adoption of vaccinations, according to Prof. Thiébaut. Getting good reviews of vaccine combinations that show what works well is crucial.
"It is good news in terms of the flexibility of any government to use what they can get as quickly as possible," he said. This flexibility is crucial. "The best way to combat these variants is to vaccinate most of the world's population as soon as possible."
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The VIVA project is funded by the European Research Council of the EU and EBOVAC2 by IMI.
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Five Things You Should Know: Mixing and Matching Coronavirus Vaccines (2021 May 5)
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