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Moderna COVID-19 vaccine validates mRNA platform, suggests success of other vaccines

To seek FDA, EMA authorization in December after data from Phase III COVE, which includes 7K aged 65 and up, plus diverse and high-risk volunteers

Nov 16, 2020 | 12:00 PM GMT

Moderna is preparing to apply to FDA for emergency use authorization and to regulators in Europe and beyond for conditional approval in the coming weeks for its lead mRNA vaccine after it demonstrated 94.5% efficacy in preventing COVID-19 in an interim analysis of the Phase III COVE trial.

Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), celebrated the data, saying that it exceeded his expectations. Speaking at an NIH press briefing Monday, Fauci recalled that at the start of COVID-19 vaccine development he said that 70-75% efficacy would be satisfactory and that “something like a 95% was really aspirational. We would like to have seen it, but it was aspirational. Well, our aspirations have been met and that is really very good news.” 

Speaking at a separate press conference Monday, President-elect Joe Biden expressed confidence in the mRNA COVID-19 vaccines. “I wouldn't hesitate to get the vaccine if Dr. Fauci and the two organizations, Moderna or Pfizer, who have been extremely responsible, conclude that it is safe.”

Biden said revitalizing the economy will require “rallying the country behind a national strategy with robust public health measures like mandatory masking, widely available testing with rapid results, scaled-up production of life-saving treatments and therapeutics and safe, equitable and free distribution of the vaccine.”

Developing effective, safe vaccines is necessary but not sufficient, Biden said. He stressed the need for effective distribution and criticized the Trump administration for preventing the transition team from discussing vaccine deployment with government officials.

Moderna Inc. (NASDAQ:MRNA) anticipates receiving an EUA as early as December, CEO Stéphane Bancel said in a television interview with CNBC Monday.

Moderna has already started rolling submissions to EMA as well as regulators in Canada, the U.K., Switzerland and other countries and could obtain conditional approvals outside the U.S. in December, Bancel told reporters on the NIH press briefing.

Following the data announcement, the U.K. government said its Vaccines Taskforce is in “advanced discussions” to gain access to mRNA-1273 for the U.K. The statement said that Moderna’s European supply chain is ramping up with the vaccine likely to become available in the U.K. next spring at the earliest. The Vaccines Taskforce has already secured access to six other COVID-19 vaccines, including 40 million doses of BNT162b2, an mRNA COVID-19 vaccine from BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE).

The efficacy data, reported Monday, are based on an interim analysis of 95 events. The EUA application will be based on a final analysis of 151 cases plus a median follow-up of more than two months, according to Moderna.

The company also released new data about temperature stability that differentiates its mRNA-1273 vaccine from BNT162b2.

Moderna’s vaccine is stable for 30 days at 2° to 8° C, so it can be stored in a standard medical refrigerator. It can safely remain at room temperature for 24 hours before vaccination and can be stored for up to six months at -20° C, Moderna said. That improves upon a previous estimate of seven days.

In contrast, BNT162b2 must be stored at -80° C, creating logistical challenges.

The Moderna vaccine was administered in two doses, 28 days apart. Efficacy was assessed starting two weeks after the second dose.

In contrast to Pfizer, which did not receive R&D funding from the U.S. government for its COVID-19 vaccine, Moderna has partnered closely with NIH and has received funding under auspices of Operation Warp Speed.  

U.S. government funding of Moderna’s COVID-19 vaccine includes $955 million from Biomedical Advanced Research and Development Authority (BARDA) for R&D, as well as a commitment from the Department of Defense to provide up to $1.5 billion to purchase mRNA-1273.

Moderna said it expects to have about 20 million doses ready to ship in the U.S. in 2020, and is “on track to manufacture 500 million to 1 billion doses globally in 2021.”

Moderna is manufacturing mRNA-1273 in the U.S. Its partner Lonza Group Ltd. (SIX:LONN) will manufacture the product at sites in the U.S. and Switzerland.

Efficacy data, diverse population

The interim data announced by Moderna are based on 95 cases of COVID-19, of which 90 cases were  in the placebo group vs. five cases observed in the mRNA-1273 group, resulting in efficacy of 94.5% (p <0.0001), the company said.

