MIX AND MATCH: Several heterologous vaccine trials are on-going, or planned by other countries, with results expected soon; if proven safe and effective, the strategy could help mitigate against vaccine supply shocks. Image Credit: Gulf News / File


  • Clinicians in Spain and UK were among the first to conduct mix-and-match trials on approved COVID-19 vaccines.
  • Initial results found that mixing and matching AstraZeneca and Pfizer vaccines was ultimately safe.
  • Both studies on “heterologous” vaccines suggest taking two different doses actually produces more antibodies.
  • The technique is likely to kick up mild side-effects such as a headache, chills or a fever after the second dose, when compared to “non-mixed” schedules.
  • Other countries are set to follow or are already en route with their own trials, thus creating a "second wave" of vaccine trials.

Dubai: There’s an emerging body of evidence that mixing-and-matching COVID-19 vaccines is safe — and effective — in producing antibodies against the coronavirus, based on initial data readouts from trials. In at least two studies, mixing vaccines demonstrated greater efficiency in kicking up antibodies against SARS-CoV-2.

Mix-and-match: 'New wave' of vaccine trials


Now, there's a "new wave" of investigations to find out whether a mix-and-match strategy would keep humanity a step ahead of the virus. Trials are on-going in Spain, UK, US and Canada. Scientists in other countries are closely following the trials, or launching their own. Initial results in two studies out shows combining different vaccines elicited better efficacy against the virus. Here’s the lowdown on what we know so far:

How many mix-and-match vaccine trials are on-going?

There are at least four at the moment, with more to more. They are also known as “heterologous” vaccine studies — there's currently one each in Spain, the UK, Canada and the US. The Spanish and the UK studies are in advanced stages and had already published preliminary results in medical journals.

What’s the Spanish study?

The Spanish trial involving 663 people was the first to show the benefits of combining different COVID-19 shots. Trial results, published in Nature on May 19, 2021, suggest taking two different doses actually produced more antibodies in the participants who took the mixes shot compared to those who had “non-mixed” vaccination.

Why is the Spanish study significant?

It’s the first to show a “heterologous” vaccination against COVID-19 is safe and more effective (than homologous), though the researchers also reported common side effects. The trial, called CombivacS, was led by a team from Carlos III Health Institute in Madrid.

When did the trial start? How many volunteers were involved?

It started in April and enrolled 663 people (under the age of 60) who had already received a first dose of the Oxford/AstraZeneca vaccine. Two-thirds of participants (440) were randomly picked to receive the mRNA-based vaccine made by Pfizer/BioNTech — eight weeks or more after their first dose. A “control” group of 232 people has not yet received a booster.

Spanish study: What are the results?

Study results are “preliminary”, but clinicians noted an increased production of antibodies against the coronavirus. Following the second dose, researchers said the volunteers began to produce much higher levels of antibodies than they did before. More importantly, these antibodies were able to recognise and “inactivate” SARS-CoV-2 in lab tests.

“Control” participants who did not receive a booster vaccination experienced no change in antibody levels. Magdalena Campins, an investigator on the CombivacS study in Barcelona, explained the Pfizer–BioNTech booster seemed to “jolt” the immune systems of the Oxford–AstraZeneca-dosed participants.

Pfizer vaccine
A medical worker administers a dose of the "Comirnaty" Pfizer-BioNTech COVID-19 vaccine in a vaccination center in Paris as part of the coronavirus disease (COVID-19) vaccination campaign in France, May 12, 2021. Image Credit: Reuters

What about the UK vaccine mix-and-match study?

The UK study covered Pfizer-BioNTech and Oxford/AstraZeneca COVID-19 vaccines on 820 adults. One group took the AstraZeneca as primary and Pfizer as booster; the other group had Pfizer as primary and AstraZeneca as booster.

Who are the trial participants and how many in the first Oxford study?

The Oxford study had a total of 820 participants — all adults aged 50 years and above.

What are there results of the UK study?

Researchers noted that the results are still preliminary. They reported that both heterologous vaccine schedules induced greater systemic “reactogenicity” following the boost dose than their homologous counterparts. This means, the antibody count for the mix-and-match group was much higher than those who had the same vaccine for both doses.

The results, published in the Lancet on May 29, 2021, confirmed the Spanish trial — and showed it's safe to mix and match and that it works. The final “reactogenicity” and safety data (primary immunological outcome) is expected later this month (June 2021).

vaccine mixing and matching
One potential benefit of mixing-and-matching of vaccines is that countries with supply shortfalls of COVID-19 vaccines could benefit from using different vaccines for the first and second dose. Image Credit: AFP

What were the side effects seen in the UK study?

Researchers reported of fever, chills and headaches among some volunteers. The research team found that those on a mixed schedule who received AstraZeneca as their second booster shot experienced slightly higher levels of side effects than those who received Pfizer as their second booster shot.

