COVID-19: Newcomer Moderna succeeds in large-scale trial

An independent board monitoring Moderna’s 30,000-person vaccine trial met on Sunday and reported to the company and U.S. government health officials that only five people in the vaccinated group developed confirmed cases of COVID-19, whereas 90 people who received placebo shots became ill with the disease. That’s an efficacy of 94.5%, the company reported in a press release this morning.

Although the clinical trial measurement may not translate into an equally high level of real-world protection, the success indicates the vaccine is Iikely more than effective enough to stop the pandemic if it can be widely distributed.

“That efficacy is just beautiful, and there’s no question about the veracity of it either,” says Lawrence Corey, a virologist at the Fred Hutchinson Cancer Research Center who co-led the clinical trials network that is testing the vaccine.

More hope after Pfizer/BioNTech

The Pfizer/BioNTech collaboration first gave the pandemic-fatigued world a shot of hope when it reported that its vaccine candidate, a strand of messenger RNA (mRNA) wrapped within a lipid particle, had an efficacy of greater than 90%. But its press release didn’t reveal much else, failing to note the number of COVID-19 cases in the vaccinated and placebo groups. (A Russian institute last week also claimed success for a non-mRNA COVID-19 vaccine, presenting little data from an interim analysis of 20 total COVID-19 cases in both arms of its trial.)

Moderna provided those details and more about its mRNA vaccine, adding to growing optimism among public health experts that the U.S. Food and Drug Administration (FDA) may soon authorize these COVID-19 vaccines for widespread use. Moderna, a company that has yet to bring a treatment or vaccine to market, offered compelling evidence that its candidate did more than just prevent symptomatic disease, the main endpoint for both trials. The company reported that 11 people in the trial’s placebo arm developed severe cases of COVID-19, whereas no one in the vaccinated group did. “Preliminary analysis suggests a broadly consistent safety and efficacy profile across all evaluated subgroups,” the press release states. This means the vaccine appears to work equally well in all populations studied, including the elderly and ethnic minorities, and people with preexisting conditions such as diabetes and heart disease that make them particularly vulnerable to severe COVID-19.

“Obviously, the data speak for themselves,” says Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), which helped support the study. “This is a very positive result.” He suspects that by late next month doses of one or both vaccines could start to be offered to people at highest risk from SARS-CoV-2, the virus that causes COVID-19.

But many questions remain about the durability of the vaccines’ protection, their safety, what FDA will demand to approve them, and the challenge of rapidly producing and distributing hundreds of millions—if not billions—of doses. For example, because warm temperatures cause the RNA and lipid particles to degrade, the vaccines must be kept frozen until days before use, requiring a “cold chain” to move them from manufacturing plants to pharmacies and clinics.

Some answers, more questions

Ruth Karron, who heads the Center for Immunization Research at the Johns Hopkins Bloomberg School of Public Health, notes that neither Moderna nor the Pfizer/BioNTech study evaluated whether the vaccine prevented infections as well as symptomatic disease, which is key to controlling the spread of the virus. “The data we have are that these vaccines protect you against severe illness, but it doesn’t mean that you can’t get infected and give it to your patient, your neighbor, your customer, or whomever,” Karron says. But she also says of the Moderna result: “Wow, fantastic, amazing.”

Moderna has been one of the pioneers of mRNA technology, attracting enormous investment for its quest to deliver RNAs that make therapeutic molecules or proteins that elicit a protective immune response. Since April, Operation Warp Speed, the U.S. government effort to develop a portfolio of COVID-19 vaccines and rapidly move them into efficacy trials, has invested $1 billion in Moderna’s COVID-19 vaccine R&D. Months later, Warp Speed committed another $1.5 billion to Moderna to purchase 100 million doses of its candidate and $1.9 billion to Pfizer for the same amount of its product, which was originally developed at BioNtech, a company that has focused on treating cancer with mRNA.

