Can you mix-and-match Covid-19 vaccines?

The Directorate General of Health Services (DGHS) announced on Wednesday that Bangladesh’s stock of Covid-19 vaccines is running out, with only some 1.4 million jabs remaining in government hands. Given the current crisis in India, there is little to no hope of receiving the next consignment in accordance with the contract signed between Beximco Pharmaceuticals and the Serum Institute of India anytime soon.

Speaking at a virtual press briefing, DGHS spokesperson Robed Amin said, “We had around 10.2 million vaccine doses in our hands … around 8.8 have already been administered as the first and second doses. Now we have some 1.4 million doses in stock.”

He warned that there would be a vaccine crisis if a fresh consignment does not arrive in the country before the existing stock is exhausted.

Robed said around 5.8 million people have so far received the first dose of the vaccine while just over three million of them have got the second, booster dose to complete their course of the Oxford University-AstraZeneca vaccine.

That leaves 2.8 million people yet to complete the course, of which 1.4 million can be covered from the current stock. In the absence of any clear data yet on whether the vaccines can be mixed or matched, concentrating the remaining doses on letting as many people as possible complete their course is probably the right thing to do.

But that still leaves 1.4 million people that current stocks cannot cover. In case a new stock of the same vaccine cannot be procured in time, is it advisable to mix vaccine doses?

The prospect of mixing vaccine doses offers a chance to bolster vaccine rollouts and, potentially boost the immunity provided, but evidence around the wisdom of this approach is scarce when it comes to Covid-19. However it is “nothing new” to medical science, according to Pierre Meulien, executive director of the Innovative Medicines Initiative (IMI), an EU and European pharmaceutical industry partnership.

“We have decades of experience in pre-clinical and clinical (work), especially in HIV, using these approaches,” Meulien told EU Horizons.

Indeed, the measure has already been introduced by France and Germany for people who received a first dose of the AstraZeneca vaccine but are in age groups for which that vaccine is no longer recommended in those countries due to rare instances of blood clotting.

On 1 April, Germany advised that those under 55 receive an mRNA vaccine alternative, such as the Pfizer and Moderna vaccines, as a follow-up shot. Soon after, France recommended the same for people under the age of 60.

All of the Covid-19 vaccines widely available, with the exception of Johnson & Johnson’s (J&J) one-and-done jab, require two doses. The first dose primes the immune system and the second dose (usually administered a few weeks after the first) boosts it.

The US Centers for Disease Control and Prevention has warned against the mixing of vaccines unless there are “exceptional situations”, such as a shortage of the first-dose vaccine because of production or distribution problems.

In the UK, Public Health England has taken a similar stance. After the government delayed second vaccine doses for up to 12 weeks so that more people could get their first jab and at least some protection, health officials acknowledged that, in exceptional circumstances, mismatched doses may be given to those who come in for their second booster only to find that the vaccine they originally had is not available.

Some experts are wondering whether flexibility in allowing mixed-dose vaccination might help people get fully vaccinated faster. Others have argued that mixing two different vaccines could actually do a better job of protecting against Covid-19 than sticking to the same one for all doses.

Covid-19 vaccines prime the body’s immune system to target the coronavirus spike protein but target different parts of the spike.

AstraZeneca’s adenovirus vaccine uses a weakened version of a common cold virus found in chimpanzees (ChAdOx1) to present the spike protein to the immune system, while Pfizer’s mRNA-based vaccine delivers genetic instructions for making the spike protein and encourages human cells to produce it, triggering an immune response.

Royal Melbourne Institute of Technology (RMIT) vaccine researcher Kylie Quinn has described Covid-19 vaccines as vehicles delivering cargo – the vehicles may be different, and they may drop off their payloads by different means, but the spike protein cargo is the same. Because the cargo is identical, the vaccines should, in theory, work well together.