Feverishness was reported by 47% of those who received AstraZeneca after Pfizer — compared to 34% of those who received Pfizer after AstraZeneca, and 21% for those who received both BNT for both prime and boost. Similar rates were observed for chills, fatigue, headache, joint pain, malaise, and muscle ache.

How long did the side effects last?

Most of this increase in side effects was observed within 48 hours after immunisation, said researchers, who noted the symptoms were “short lived”. There were no hospitalisations.

What are the disadvantages reported from UK’s mix-and-match vaccination trials?

The data suggest that the two heterologous vaccine schedules might have some “short-term disadvantages”. Researchers said they are still investigating side effects on participants receiving prime and boost vaccines at 12-week intervals.

Child vaccine
At least 4 studies are investigating the new technique — mixing-and-matching of vaccines — with encouraging initial results in triggering potent immune response against SARS-CoV-2.

What were participants given to reduce vaccine side-effects?

Participants were advised that paracetamol might reduce vaccine side-effects but were not actively counselled to medicate prophylactically. Paracetamol use in the 48 hours post-boost vaccine was reported by 36% of recipients of ChAd (Oxford/AstraZeneca) for both prime and boost.

Paracetamol use was higher in the mix-and-match group: 57% of recipients of ChAd for prime and BNT for boost; 41% of recipients of BNT for both prime and boost, and 60% of recipients of BNT for prime and ChAd for boost. Since the data were obtained in participants aged 50 years and older, researchers said “reactogenicity" might be higher in younger age groups.

What other vaccines are undergoing heterologous trials in the UK?

The UK today is spearheading mix-and-match COVID-19 vaccine studies. Further trials will evaluate heterologous prime-boost schedules, specifically for vaccines for the following vaccines:Moderna and Novavax.  

  • Moderna
  • Novavax

US: What are they doing in terms of mix-and-match vaccine studies?

There’s an ongoing, early-stage trial in the US exploring whether people can be given a booster shot different from their original COVID-19 vaccine. Officials said the trial will look at what happens when an adult who is fully vaccinated with one type of COVID-19 vaccine, like Pfizer’s, is boosted with a different shot about three to four months later.

Will the US study also cover the known variants of concern?

Yes. The new study will find out whether mixing different COVID-19 vaccines can prolong immunity and better protect people from coronavirus, including the so-called “variants of concern”.

US Vaccine
In this March 3, 2021, file photo, Iowa Governor Kim Reynolds gets the Johnson & Johnson COVID-19 vaccine during a news conference at Iowa PBS in Johnston, Iowa. Image Credit: AP


What does the US trial involve?

The trial is in the recruitment stage. The initial plan is to conduct trials in different groups. One group will include 150 adults who have been fully vaccinated with the Johnson & Johnson, Moderna or Pfizer Covid vaccines, according to the US National Institutes of Health (NIH).

Another group will include those who have not yet received an authorised vaccine and are eligible to enrol in the trial, said US health officials.

Who's funding the US trial?

Funding for the study is provided by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The study is being conducted through a network of researchers who specialise in vaccines and infectious diseases.

What’s the Canadian mix-and-match COVID-19 vaccine study?

A research team launched a study on May 20, 2021, known as MOSAIC (“Mix and match of the second COVID-19 vaccine dose for Safety and Immunogenicity”). It seeks to assess the safety and effectiveness of using two different COVID-19 vaccines for the first and second dose. It will also study the effects of increasing the interval between doses. Canada has authorised four vaccines (Moderna, Pfizer-BioNTech, AstraZeneca/Covishield and Janssen (Johnson & Johnson). As other vaccines become available, they will be added to the study to address public health knowledge gaps, Dr Sadarangani added.

How many participants are in this Canadian mix-and-match vaccine study? Who is funding it?

The $4.8 million study, funded by the Canadian government, seeks to enroll 1,300 participants across clinical trial sites in Nova Scotia, Quebec, Ontario, Manitoba, Alberta and British Columbia.

What did Canadian health authorities do next?

Canadian health authorities announced a change in guidelines on mixing-and-matching second doses of COVID-19 vaccines on June 1, 2021. They are now advising Canadians to combine either the AstraZeneca-Oxford, Pfizer-BioNTech or Moderna shots interchangeably, in certain situations.

Canadian health authorities announced a change in guidelines on mixing-and-matching second doses of COVID-19 vaccines on June 1, 2021. They are now advising Canadians to combine either the AstraZeneca-Oxford, Pfizer-BioNTech or Moderna shots interchangeably, in certain situations.


The National Advisory Committee on Immunization (NACI) updated its guidance and recommended that a first shot of the AstraZeneca vaccine can be followed by either Moderna or Pfizer. For those who have had a first dose of Moderna or Pfizer, NACI recommends they can now take either of the two shots as a second dose — because they both use a similar mRNA technology — if the same first dose is unavailable or “unknown”.

