According to an early study issued this week, two vaccines based on messenger RNA (mRNA) have proven phenomenally effective against COVID-19, while a third mRNA-based option has failed in a final-stage experiment. Researchers are now trying to figure out why, and some believe it has something to do with the sort of mRNA chemistry employed. Any information gained might aid in the development of mRNA vaccines for COVID-19 and other illnesses in the future.
CureVac, located in Tübingen, Germany, published early findings from a 40,000-person study on June 16th, showing that their two-dose vaccination was only 47% efficient at preventing illness.
CureVac’s mRNA vaccine was predicted to be less expensive and survive longer in refrigerated storage than Pfizer’s BioNTech and Moderna mRNA vaccines. Many believed it would help spread mRNA-based vaccinations to low-income countries, and European governments were planning to purchase hundreds of millions of doses.
“I’m both shocked and disappointed,” says Philip Santangelo, a biomedical engineer at Georgia Tech in Atlanta who has worked with several mRNA-focused startups, including CureVac.
He and others believe CureVac’s failure to modify the biochemical make-up of its mRNA, as Pfizer–BioNTech and Moderna did, is to blame, but it’s too soon to say for sure.
PROBLEM WITH VARIATION
The bad findings, according to CureVac officials, are due to the large variety of coronavirus variations prevalent in the 10 nations where the firm is conducting its trial, including new ones like the Lambda version originally discovered in Peru. Only one of the 124 COVID-19 cases for which scientists got a genetic sequence was caused by the initial SARS-CoV-2 strain.
Other mRNA vaccines, on the other hand, have fared considerably better in the face of variations.
For example, researchers in the United Kingdom found that the Pfizer–BioNTech shot provided 92 percent protection against symptomatic COVID-19 cases caused by the Alpha version (originally discovered in the UK) and 83 percent protection against the Delta variant (initially reported in India). In research conducted in Qatar, the vaccine was shown to be about 90% effective against the Alpha strain and 75% effective against the Beta strain that appeared in South Africa.
Because of the disparities in efficacy, study investigators and other experts believe the issue lies with the vaccination itself.
DOSE OF RESISTANCE
“My best guess is that the dosage is the problem,” says Peter Kremsner, a Tübingen University Hospital infectious disease expert who is directing CureVac’s clinical trials.
Kremsner and his colleagues tested dosages ranging from 2 to 20 micrograms of mRNA per injection in phase I testing. The vaccination caused too many adverse effects at higher dosage levels, with study participants commonly reporting severe headaches, tiredness, chills, and injection-site discomfort.
The vaccination was more acceptable at 12 micrograms, and all patients produced antibodies that prevented the virus from entering cells. However, the levels of such ‘neutralizing’ antibodies were modest — comparable to those seen in persons who have recovered from SARS-CoV-2 infections, but far lower than those detected in recipients of the Moderna and Pfizer–BioNTech vaccines, both of which are given at larger dosages.
Perhaps it’s no wonder, therefore, that CureVac’s attempt failed, according to Nathaniel Wang, CEO of Replicate Bioscience, a San Diego-based RNA-focused biotech start-up. Early on, the low antibody titers were “already a warning flag,” he adds.
Some scientists are perplexed as to why the vaccine can’t be given in greater dosages without causing negative effects.
The lipid bubbles that mRNA vaccines are encased in, which assist the transfer of their genetic payloads into cells, can cause adverse effects like those shown in the CureVac study. However, Santangelo claims that the CureVac and Pfizer–BioNTech vaccines employ lipid bubbles that are almost comparable, if not identical.
He and others believe the issue is related to the mRNA sequence.
RNA THAT HAS BEEN MODIFIED
The coronavirus spike protein, which enables virus particles to infiltrate human cells, is encoded by all three mRNA vaccines. In place of uridine, the Moderna and Pfizer–BioNTech vaccines employ modified RNA, which includes an mRNA nucleotide termed pseudouridine, which is identical to uridine but has a natural change. This is considered to work by preventing the body from reacting to foreign mRNA with inflammation. CureVac’s vaccine employs regular uridine and depends on changing the sequence of RNA letters in a way that doesn’t impact the protein it codes for but aids immune evasion.
The chemical modification, according to proponents of modified mRNA, is critical to the success of vaccination technology. Drew Weissman, an immunologist at the University of Pennsylvania in Philadelphia, defines pseudouridine as the “greatest platform for antibody and neutralization levels” in this context, which he co-discovered in the mid-2000s4. Many scientists who spoke to Nature agreed in light of the new CureVac results.
“Modified mRNA has won this game,” says Rein Verbeke, a Ghent University mRNA vaccine researcher.
CureVac’s tolerability issues might be explained in a variety of ways. Structure variations in the CureVac sequence’s non-coding regions might be a factor. Alternatively, CureVac’s jab’s greater storage temperature might have hastened the breakdown of mRNA in the vial, resulting in fragments of genetic code that would irritate the immune system. In theory, any contaminants added throughout the production process of the firm would have the same impact.
As a result, some experts believe it is still too early to draw judgments. According to Jeffrey Ulmer, a former pharmaceutical executive who now consults on vaccine development concerns, “the jury is still out on whether of them is a better technology.” Both modified and unmodified mRNA, he believes, will be beneficial in different situations. “It’s possible that no one-size-fits-all answer exists for everything.”
CureVac is hopeful that their vaccine, or at the very least its unmodified mRNA technology, will succeed. The experiment is still ongoing, and a final report is expected in the coming weeks. Even if the vaccine fails, adds Jacob Kirkegaard, a vaccine supply specialist at the Peterson Institute for International Economics, a think-tank in Washington DC, “I don’t think it will put the globe back much”.
He points out that a second-generation vaccination with many of the same logistical selling features as CureVac, such as long-term refrigerator storage, has fared well against the variation test. Novavax of Gaithersburg, Maryland, said earlier this week that their protein-based vaccine was more than 90% successful at preventing COVID-19 in a major US study conducted during a time when the Alpha form was common.
Kirkegaard claims that the volume of manufacture of other vaccines more than compensates for the unavailability of CureVac’s product.
According to data from rat and monkey studies, CureVac, in collaboration with London-based GlaxoSmithKline, is developing a second-generation COVID-19 vaccine that, like its predecessor, uses unmodified mRNA but has been fine-tuned to elicit levels of neutralizing antibodies that are around ten times higher. Mariola Fotin-Mleczek, CureVac’s chief technical officer, adds, “Our optimization has never ceased.” “It’s too early to rule out the use of unaltered natural messenger RNA.” Human testing will begin later this year.