Although small studies have shown mRNA vaccines can trigger immune responses and don’t have obvious, significant safety issues, the two efficacy trials are the first to show that they can actually protect people from a pathogen. Both vaccines rely on a snippet of mRNA that codes for the SARS-CoV-2 surface protein, designed by a research team led by Barney Graham of NIAID’s Vaccine Research Center. When he learned last week that the strategy worked, Graham says, “I had my moment of relief and sobbing tears.”

Both mRNA vaccines have yet to complete their efficacy trials, which aim to accrue about 150 to 165 cases of COVID-19 to provide greater statistical certainty of any efficacy result. But they should hit those targets by December, when FDA plans to convene an advisory committee to review the data, as most trial sites are in the United States, where the epidemic is exploding.

Moderna ready to release 20 million doses

If the advisory committee recommends that FDA issues what’s known as emergency use authorizations for the vaccines, Warp Speed plans to start to deliver them to pharmacies and clinics around the country the next day. Moderna projects it can have about 20 million doses for the United States by the end of the year. Pfizer, which has made sales agreements with several countries in addition to the one it made with Warp Speed, projects it can supply a total of 50 million doses by the end of this year. The first doses will go to groups deemed at the highest risk of infection by the U.S. Centers for Disease Control and Prevention, but the companies say there should be enough to vaccinate the entire United States by the spring.

Whereas the Pfizer/BioNTech vaccine uses 30 micrograms of mRNA, Moderna’s contains 100. (The company gave an even higher dose of its vaccine in earlier clinical studies, but found it sometimes led to serious side effects.) Both vaccines require two doses separated by several weeks. A key difference is that the Pfizer/BioNTech candidate must be stored at –70°C, whereas Moderna’s can be kept at –20°C. Moderna revealed today that once thawed, its vaccine can remain stable for 30 days at 2°C to 8°C, home refrigerator temperatures. In much of the world, maintaining a cold chain for a –70°C vaccine presents formidable challenges, and even –20°C presents obstacles.

Moderna hopes to produce 500 million to 1 billion doses in 2021, but it does not see a way to go beyond that amount. “We don’t have a billion-dose manufacturing capacity sitting idle somewhere. We are increasing our output more and more and all our key engineers are working to make that happen,” says Stéphane Bancel, Moderna’s CEO. “So if we pull them out and say, ‘Hey, you have to go and get on a plane on the other side of the world to teach somebody else how to do it,’ they won’t be able to scale up manufacturing in the U.S. or in Switzerland.”

The cost of the vaccine may also be far too high for many countries. Bancel says the company is in discussions with the COVID-19 Vaccines Global Access Facility, a nonprofit set up to help resource-limited countries purchase the vaccine at discounted prices.

As countries begin to get supplies of mRNA vaccine, the question will become whether the many people who are hesitant about receiving a COVID-19 vaccine—especially a novel type that has no long-term safety record—will roll up their sleeves. Some trial participants did report fevers or other mild reactions to the vaccine, so making sure everyone gets their second dose could be a hurdle.

Still, Karron suspects hesitancy will drop as people see the vaccine works and no serious side effects surface. She also imagines pressure will build to contribute to the social good. “There’s going to come a moment where you’re going to be able to say, you know, we could open up our community, except for people like you,” Karron says. “If you would get vaccinated, we could get back to some semblance of life as we knew it.”

Fauci cautiously optimistic

Fauci, a huge fan of the Washington Nationals baseball team, says he could imagine attending a game next season, although he doesn’t want people to think the whole country will be immunized by Opening Day in April. “If we have really good uptake throughout the country, and 95% vaccine efficacy, the blanket of immunity that we could have in this country could really dramatically end this as an outbreak,” Fauci says. “There will still be infections in society, but they likely would be so low that it would be possible to have some spectators in the stands in the summer.”

Eight other COVID-19 vaccines have entered efficacy trials and there are nearly 30 others in the early stages of human studies. “We don’t yet know whether these are the ideal vaccines,” says Stanley Plotkin, who developed the rubella vaccine and had his hand in several more. And Plotkin and many others suspect that alternative vaccines may be better suited for certain populations. “The bottom line is that the game is not over,” Plotkin says.

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