France vaccine covid
Maria, 93, receives a dose of the Pfizer/BioNTech COVID-19 vaccine by a fire-fighting nurse at her home in Saint-Bonnet-en-Champsaur, southeastern France, on March 30, 2021. Image Credit: AFP

What countries are contemplating to use a mixed vaccination schedule?

A heterologous vaccine regime is being advocated in Germany, France, Sweden, Norway, and Denmark — especially among those who have received a ChAd (Oxford/AstraZeneca) prime dose, in light of concerns regarding thrombotic thrombocytopenia after the first dose of ChAd.

What’s the significance of these studies?

  • Initial results show a mix-and-match protocol is generally safe, though more clinical data must be gathered and analysed to confirm this.
  • There’s a valid interest in heterologous prime-boost vaccination to help mitigate against supply shocks or shortages that might otherwise reduce the speed of vaccine roll-out.
  • Researchers hope that such mix-and-match COVID-19 regimens will trigger stronger, more robust immune responses than will two doses of a single vaccine.
  • It gives health authorities more flexibility in their COVID-19 vaccination drive.
People queue at a vaccination centre in Ebersberg near Munich, Germany.
People queue at a vaccination centre in Ebersberg near Munich, Germany. Several countries (notably in Europe) are already recommending that some — or all — people who were given a first dose of the vaccine developed by the Oxford/AstraZeneca, get another vaccine for their second dose.

What are other countries doing on heterologous vaccine trials?

A growing number of countries are looking at switching to different COVID-19 vaccines for second doses amid supply delays and safety concerns that have slowed their vaccination campaigns. Several clinical studies to test the efficacy of switching, or mixing-and-matching COVID-19 vaccines are under way.

Justin Trudeau vaccine covid canada prime minister
Justin Trudeau, Canada's prime minister, gives a thumbs up before receiving a dose of the AstraZeneca COVID-19 vaccine with his wife Sophie Grgoire Trudeau, left, in Ottawa, Ontario, Canada, on Friday, April 23, 2021. Image Credit: Bloomberg

The following are countries that are weighing, or have decided to adopt, such a solution:


The country's National Advisory Committee on Immunization said on June 1 that recipients of a first dose of AstraZeneca's vaccine can choose to receive a different vaccine for their second dose. It added that vaccines from Pfizer and Moderna could be used interchangeably.


Chinese researchers in April were testing the mixing of vaccine doses developed by CanSino Biologics, and a unit of Chongqing Zhifei Biological Products, according to clinical trial registration data.

China vaccine
People arrive at a vaccination site following an outbreak of the coronavirus disease (COVID-19) in Beijing, China January 6, 2021. Image Credit: Reuters


Finland's Institute of Health and Welfare said on April 14 recipients of a first dose of AstraZeneca's vaccine who were younger than 65 might get a different shot for their second dose.


France's top health advisory body has recommended in April that people under 55 injected with AstraZeneca first, should receive a second dose with a so-called messenger RNA vaccine, although dose-mixing has not yet been evaluated in trials.


Norway said on April 23 it would offer those who have received a dose of the AstraZeneca vaccine an injection with an mRNA vaccine as their second dose.


Russia put on hold the approval in the country of clinical trials combining AstraZeneca and Sputnik V vaccines, after the health ministry's ethical committee requested more data, AstraZeneca official told Reuters on May 28.

South Korea
Elderly residents queue in line to receive the first dose of the Pfizer Inc.-BioNTech SE Covid-19 vaccine in Goyang, South Korea, on Thursday, April 1, 2021. Image Credit: Bloomberg

South Korea

South Korea said on May 20 it would run a mix-and-match trial, mixing AstraZeneca doses with those developed by Pfizer and other drugmakers.


Spanish Health Minister Carolina Darias said on May 19 the country would allow those under 60, who got an AstraZeneca shot first, to receive a second dose of either AstraZeneca or Pfizer's vaccine, after preliminary results of a study by state-backed Carlos III Health Institute.


Sweden's health agency said on April 20 that people under 65, who have had one shot of AstraZeneca's vaccine, would be given a different vaccine for their second dose.

Sweden vaccinate influenza
A member of nursing staff vaccinates a person against influenza as vaccination to high risk group patients is administered outdoors to prevent the spread of the coronavirus disease (COVID-19), in Trelleborg, southern Sweden November 19, 2020. Image Credit: Reuters


Novavax said on May 21 it would take part in a mix-and-match vaccine trial to test the use of an additional vaccine dose from a different producer as a booster. The trial will start this month (June 2021). The first findings of an Oxford University-led study released last month found that people who received Pfizer's vaccine followed by a dose of AstraZeneca, or vice versa, were more likely to report mild or moderate common post-vaccination symptoms than if they received two doses of the same type.


The US National Institutes of Health (NIH) said on June 1 that it started a clinical trial on fully vaccinated adults to evaluate the safety and immunogenicity of a booster shot of a different vaccine.

(With inputs from Reuters)