It does make some simple sense that sparking more than one arm of the immune system could boost immunity on the whole, according to an article published on the website of Clinical Trials Arena, a publication focused on the pharmaceutical industry globally.

Mount Sinai Hospital epidemiologist and assistant professor of medicine Dana Mazo explained to US-based website HealthLine that, in some cases, one type of vaccine can indeed enhance the effectiveness of another.

“There are two different types of pneumococcal vaccines that have different mechanisms of action, and in certain situations we recommend boosting one with the other,” she said.

The Sputnik V Covid-19 vaccine produced by Russia’s Gamaleya Research Institute already uses the theory over its two-dose course. Unlike the other vaccines, its first and second doses actually differ, by harnessing two kinds of adenoviruses in its prime and booster doses to deliver genetic instructions to the immune system. The first jab uses a harmless common cold virus (Ad26) and the second, given 21 days later, uses another safe but scientifically engineered cold virus (Ad5).

Using an alternative vehicle to deliver the cargo allows the vaccines “genetic payload” to skirt any inadvertent immune response to the first shot. The kind of immune response they’re trying to avoid here is not dangerous, but rather one that “could dampen the vaccine’s effect”, according to Pia Dosenovic, an immunologist at Sweden’s Karolinska Institute, which awards the Nobel Prize in Physiology and Medicine.

The method paid off, and Sputnik V has been found to be one of the most effective vaccines at 91.6 per cent and has been rolled out in Russia and 56 other countries.

Health minister Zahid Maleque on 6 May said they are now “at the stage” of signing a deal with Russia to procure the Sputnik V vaccine.

The most important unanswered question is whether mixing vaccines from different manufacturers will cause unwanted adverse reactions.

Currently, in the UK, an eight-arm study assessing the mix-and-match theory is underway, according to the BBC. The ambitious University of Oxford-run trial called Com-COV2 is testing various combinations of the vaccines currently approved in Britain – Pfizer-BioNTech, AstraZeneca and Moderna, as well as Novavax’s candidate, which is expected to be approved in the coming weeks.

The trial will enroll 1,050 adult subjects aged 50 years or older who received their first dose of a Covid-19 vaccine in the past eight to 12 weeks.

Recipients will have received either the Oxford-AstraZeneca or Pfizer vaccine and will be randomly allocated to receive either the same vaccine for their second dose or a dose of Novavax or Moderna’s jabs. If more vaccines are approved over the coming months, they may also be added to the trial.

While announcing Com-COV, University of Oxford associate professor in paediatrics and vaccinology and chief investigator on the trial, Matthew Snape, cited experiments in mice in which combinations of the Pfizer and AstraZeneca vaccines boosted immunity better than two doses of either one alone. Now this cocktail and others are being tested in humans.

“If we can show that these mixed schedules generate an immune response that is as good as the standard schedules, and without a significant increase in the vaccine reactions, this will potentially allow more people to complete their Covid-19 immunisation course more rapidly,” Snape told the BBC.

“What I’m hoping is that we won’t rule out any combinations. That’s how we need to look at it: are there any combinations we shouldn’t be giving, because they don’t generate a good immune response? And I’m hoping that won’t be the case,” he added.

Results of the trial are expected in June.

Gamaleya and AstraZeneca have registered a pair of clinical trials in which volunteers will receive a dose of AstraZeneca’s vaccine and another of Sputnik V. One trial in Azerbaijan is underway, and a second in Russia is still under review by the country’s ministry of health.

Meanwhile, Norway is awaiting the results of a clinical trial assessing the effectiveness of mixing vaccines before making a decision. Government researchers in Spain said they will study the effects of mixing Covid-19 vaccines in response to the shifting guidelines on the safety of the AZ shot.

For now, it’s too soon to tell whether mixing and matching vaccines is effective, more effective or safe. The world is watching these trials closely to see the outcomes. Mixing the platforms would not seem to contain any obvious, inherent risk, but the main concern is it is not very well tested yet.