The 95 cases include 11 severe cases of COVID-19, which all occurred in COVE’s placebo group.

Moderna said the study included communities that have “historically been under-represented in clinical research and have been disproportionately impacted by COVID-19.” It enrolled more than 11,000 participants from communities of color, representing 37% of the study participants, a proportion that matches the diversity of the U.S. population.

The company said the COVID-19 cases in COVE included 15 adults aged 65 or more and 20 participants identifying as being from diverse communities, including 12 Hispanic or LatinX, four Black or African Americans, three Asian Americans and one multiracial.

The DSMB did not report any significant safety concerns, according to Moderna.

There were severe adverse events after the second dose in the COVE trial that could cause some people to avoid the vaccine or forgo the second dose. Grade 3, or severe, events that occurred after the second dose included fatigue, which affected 9.7% of trial participants, myalgia (8.9%), arthralgia (5.2%), headache (4.5%) and pain (4.1%).

COVE enrolled 30,000 participants 18 and older in the U.S. Recruitment focused on individuals at high risk of severe complications from COVID-19 and targeted a diverse population.

The trial included more than 7,000 Americans over age 65, more than 5,000 Americans under 65 with high-risk chronic diseases that put them at increased risk of severe COVID-19.

Validation of mRNA, other vaccine platforms

Interim data from the two mRNA vaccine candidates validates the platform and the COVID-19 vaccine testing paradigm, and bodes well for vaccines developed using other technologies, Fauci said.

“There was uncertainty as to whether the [mRNA] platform, since it’s a new platform, would work,” he said. “There was uncertainty with regard to the protocol, since the primary endpoint for this and other protocols is generally clinically apparent disease and the question was, could it actually prevent severe disease?” With interim data from Phase III trials of the Moderna and Pfizer vaccine candidates, “all the boxes have now been checked in the sense that the platform clearly works. It worked here with Moderna, it worked with Pfizer.”

Fauci added that data demonstrating the Moderna vaccine’s efficacy in preventing severe disease is “absolutely critical” for assessing its public health value.

He also stressed the importance of Moderna’s success in recruiting a diverse population, and the consistency of the efficacy across multiple subgroups.

The success of the mRNA vaccines augers well for other COVID-19 vaccines that target the spike protein, Fauci said. “Although you never want to get ahead of yourself and make predictions before the results of the trial are in, conceptually this looks good. And it looks like we’re on firm ground for continued positive results coming in because of the commonality of the immunogen involved.”

Fauci noted that like the mRNA vaccines, the other two vaccine modalities that Operation Warp Speed is supporting, vector expression of the spike protein gene and protein-based vaccines, target the spike protein. He added that “we have now shown with two vaccines that the immune response against the spike protein is a protective response.”

Uncertainty about unblinding

Moderna and Pfizer are likely to complete the event-based efficacy portion of their Phase III trials by the time they submit EUA applications in the U.S., but it isn’t clear how long into the planned two-year safety follow-up they will get before the trials are unblinded.

There is a debate about whether and when to unblind the BioNTech- Pfizer and Moderna trials and offer participants who received placebo the opportunity to be vaccinated.

“Although there are these interim analysis data, this is not yet an approved vaccine,” John Mascola, director of NIAID’s Vaccine Research Center, told reporters Monday. “While the FDA is reviewing the data, the studies will remain blinded.” Before FDA issues an EUA, he said, FDA and NIH and Moderna will discuss in detail “whether those in the placebo group should get vaccinated.”

The strength of the efficacy data could tip the balance in favor of unblinding the trials when the vaccines are widely available, Fauci said. The decision about unblinding depends, he said, “on the availability of vaccines throughout the country, as well as what the level of efficacy is. I think when you have a vaccine of this high degree of efficacy it weighs more towards making sure that you do something with the placebo group that's fair and does not put them at a disadvantage.”

Fauci suggested that rather than cross-over all the participants in the placebo arms to receive the two-dose vaccine regimen, it might be possible to randomize them to receive either a single dose or two doses. This would provide data on the safety and efficacy of the single dose administration.

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