Once-promising mRNA COVID-19 vaccine disappoints with final trial data
Behind Pfizer and Moderna, CureVac’s mRNA COVID-19 vaccine was long-anticipated, with hundreds of millions of doses already pre-ordered. But its final large trial data has disappointed with only 48 percent efficacy at preventing symptomatic disease.
Late in 2020, two experimental mRNA COVID-19 vaccines delivered stunningly positive final phase human trial results. With efficacy higher than 90 percent, the Pfizer and Moderna vaccines introduced the world to an entirely new kind of biotechnology, and offered a way out of this devastating global pandemic.
Trailing behind those two vaccines was a third mRNA COVID-19 candidate from a German company called CureVac. Founded in 2000 by Ingmar Hoerr, CureVac was one of the first biopharmaceutical companies to really focus on mRNA therapies.
Following the success of other mRNA COVID-19 vaccines in late 2020, a great deal of attention shifted to CureVac’s promising candidate. The company was a little slower to get development going early in the pandemic, partially due to a notorious refusal of a billion-dollar buyout offer from US president Donald Trump. Eventually the German government invested hundreds of millions of euros to get CureVac’s research moving but large-scale clinical trials still didn’t get started until the end of the year.
CureVac’s vaccine promised significant benefits over Pfizer and Moderna’s candidates. It was cheaper and crucially didn’t require the extreme cold storage needed to preserve other mRNA vaccines.
Members of the European Union pre-ordered nearly half a billion doses of CureVac’s vaccine and it was set to play a major role in global vaccination efforts.
Over the last couple of weeks the first data from CureVac’s massive global Phase 3 trial has been revealed. The trial enrolled around 40,000 people, spanned 10 countries and covered 15 different SARS-CoV-2 variants.
According to the company, its vaccine, dubbed CVnCoV, showed an efficacy of just 48 percent against symptomatic disease of any severity. A more detailed breakdown of the data reveals a slightly rosier picture with efficacy rising to 77 percent when focusing on preventing moderate to severe disease in subjects aged 18 to 60. And, perhaps most importantly, there were zero hospitalizations or deaths in the vaccine cohort.
“In this final analysis, CVnCoV demonstrates a strong public health value in fully protecting study participants in the age group of 18 to 60 against hospitalization or death and 77 percent against moderate and severe disease – an efficacy profile, which we believe will be an important contribution to help manage the COVID-19 pandemic and the dynamic variant spread,” says CureVac CEO Franz-Werner Haas.
Exactly why CureVac’s mRNA COVID-19 vaccine does not seem to be as effective as Pfizer or Moderna’s is a massive mystery. CureVac contends the primary reason is due to the prevalence of SARS-CoV-2 variants circulating during its clinical trial. Only three percent of COVID-19 cases detected in the CVnCoV trial came from the original SARS-CoV-2 strain.
“In the current context of an increasingly diverse environment of COVID-19 variants, and with very little residual prevalence of the original strain, we are confident that the HERALD study offers clinically relevant data regarding the effect of emerging variants on vaccine efficacy,” notes Franz-Werner Haas.
Kathleen Neuzil, a vaccine expert from the University of Maryland, is skeptical these discordant results can be fundamentally explained by virus variants. Increasing volumes of real-world data do indicate current mRNA COVID-19 vaccines do seem to offer strong, albeit slightly reduced, protection from disease caused by these new variants.
“It’s just hard for me to believe that the variants could have this degree of effect,” Neuzil said recently to ScienceMag.
One of the big differences between CureVac’s mRNA vaccine and those developed by Pfizer and Moderna is how the mRNA molecules are designed. CureVac has long touted its use of a natural, unmodified form of mRNA, while the other two vaccines rely on several key RNA base modifications.
CureVac’s chief technology officer has recently said it is too early to completely write-off unmodified natural mRNA, and the company is already working on a new iteration of its COVID-19 vaccine, still using unmodified mRNA. But other mRNA researchers seem more convinced unmodified mRNA is simply a less effective vaccine technology.
A pointed recent analysis from chemist and pharma researcher Derek Lowe suggests the failure of CureVac is a potent reminder of how difficult it is to develop an effective vaccine. And despite CureVac’s mRNA stumble we are quickly learning how to optimize these vaccines with newer, safer, and more effective iterations in development.
“It should be obvious by now, given the number of prominent failures, that generating an effective coronavirus vaccine is not something you can just stroll up to,” writes Lowe. “The fact that we have any vaccines at all is worth celebrating, and the fact that we have some that work so well, and with such good safety records, is a world-historical stroke of good news.”