The COVID-19 pandemic was a time of many firsts, including the first widespread use of mRNA vaccines to combat a global pandemic. Since then, questions have been asked about their safety and efficacy, often fuelled by genuine concerns and harmful health misinformation in equal measure. Today, the Pfizer-BioNTech mRNA COVID-19 and Moderna COVID-19 vaccines remain the only two licensed mRNA vaccines for public use.

To combat health misinformation around the new vaccine type, Professor Heidi Larson, Director of the Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine (LSHTM) and researchers from several other institutions have reviewed all the evidence on the COVID-19 mRNA vaccines. They reviewed the scientific evidence on the vaccines, from their ingredients and safety record to their ongoing monitoring and real-world effectiveness. Their findings, published in The Lancet, give a comprehensive, evidence-based picture of mRNA vaccines.

Julius Hafalla Associate Professor and Vaccine Centre Co-Director said: “This review brings together the best available evidence from many studies into a single, accessible resource and reinforces that mRNA vaccines have a strong safety profile and have provided substantial protection against severe disease, hospitalisation and death.

“Beyond COVID-19, mRNA platforms are currently being explored for several infectious diseases and could help accelerate vaccine development against future emerging threats. Continued innovation, alongside efforts to improve affordability and global access, will be essential to ensuring these scientific advances benefit populations worldwide.”

1. mRNA vaccine ingredients have almost no impurities

Because mRNA vaccines were the first vaccines based of this technology to be used at a global scale, questions were raised about their ingredients and manufacturing process. One area of public discussion was the presence of trace amounts of residual DNA left over from the manufacturing process. However, these impurity levels are strictly monitored by regulatory bodies including the World Health Organization and US Food and Drug Administration. Multiple analyses by these regulators and independent laboratories have found that impurity levels in the mRNA vaccines are well below the required legal limits.

2. mRNA vaccine ingredients are stable at different temperatures

Vaccines are often produced in temperature-controlled environments to ensure the stability of their ingredients. However, real-world conditions are far less controlled – temperatures can vary as vaccines are distributed and used across the world. As such, vaccines must have ingredients that retain their structure (stability) as temperatures fluctuate above and below zero Celsius (the freeze-thaw cycle).

The issue of vaccine stability and storage is not unique to mRNA vaccines as all vaccine types have storage requirements. Vaccines can lose potency due to temperature shifts and this is a longstanding concern in immunisation programmes.

Pfizer's COVID-19 vaccine initially required storage at around -70°C. This raised concerns about whether the vaccines could be transported and distributed globally, particularly in low-resource settings. This led to questions regarding whether repeated freezing and thawing during transport might damage the mRNA and reduce vaccine quality or effectiveness.

The review is reassuring because it shows that studies consistently found high levels of mRNA integrity, even after freeze-thaw cycles, and that the vaccines remained stable under approved storage and handling conditions.

The initial and continued concerns were largely addressed through extensive testing, monitoring and improvements in storage guidance.

This review highlights studies that show that mRNA vaccines, even after the freeze-thaw cycle, retain 95% of their intact mRNA. This confirms that they can be safely rolled out worldwide, despite exposure to varying temperatures.

3. mRNA vaccines are safe with low risk of complications and negative reactions based on safety surveillance

As part of the routine monitoring of this new vaccine technology, the mRNA COVID-19 vaccines were monitored for any potential adverse reactions during both clinical trials and during their first global roll out. As part of this, regulators became aware of several potential complications including increased risks of anaphylaxis, myocarditis and pericarditis, thromboembolic events and Bell’s palsy.

This review found that:

• The risk of anaphylaxis was very low (2.3-8 per 1,000,000 mRNA vaccine recipients);
• myocarditis and pericarditis risk was lower compared to when being infected by COVID-19;
• thromboembolic events (blood clots), a known side effect of COVID-19 infection, have not been associated with the mRNA vaccines;
• Bell’s palsy was highlighted as a potential risk during phase three clinical trials of the mRNA vaccines. This increased risk was not seen consistently as the COVID-19 vaccines were rolled out more widely.

4. COVID-19 mRNA vaccines provided strong protection to many groups against hospitalisation and death but protection wanes over time

Even before they were made public, the COVID-19 vaccines showed high vaccine efficacy – over 90% after two doses. Gavi explains vaccine efficacy as the degree to which a vaccine prevents disease, and possibly also transmission, under ideal and controlled circumstances.

