What went wrong with CureVac's mRNA vaccine?

doi:10.1126/science.372.6549.1381

GSTDTAP > 气候变化

DOI	10.1126/science.372.6549.1381
	What went wrong with CureVac's mRNA vaccine?
	Jon Cohen
	2021-06-25
发表期刊	Science
出版年	2021
英文摘要	Science's COVID-19 reporting is supported by the Heising-Simons Foundation The startlingly poor performance revealed last week for a COVID-19 vaccine made by the German company CureVac isn't just a disappointment, it's a scientific puzzle. The company blames the rapidly changing pandemic virus. But several outside researchers suspect the vaccine's design is at fault. Many scientists and investors alike had expected CureVac's candidate, which uses messenger RNA (mRNA) to code for the spike surface protein of SARS-CoV-2, had a good chance of becoming one of the most powerful new weapons against the pandemic. It relies on essentially the same novel mRNA technology as vaccines from the Pfizer-BioNTech collaboration and Moderna, which demonstrated more than 90% efficacy in their trials, and it holds some practical transportation and storage advantages over those rival shots. But preliminary data from a trial enrolling some 40,000 people, about 75% in Latin America and 25% in Europe, suggest the efficacy of the CureVac vaccine is a lackluster 47%—low enough that, if further data are equally disappointing, health regulators likely won't authorize it for emergency use. The topline finding came from an interim analysis evaluating 134 participants who developed at least one COVID-19 symptom. Although the company did not give a breakdown, the reported 47% efficacy translates to roughly 88 COVID-19 cases in the placebo group and 46 among the vaccinated. “The results are sobering,” said Franz-Werner Haas, CureVac's CEO. The vaccine's mRNA was designed for a version of spike that was dominant among the SARS-CoV-2 circulating early in the pandemic, but since then the virus has evolved into many variants. Only 1% of infected trial participants had a virus with the original spike protein; the others harbored a total of 12 different variants. “We are virtually fighting a different virus, different pandemic over the last 6 months,” Haas said. “Demonstrating high efficacy in this unprecedented broad diversity of variants is quite challenging.” Other efficacy trials have found that certain mutant strains of the coronavirus can compromise the ability of COVID-19 vaccines to protect against mild disease, but the variant that has most powerfully undermined other vaccines, Beta, was not seen in the CureVac study. In contrast, Alpha, first seen in the United Kingdom and one of the earliest variants of concern, caused 41% of the 124 cases overall and 91% of the 44 cases that occurred in Europe. Kathleen Neuzil of the University of Maryland School of Medicine doubts variants fully explain the poor performance of CureVac's vaccine. Unlike CureVac's mRNA shot, she says, the Pfizer-BioNTech and Moderna vaccines “work very well against Alpha.” She cautions that it's difficult to compare trials of different vaccines, but says, “It's just hard for me to believe that the variants could have this degree of effect.” CureVac did not provide any data about how many of the people infected in the trial developed severe disease. Other vaccines continue to prevent most hospitalizations and deaths even when variants reduce their protection against mild COVID-19. Some scientists trying to make sense of the CureVac result point to an earlier, phase 1 study of the vaccine. It showed that serum levels of so-called neutralizing antibodies, which prevent the virus from binding to cells, were relatively low in vaccine recipients compared with people naturally infected with the coronavirus. “It's certainly a good possibility that the vaccine is just not immunogenic enough,” says immunologist John Moore of Weill Cornell Medicine. The type of mRNA used by CureVac may undermine antibody formation, contends Drew Weissman of the University of Pennsylvania's Perelman School of Medicine, who helped pioneer certain mRNA modifications used in the Pfizer-BioNTech and Moderna vaccines. (Those companies license the technology, which may financially benefit the university and Weissman.) CureVac's vaccine used an unmodified form of mRNA. When natural mRNA is injected into the body, it triggers the production of interferons, signaling molecules that can rev up the immune system. CureVac touted that as an advantage of its formulation. But Weissman notes interferons can also block the generation of T helper cells that, in turn, direct B cells to make antibodies. The other companies' mRNA vaccines, in contrast, use chemically altered uracils, one of the four nucleotides that make up RNA. Weissman's group had shown in 2018 that uracil-modified mRNA triggered potent neutralizing antibodies and other protective immune responses in animal models. He notes that a BioNTech study comparing modified and natural mRNA vaccines also found that the modifications boosted the antibody response. Peter Kremsner of University Hospital Tübingen, who helped run the CureVac efficacy study, suggests the company may have given people too low a dose of its vaccine. “I am uncertain what it was finally, natural uracil or only dose or both,” he says. CureVac's phase 1 study had compared the safety and immune responses generated by doses between 2 and 20 micrograms, but because of side effects at the highest doses, the company settled on a standard dose of 12 micrograms. (The Pfizer-BioNTech vaccine uses a 30-microgram dose and Moderna's is 100 micrograms.) Other data presented by CureVac last week suggest, however, that the design of the vaccine is more important than the dose. It reported data from a monkey study that compared the current vaccine with a next-generation version, whose mRNA is more stable inside of cells: Even when the dose was the same, the new candidate produced higher levels of the spike protein, triggering a 10-fold higher level of neutralizing antibodies. Dose-ranging studies of the Pfizer and Moderna vaccines have also found that higher mRNA doses offer relatively modest gains in antibody levels. Still, CureVac says it must wait for the final analysis of the current efficacy trial, expected to amass more than 200 COVID-19 cases, before it decides whether to make a “strategic shift” to the second-generation vaccine. “For now, we are going full speed exactly where we are,” Haas said. “We are expecting the data to come within the next 3 weeks.”
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推荐引用方式 GB/T 7714	Jon Cohen. What went wrong with CureVac's mRNA vaccine?[J]. Science,2021.
APA	Jon Cohen.(2021).What went wrong with CureVac's mRNA vaccine?.Science.
MLA	Jon Cohen."What went wrong with CureVac's mRNA vaccine?".Science (2021).