Seven vital questions about RNA Covid-19 vaccines

Both the Pfizer-BioNTech and Moderna Covid-19 vaccines, unlike the vaccines we already use for other diseases, have been developed using ribonucleic acid (RNA) technology. So, how do they work, are they safe, and what else do we know about them? 

Hand holding a vaccine next to a sequence of messenger RNA genetic code
Credit: Wellcome
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Seven vital questions about RNA Covid-19 vaccines
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1. How do RNA vaccines work? 

RNA, closely related to DNA, is present in all living cells. The strand of it called messenger RNA (mRNA) is a sequence of genetic code that tells cells what proteins to build so that they can function. 

Professor Luke O'Neill, Chair of Biochemistry at Trinity College Dublin, explains what mRNA vaccines are.

To produce an RNA vaccine, scientists develop a synthetic version of some of the virus’ messenger RNA. 

When this is injected into the human body, our cells read it as an instruction to start building the proteins, including, in this case, Covid-19's distinctive 'spike' protein.

Our bodies then mount an immune response by producing antibodies to fight the virus proteins made by our cells. This prepares our immune system to fight the real virus if we encounter it later on. 

This is different to the way some other vaccines work, where a small part of the virus itself, or the whole virus (weakened or dead), is injected into the body to trigger an immune response. 

Graphic showing how RNA vaccines work

A synthetic version of part of the virus' genetic code is injected. It tells our cells to start building the virus protein, triggering an immune response.

2. How is RNA vaccine development different to other vaccine development? 

RNA vaccines hold the promise of being faster, cheaper, more adaptable and easier to mass-produce than other vaccines, because:

  • They can be generated quickly. RNA vaccines are based on a process of biochemical synthesis that involves fewer components and fewer steps than the more complex traditional methods, like using inactivated live viruses. This means they are quicker to get into clinical trials and quicker to manufacture once the trials are completed – in a matter of weeks and months. 
  • They should be cheaper to develop. Only a small amount of RNA needs to be delivered into the body’s cells, compared to the much larger micrograms of protein that are required for many other vaccines. This means each individual vaccine dose should be cheaper to purchase, although it is dependent on the price set by pharmaceutical companies and the costs of delivery.
  • They could be more adaptable and easier to manufacture at scale. The same RNA vaccine platform could be used to produce vaccines against different diseases – both known and emerging. A manufacturing plant could, in theory, produce multiple vaccines using the platform, whereas other vaccines, such as MMR (measles, mumps, and rubella) and Ervebo (one of the Ebola vaccines), each require their own dedicated manufacturing plant.

3. Have there been any other RNA vaccines? 

The Pfizer-BioNTech and Moderna vaccines are the first RNA vaccines ever to be approved for use against any disease.

However, researchers have been using the technology for a while, and people have been given RNA vaccines in clinical trials for other diseases, like cancer.

A major challenge in the past has been figuring out how to deliver the RNA vaccine into the cell so it survives – our bodies naturally want to destroy foreign RNA molecules. 

This new use of RNA has only been made possible due to the enormous level of research funding and focus during the pandemic, which has allowed breakthroughs in new technologies.

The cutting-edge method could revolutionise vaccine development for existing conditions and diseases – and future outbreaks. A vaccine for HIV and therapies for cystic fibrosis and multiple sclerosis are just some of the new mRNA treatments in development.

Researchers at Imperial College London are also using RNA technology to develop vaccines, including for Covid-19.

4. Are the vaccines safe? 

Before any vaccine can be approved for use it must go through rigorous testing, to make sure it is safe, as well as effective. 

Around 43,500 people were enrolled in the Pfizer-BioNTech clinical trials, and 30,000 people in the Moderna clinical trials. Safety was assessed throughout, and no major side-effects were reported during the phase I, II and III trials.

Once the trials are complete and the full data has been analysed, regulators around the world review it and decide whether the vaccines can be approved for use in their countries. They look at all the preclinical, clinical and manufacturing process data, including the safety and efficacy data. 

Once approved, the vaccines will be monitored as they are given to prioritised high-risk groups, to understand how they perform in different population groups over time, and to look for very rare side-effects or long-term safety issues. Of the billions who have received the vaccines so far, few people have had a very rare allergic reaction.

Nothing in medicine is 100% safe, and very rare side-effects may emerge as billions of people are vaccinated. This is the same for all vaccines.

Infectious disease

Our vision is a world in which escalating infectious diseases are under control in the communities most affected. 

5. How many vaccines are being produced? 

Pfizer-BioNTech produced three billion doses in 2021 and aims to boost supply to four billion doses in 2022.

Moderna manufactured around 800 million doses in 2021 and plans to produce up to three billion doses in 2022.

There are now 21 Covid-19 vaccines – made using very different technologies – being rolled out in countries around the world, and hundreds of candidates in development.

6. What are the potential limitations of the vaccines? 

Both vaccines showed efficacy of around 95% in phase III clinical trials in December 2020. This figure has changed over time, with the vaccines being rolled out and monitored in a ‘real world’ setting.

At six months after vaccination, Moderna has said its vaccine has 90% efficacy against infection and Pfizer-BioNTech has said its vaccine has 91.3% efficacy against infection.

But there are still many outstanding questions, for example how long immunity will last for, how effective the vaccines will be in different populations, whether people can still transmit the disease to others if they’ve been immunised – and how well the vaccines will work against new variants

Pfizer-BioNTech has reported high levels of vaccine efficacy in over 65 year olds – one of the groups most at risk of serious illness – which is very promising.

Although many vaccines need to be refrigerated – usually around 2 to 8C – the Pfizer-BioNTech Covid-19 vaccine needs to be kept cooler. In the initial distribution push, the vaccine needed to be stored at at least -70C. This posed problems for transporting and storing it, particularly in low- and middle-income countries where refrigeration facilities may be limited.

In May 2021, following new data shared by Pfizer, the vaccine was approved for storage in fridge temperature for up to one month, making it more widely available.

The Moderna vaccine can also be stored at fridge temperature for 30 days (2 to 8C) once delivered to healthcare facilities, but requires -20C for long-term storage and transportation.

It is critical that we continue with efforts to ensure fair access to Covid-19 vaccines, for example through the COVID-19 Vaccine Global Access Facility (COVAX). This will be instrumental to ensuring effective vaccines are prioritised for those most in need around the world.

7. Why do we need to continue to invest in different vaccine approaches? 

The world needs a range of vaccines that have different characteristics, are suitable for people of all ages and ethnic groups – including people with underlying health conditions, and able to be distributed and used in all settings around the globe. They must also be available in the billions of doses. One or two vaccines won't be able to achieve this, and so we must continue to develop multiple vaccines using multiple scientific approaches to be able to control the pandemic.

Learning from pandemics

Head of Prevention, Charlie Weller spoke to us about how the lessons of previous epidemics helped us respond to Covid-19.

Over the past decade we’ve seen the health and economic impact of influenza, SARS, Zika, Ebola and now Covid-19. There are certainly more outbreaks to come, but we don’t know when and where they will emerge, which makes preparation difficult. If we can hone new methods of developing vaccines, we’ll be much better prepared for any future outbreaks and able to save more lives with vaccines, faster.

That is why the urgent funding gaps in the global response to Covid-19 must be addressed. Only through appropriate funding can innovations like RNA vaccines be made possible.

This explainer was first published on 13 November 2020.