In the real-world, the review concluded that the vaccines were also shown to be effective, with a comprehensive analysis of existing studies showing 87% protection against any documented infection, 93% against hospitalisation, and 94% against mortality 14–42 days after vaccination. Importantly, this protection also extended to some of the most vulnerable groups in society; pregnant people, children and teenagers, and immunocompromised people.

Importantly however, the review stated that studies found that protection waned over time: 48% protection against infection and 80% against hospitalisation by 224–251 days post-vaccination with the Omicron variant vaccine. This, alongside continued viral evolution, led to recommendations of annual booster doses for high-risk groups in many countries.

5. COVID-19 mRNA vaccines did not prevent infection but did reduce transmission

The review concluded that the COVID-19 vaccines effectively prevented the spread of the virus by reducing the risk of transmission by 31% if someone had been vaccinated less than six months before exposure. Importantly however, the vaccines did not “elicit true sterilising immunity at the mucosal surface”, meaning they did not completely prevent infection but instead significantly reduced the risk of an infected person transmitting the virus to others. 

6. COVID-19 mRNA vaccines are still monitored for safety and efficacy today

Surveillance doesn’t end after the initial rollout, stresses the review, with the authors showing that COVID-19 vaccines continue to be monitored today through passive and active surveillance systems globally. In fact, vaccine manufacturers must continually provide regulators with ongoing safety information to maintain the regulatory approval of the vaccines and independent academic groups and national public health agencies often conduct their own large-scale surveillance studies to independently verify these reported safety claims.

7. People were and continue to be worried about new vaccine technologies like mRNA vaccines

During the pandemic, many people were worried about the perceived newness of the COVID-19 mRNA vaccines - how quickly they were developed and made available. While these concerns are understandable, vaccines undergo extensive testing before approval and continue to be monitored after they are introduced for routine use.

This vaccine hesitancy was further fuelled by health misinformation, something that LSHTM has been working to combat through its Health Information Integrity Network and regular news articles focused on health misinformation around measles in the UK and the false link between paracetamol and autism.

In June it was also announced that Professor Heidi Larson, Director of the Vaccine Confidence Project at LSHTM, will co-lead the new Lancet Commission on rethinking misinformation, health, and human security.

The NHS, WHO and national regulatory agencies provide detailed information on how vaccine safety is assessed and monitored.

8. mRNA vaccine development has a bright future but does face tough challenges

mRNA vaccines have already transformed vaccine development, and new mRNA vaccines against mpox, HIV, chickenpox, norovirus, and Mycobacterium tuberculosis are already in clinical trials.

The authors do warn that barriers to the technology do exist;

• mRNA vaccines don’t necessarily prevent initial infection due to their low mucosal immunity
• Due to nature of the immune response they generate, mRNA vaccines may provide strong short-term protection, while long-term protection can be more limited.
• Global access to mRNA vaccines remains a major challenge, particularly due to their technology-intensive production and storage requirements, meaning that production costs are high; costing between US$85–290 per dose. This effectively makes mRNA vaccines unaffordable for many low- and middle-income countries that would often benefit from them most.

Commenting on the importance of the Lancet review, Professor Muhammed Afolabi and Dr Julius Hafalla, Co-Directors of LSHTM’s Vaccine Centre said:

Dr Muhammed Afolabi, Clinical Associate Professor and Vaccine Centre Co-Director at LSHTM said: “While COVID-19 demonstrated the speed of vaccine development, our focus must now broaden to the 'silent' emergencies. We are seeing encouraging progress on vaccines against respiratory syncytial virus (RSV), norovirus, and group B streptococcus, as well as novel candidates for tuberculosis and malaria.”

For low- and middle-income countries, the cost of vaccines is often just the tip of the iceberg. Our priorities must therefore be twofold: first, to negotiate tiered pricing and transparent, volume-guaranteed procurement (like Gavi's model); and second, to invest in thermostable formulations and needle-free delivery systems that reduce the burden on fragile health systems. Affordability is not just about the price per dose; it is about the total cost of immunisation.”

Read the full article: Safety and efficacy of mRNA vaccines: a mechanistic and public health perspective