Dive Brief:

• An experimental coronavirus vaccine from drugmaker CureVac was only 47% effective at preventing COVID-19 in a preliminary analysis of results from a large clinical trial, a disappointing result that the German biotech company attributed to the widespread prevalence of virus variants.

• According to CureVac, the efficacy estimate could change as more of the COVID-19 cases reported in the study are assessed and a final analysis is completed. At that point, the company will share the full results with European regulators to determine the “most appropriate regulatory pathway,” CureVac said in a June 16 statement.

• Currently, however, the results fall short of the 50% efficacy threshold regulators have established for coronavirus vaccines, a significant setback for CureVac and a perplexing contrast to the data supporting vaccines from Moderna and partners Pfizer and BioNTech, which rely on similar messenger RNA technology. Shares in CureVac collapsed by nearly 50% in post-market trading Wednesday, erasing billions in market value.

Dive Insight:

Like Moderna and BioNTech, CureVac has spent years working on messenger RNA technology, which until the pandemic was an unproven approach for designing effective vaccines. The company’s previous research enabled it to quickly pivot and pour resources toward development of a vaccine for COVID-19.

But the paths taken by Moderna and BioNTech and by CureVac diverged from there. Moderna received significant help from National Institutes of Health scientists and billions of dollars from the U.S. government. BioNTech allied with Pfizer, which poured billions of dollars into a program that sped forward. Their vaccines entered Phase 3 testing within days of one another last summer, which, given the high number of COVID-19 cases in the U.S. at the time, resulted in fast clinical trial progress.

CureVac received support from the U.S. and German governments last year as well. But the company was also subsumed in an international controversy over reports the Trump administration had attempted to secure exclusive access to its vaccine. CureVac wasn’t selected for the U.S. Operation Warp Speed program, and lacked a larger partner until much later on. A large Phase 3 trial didn’t begin until December.

Still, expectations were high for CureVac as both Moderna and BioNTech’s vaccines were found to be more than 90% effective at preventing COVID-19 in their respective late-stage trials. Those results have since been reinforced by similarly strong data from real-world use in major vaccination campaigns in the U.S., Israel and other countries.

Shares of CureVac, which went public last August, soared as high as $136 apiece late last year, more than 8 times the initial public offering price of $16.

Yet there were several question marks for CureVac’s vaccine and how it might perform. Based on early testing data, the company chose a significantly lower dose than either BioNTech or Moderna. Immune response results were positive, but appeared somewhat weaker. CureVac also didn’t chemically modify the mRNA sequence used in its vaccine, as BioNTech and Moderna did.

Perhaps most importantly, CureVac’s Phase 3 study began after variants had already spread widely, meaning participants were exposed to potentially more formidable strains of the virus than Moderna’s or BioNTech’s vaccines had been in testing.

Until the full data are disclosed, it won’t be clear which of those factors contributed most to the disappointing results. CureVac, for its part, claims variants are to blame. In a statement, the biotech said its study was run in the “unprecedented context of at least 13 variants,” although only a little more than half of the COVID-19 cases were attributed to the variants that most concern public health officials. The study was run at sites in Latin America and Europe.

CureVac dealt with a “dramatically transformed variant environment, suggesting that we are virtually fighting a different virus, different pandemic over the last six months,” said CEO Franz-Werner Haas, on a conference call Thursday morning.

Just one case was caused by the original virus strain that emerged in China last year — the version Moderna’s and BioNTech’s shots were primarily tested against — while 21% were from a less studied variant called Lambda that was first detected in Peru. Forty-one percent of cases were linked to the Alpha variant that originated in the U.K., according to the company’s presentation.

The mix of variants makes comparing the 47% figure to the clinical trial efficacy estimates from Moderna and BioNTech “technically apples to oranges,” wrote Umer Raffat, an analyst at Evercore ISI, in a note to clients. The version of Alpha that CureVac confronted, for example, may have acquired an evasive mutation known as E484K, Raffat wrote.

Nonetheless, the other mRNA vaccines have proven strongly protective against a variety of variants, including Alpha, in real-world use. They’ve even proven effective against Beta and Delta variants, which are though to diminish vaccine potency. CureVac’s results, then, could point to a threshold for the levels of neutralizing antibodies needed to protect against COVID-19, Raffat wrote. Researchers have not yet established what such a “correlate of protection” looks like for coronavirus disease.

Another vaccine developer, Novavax, also reported results this week from a late-stage study heavily impacted by virus variants, but showed much higher overall efficacy, of about 90%.

CureVac did suggest efficacy might be greater in younger study participants than in older ones, but did not specify further. The interim analysis, one of two specified in the trial’s protocol, was based on 134 COVID-19 cases that occurred at least two weeks after participants received their second dose. Another 474 cases have been reported, but have not yet been fully assessed so weren’t included in the efficacy calculations.

CureVac plans to finish assessing the results and discuss its findings with regulators, so the vaccine could still potentially have a future. The final analysis should take place within two to three weeks and include more details on how well the shot performed in different age groups and variants, as well as how many volunteers had severe disease, executives said on the call. Those details will be important, as they could help regulators figure out which people CureVac’s shot could help the most.

“We don’t really know at the moment,” said Haas. “We wait for the final data.”

But the company is also working with GlaxoSmithKline to develop shots specifically tailored to coronavirus variants, and should begin human testing of a new candidate in the third quarter.