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Explained: The merits and concerns of mixing Covid-19 vaccines

India is considering whether people can be given a mix of different Covid-19 vaccine doses. What can be the merits of such a programme, and what are the concerns? Which other countries are trying this?

Written by Prabha Raghavan | New Delhi |
Updated: June 14, 2021 11:56:05 am
Frozen vials of a Covid-19 vaccine are taken out to thaw. (AP Photo: Francisco Seco, File)

India plans to embark soon on an exercise to investigate if it can immunise people using a “mix and match” of different Covid-19 vaccines. This would mean following up one dose of a particular vaccine with a second dose of a different vaccine. In scientific terms, this is called “heterologous” immunisation.

In India, whose vaccination programme currently uses Covishield, Covaxin and Sputnik V, this practice has not been approved yet. Other countries have already been testing this out.

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Why mix and match Covid-19 vaccines?

There are various reasons to try this out.

BETTER IMMUNE RESPONSE: Some scientists believe that using a different vaccine for the second dose could potentially boost the immune response against the virus. This may especially be true for viral vector vaccines like Covishield/AstraZeneca, which use a modified and weakened chimpanzee ‘adenovirus’ (common cold virus) to deliver the genetic code of the SARS-CoV-2 spike protein to the body. Using the same adenovirus could make the vaccine less effective the second or third time around.

“The first time, your body is naive not only to the spike protein, but also to the vector which is injected into your body–in the case of Covishield, it would be the chimpanzee adenovirus. So, while you are developing antibodies against the spike protein, you are also inadvertently developing antibodies against the adenovirus,” said Dr Chandrakant Lahariya, a vaccinologist specialising in public policy and health systems.

This is why Sputnik V uses two different adenoviruses to deliver the spike protein’s code to our bodies, according to Dr Srinath Reddy, President, Public Health Foundation of India.

MUTATIONS & VARIANTS: Mixing and matching vaccines of different technologies — for example, a viral vector vaccine followed up with an mRNA vaccine like Pfizer’s — might encourage our immune system to build a wider response. “They’re all ultimately looking at the same target protein here —the spike protein — but presenting that to the immune system in different ways is potentially a great way of actually generating a better and broader immune response,” the Oxford Group’s Professor Matthew Snape explained during an episode of The Economist Radio’s podcast, The Jab, on May 31. Professor Snape is the chief investigator in the group’s Com-COV trials to mix and match Covid-19 vaccines.

Such combinations could potentially provide wider protection against certain mutations or variants of the SARS-CoV-2 virus. “Theoretically, there is an advantage of mixing and matching in this situation, because the AstraZeneca vaccine has less efficacy against the Delta variant, as seen from studies in the UK,” Dr Reddy said. “If this is true for Covishield in India, then it makes sense that those who received this vaccine in their first dose receive another vaccine that covers a broader platter of antigens as their second dose. In theory, doing so could extend the body’s immunity spectrum against more antigens,” he said.

SHORTAGES IN SUPPLY: Current Covid vaccine production cannot sufficiently cater to the existing demand, resulting in stock-outs. In parts of India, government vaccination centres for those in the 18-44 age group had closed down due to limited Covishield and Covaxin supplies.

“In the short term, mixing solves your programme problems, because then people don’t have to come again and again to get the dose that they are interested in or the vaccine that they got in their first dose,” said Dr Gagandeep Kang, leading vaccine expert and Professor at the Wellcome Trust Research Laboratory in Christian Medical College—Vellore’s Division of Gastrointestinal Sciences. “If it’s a long-term issue, you want to look at what gives you the best results in terms of what is the best protection that you can get,” she added.

SAFETY CONCERNS: Countries like Germany, France, the UK and Canada have halted the use of the AstraZeneca vaccine in younger age groups due to concerns of rare blood clots. Here, mixing and matching allows the completion of immunization while ensuring safety.

What are the concerns?

Many unknowns: The Covid-19 vaccines in use have received restricted emergency use permissions in the last six months after fast-tracked trials, and tests to mix and match them began only a few months ago. Questions about how safe it is to mix and match, and whether the approach can prompt a better immune response, are still being answered.

Even the order of mixing and matching needs to be closely studied — would giving Covishield before Covaxin, for instance, prompt a better immune response than giving Covishield as the second dose?

UNTESTED COMBINATIONS: Some vaccines like Covaxin have not even been administered in a mix and match scenario — save for an incident in May where 20 villagers in East Uttar Pradesh were accidentally given Covaxin as their second dose although they received Covishield first.

DIFFERENCES IN VACCINES: International bodies like the Coalition for Epidemic Preparedness Innovations, which is looking into mixing and matching Covid-19 vaccines, have highlighted certain complexities. These include differences in the shelf life of these vaccines, their shipment and storage conditions and contraindications — some vaccines may have more side-effects or may not work as well as others in people with specific ailments.

SIDE EFFECTS: Studies such as the Com-COV trials show that some combinations, like AstraZeneca with Pfizer vaccines, could lead to an increase in side effects.

THE SILVER LINING: As of now, there are no issues theoretically that could make mixing and matching of Covid-19 vaccines a major safety threat. “Our immune systems are capable of handling a lot — we are seeing an increase in minor side-effects with mixing, but do not expect major side effects,” said Dr Kang.

Have vaccines been mixed before Covid?

Mixing and matching of vaccines has been tested for decades, especially for viruses like Ebola. However, most combinations had initially been restricted to vaccines that use the same technology.

In India, combinations of rotavirus vaccines have also been used and tested out. “For the last three years, there has been a study looking at combining two rotavirus vaccines… That was a mix and match of a monovalent and a multivalent vaccine,” said Dr Kang. “All the rotavirus vaccines are live attenuated vaccines, but the two vaccines used in the Indian programme are different in that one is a pentavalent vaccine based on a bovine rotavirus and the other is a monovalent vaccine based on a human rotavirus.”

Where has mixing of Covid-19 vaccines been tried?

Most mix-and-match tests currently include the AstraZeneca and mRNA vaccines.

Canada, the UK and countries in the EU have offered their younger population the Pfizer or Moderna vaccine as an alternative to AstraZeneca. Spain and South Korea have also been looking into a mix and match of these vaccines.

The UK’s Com-COV trials are also studying a mix and match of Moderna’s mRNA vaccine and Novavax’s protein subunit vaccine and results are expected by August, Professor Snape told The Economist.

Russia and China, too, are looking at a mix and match of other vaccines. Russia, for instance, has been planning on testing a combination of the AstraZeneca and Sputnik V vaccines.

In the US, the Centers for Disease Control in January allowed a mix and match of the Pfizer and Moderna vaccines — both mRNA jabs — under “exceptional” circumstances.

What could set India apart?

The government expects seven or eight Covid-19 vaccines made using vastly different technologies — viral vector, mRNA, DNA and recombinant protein — to be available by December. This gives India an opportunity to test combinations not tried globally. With some of the upcoming vaccines expected to be cheaper and easier to mass manufacture, successful combinations of these vaccines could especially be useful for low-and middle-income countries struggling to get sufficient supplies for standard vaccinations.

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