CureVac COVID vaccine let-down spotlights mRNA design challenges

Two vaccines made using messenger RNA (mRNA) have proved spectacularly successful at warding off COVID-19, but a third mRNA-based candidate has flopped in a final-stage trial, according to an initial report released this week. Researchers are now asking why — and some think that choices about the type of mRNA chemistry used might be to blame. Any insight could help to guide the future design of mRNA vaccines against COVID-19 or other diseases.

The company behind the beleaguered trial, CureVac, based in Tübingen, Germany, announced preliminary data on 16 June from a 40,000-person trial, which showed that its two-dose vaccine was just 47% effective at preventing disease.

Six months of COVID vaccines: what 1.7 billion doses have taught scientists

CureVac’s mRNA vaccine was expected to be cheaper and to last longer in refrigerated storage than the earlier mRNA vaccines made by Pfizer–BioNTech and Moderna. Many had hoped that it could help to expand the reach of mRNA-based vaccines in lower-income countries, and European countries were expecting to order hundreds of millions of doses.

“I’m definitely surprised — and also disappointed,” says Philip Santangelo, a biomedical engineer at the Georgia Institute of Technology in Atlanta who has worked with many mRNA-focused companies, including CureVac.

He and others suspect that CureVac’s decision not to tweak the biochemical make-up of its mRNA, as Pfizer–BioNTech and Moderna did, might be behind its poor performance — although it is too early to know for sure.

Variant problem

CureVac executives put the poor results down to the high number of coronavirus variants — including emerging ones such as the Lambda variant first detected in Peru — circulating in the ten countries across Europe and Latin America where the company is running its trial. Of 124 COVID-19 cases for which scientists obtained a genetic sequence, only one was caused by the original version of SARS-CoV-2.

But the other mRNA vaccines have fared much better in the face of variants.

Researchers in the United Kingdom have reported, for instance, that the Pfizer–BioNTech shot offered 92% protection against symptomatic cases of COVID-19 caused by the Alpha variant (first identified in the United Kingdom) and 83% protection against the Delta variant (initially reported in India)¹. A study in Qatar similarly found the vaccine to be around 90% effective against the Alpha strain and 75% effective against the Beta variant that emerged in South Africa².

Those differences in efficacy have led trial investigators and other scientists to suggest that the problem is with the vaccine itself.

Dose of reality

“My best take is that the dose is the culprit,” says Peter Kremsner, an infectious-disease specialist at Tübingen University Hospital who is leading CureVac’s clinical studies.

In phase I testing, Kremsner and his colleagues evaluated doses ranging from 2 to 20 micrograms of mRNA per injection. At the higher dose levels, the vaccine caused too many side effects, with trial participants frequently complaining of problems such as severe headaches, fatigue, chills and injection-site pain.

Nature 594, 483 (2021)

doi: https://doi.org/10.1038/d41586-021-01661-0

Related Articles

• Six months of COVID vaccines: what 1.7 billion doses have taught scientists

• Scientists zero in on long-sought marker of COVID-vaccine efficacy

• Mix-and-match COVID vaccines trigger potent immune response

• COVID vaccines and blood clots: five key questions

• WHO approval of Chinese CoronaVac COVID vaccine will be crucial to curbing pandemic

• Why COVID vaccines are so difficult to compare

• Rare COVID reactions might hold key to variant-proof vaccines

Subjects

• SARS-CoV-2
• Vaccines

Latest on:

SARS-CoV-2

US trust in scientists plunged during the pandemic — but it’s starting to recover

News 14 NOV 24

Design of customized coronavirus receptors

Article 30 OCT 24

How long COVID could lift the fog on neurocognitive disorders

Nature Index 02 OCT 24

Vaccines

This malaria vaccine is delivered by a mosquito bite

News 20 NOV 24

Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

Article 07 NOV 24

Mumps is rising in some nations — but a fresh dose of vaccine might help

Research Highlight 14 OCT 24