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Two vaccines made using messenger RNA (mRNA) have been shown to be spectacularly effective in warding off COVID-19, but a third mRNA-based candidate has failed in an end-stage trial, according to an initial report released this morning. week. Researchers are now wondering why – and some believe the choices about the type of mRNA chemistry used could be to blame. Any ideas could help guide the future design of mRNA vaccines against COVID-19 or other diseases.
The company behind the struggling trial, CureVac, based in Tübingen, Germany, announced preliminary data from a 40,000-person trial on June 16, which showed that its two-dose vaccine did not was only 47% effective in preventing disease.
CureVac’s mRNA vaccine was expected to be cheaper and last longer in refrigerated storage than earlier mRNA vaccines made by Pfizer-BioNTech and Moderna. Many had hoped it could help expand the reach of mRNA-based vaccines in low-income countries, and European countries expected to order hundreds of millions of doses.
“I’m really 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 change the biochemical makeup of its mRNA, as Pfizer-BioNTech and Moderna did, could be at the root of its poor performance – although it is too early to be sure.
Variant problem
CureVac executives attribute the poor results to the high number of coronavirus variants – including emerging variants such as the Lambda variant first detected in Peru – circulating in the ten countries in Europe and Latin America where the company conducts its test. Of 124 cases of COVID-19 for which scientists have obtained a genetic sequence, only one was caused by the original version of SARS-CoV-2.
But the other mRNA vaccines fared much better against the variants.
Researchers in the UK reported, for example, that the Pfizer-BioNTech shot offered 92% protection against symptomatic cases of COVID-19 caused by the Alpha variant (first identified in the UK) and a 83% protection against Delta variant (originally reported in India). A study in Qatar also found that the vaccine was around 90% effective against the Alpha strain and 75% against the beta variant that appeared in South Africa.
These differences in efficacy have led trial investigators and other scientists to suggest that the problem lies with the vaccine itself.
dose of reality
“My best opinion is that the dose is the culprit,” says Peter Kremsner, an infectious disease specialist at Tübingen University Hospital who heads the clinical studies for CureVac.
In Phase I testing, Kremsner and his colleagues evaluated doses ranging from 2 to 20 micrograms of mRNA per injection. At the highest doses, the vaccine caused too many side effects, with trial participants frequently complaining of problems such as severe headaches, fatigue, chills, and pain at the injection site.
At 12 micrograms, the vaccine was found to be more tolerable and all recipients developed antibodies that prevented the virus from entering cells. But the levels of these “neutralizing” antibodies were relatively low – on par with the amounts found in people who have recovered from SARS-CoV-2 infections, but well below the levels seen in Moderna and Pfizer vaccine recipients. -BioNTech, both of which are given in higher doses.
So it’s perhaps no surprise that CureVac’s shot failed, says Nathaniel Wang, managing director of Replicate Bioscience, an RNA-focused biotech startup based in San Diego, Calif. These low titers of antibodies in the first tests were “already a red flag”, he says.
Some researchers wonder why the vaccine could not be given in higher doses without inducing side effects.
The tiny bubbles made of lipids that mRNA vaccines are encapsulated in – to help transmit their genetic charges to cells – can trigger side effects such as those documented by the CureVac trial. But Santangelo says the CureVac and Pfizer-BioNTech vaccines use virtually indistinguishable, if not identical, lipid bubbles.
He and others believe the problem could lie in the mRNA sequence.
Modified RNA
All three mRNA vaccines encode a form of the coronavirus spike protein, which helps viral particles enter human cells. But the Moderna and Pfizer-BioNTech vaccines use modified RNA, incorporating an mRNA nucleotide called pseudouridin – which is similar to uridine but contains a natural modification – in place of uridine itself. It is believed to bypass the body’s inflammatory responses to foreign mRNA. CureVac’s vaccine uses normal uridine and relies on changing the sequence of RNA letters in a way that does not affect the protein it codes for, but helps the vaccine escape immune detection.
Proponents of modified mRNA have long argued that chemical adjustment is integral to the success of vaccine technology. Drew Weissman, an immunologist at the University of Pennsylvania in Philadelphia who co-discovered the importance of pseudouridin in this context in the mid-2000s4, describes it as the “best platform for antibody and neutralization levels”. In light of new data from CureVac, many scientists who spoke to Nature I agree.
“The modified mRNA won this match,” says Rein Verbeke, researcher on mRNA vaccines at Ghent University in Belgium.
There are a few other possible explanations for the tolerance problems of CureVac. Structural differences in the non-coding regions of the CureVac sequence could play a role. Alternatively, the higher storage temperature of CureVac’s jab could have accelerated the degradation of the mRNA in the vial, producing pieces of genetic code that would increase immune hacks. And if impurities were introduced during the company’s manufacturing process, they would, in principle, have the same effect.
So, for some scientists, it is still too early to draw any conclusions. “The jury is still out on which of these technologies is the best,” says Jeffrey Ulmer, a former pharmaceutical executive who now consults on vaccine research issues. He predicts that modified and unmodified mRNAs will be useful in different contexts. “There may not be a one-size-fits-all solution. “
CureVac is hoping its vaccine – or at least its unmodified mRNA technology – could still deliver. The company is continuing its trial and expects a final analysis in the coming weeks. On the public health front, even if the vaccine fails, “I don’t think it’s going to set the world back much,” says Jacob Kirkegaard, vaccine supply expert at the Peterson Institute for International Economics, a think tank in Washington DC.
He points out that another second-generation vaccine that offers many of the same logistical selling points as CureVac, such as long-term storage in the refrigerator, has stood up to the challenge of variants well. Earlier this week, Novavax in Gaithersburg, Maryland, reported that its protein-based vaccine was over 90% effective in preventing COVID-19 in a large US trial, conducted at a time when the Alpha variant was prevalent.
The scale of production of other vaccines more than makes up for CureVac’s lack of product, Kirkegaard says.
CureVac, in collaboration with London-based company GlaxoSmithKline, also has a second-generation COVID-19 vaccine in the works which, like its predecessor, uses unmodified mRNA, but has been refined to trigger levels of Neutralizing antibodies approximately ten times higher, based on data from studies in rats and monkeys. “Our optimization has never stopped,” says Mariola Fotin-Mleczek, CureVac CTO. “It is too early to say that natural unmodified messenger RNA is not an option.” Human trials are expected to start later this year.
This article is reproduced with permission and was first publication June 18, 2021.
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