Severe and Asymptomatic Data Could Give Moderna’s COVID-19 Vaccine Slight Edge Over Pfizer’s
Executive Summary
Moderna’s COVID-19 vaccine looks better than Pfizer/BioNTech’s at preventing severe disease and like it may offer some benefit in preventing asymptomatic infections, but these advantages may be short-lived and hard to capitalize on due to supply limitations.
Moderna, Inc.’s COVID-19 vaccine will head into its 17 December US Food and Drug Administration advisory committee review with more solid data on its impact on severe disease than competitor Pfizer Inc./BioNTech SE’s had when that vaccine went in front of the same committee last week. Moderna also has some preliminary data on its vaccine’s ability to prevent transmission of the virus, of which Pfizer had none.
With an overall similar efficacy and safety profile to Pfizer’s product, Moderna is all but guaranteed to receive the second emergency use authorization for a COVID-19 vaccine in the US, despite some late-breaking data that may suggest slightly lower efficacy in older patients. (See sidebar.) The impact of any slight differentiators between the two products may be minimal given both are currently in such short supply and there is almost no ability to choose which product to receive. Plus, given the similarity of the vaccines Pfizer may end up with similar selling points for its vaccine once it collects more data.
FDA’s review of Moderna’s vaccine said that the known benefits of the vaccine include reduction in the risk of confirmed COVID-19 occurring at least 14 days after the second dose as well as the reduction in risk of confirmed severe COVID-19 at that time point.
Evaluation of severe COVID-19 was a secondary endpoint in the Moderna Phase III trial, but its real world importance is perhaps greater than the ability to prevent any symptomatic COVID-19, and was a key gap that Vaccines and Related Biologics Products Advisory Committee members cited at Pfizer and BioNTech’s 10 December meeting. At FDA’s 22 October VRBPAC committee on general EUA criteria for COVID-19 vaccines, some advisors felt the agency should have pushed harder to make severe disease a primary endpoint in trials. (Also see "COVID-19 Vaccines: Advisory Committee Picks Apart US FDA Guidance On Efficacy Endpoints" - Pink Sheet, 22 Oct, 2020.)
While FDA confidently weighed in on Moderna’s vaccine’s impact on severe disease, FDA’s briefing documents ahead of Pfizer’s advisory committee said that secondary analyses “suggest benefit of the vaccine in preventing severe COVID-19,” but that “available data for these outcomes did not allow for firm conclusions.” (Also see "Pfizer's COVID-19 Vaccine Brings Gaps In Efficacy And Safety Data To US FDA Panel" - Pink Sheet, 9 Dec, 2020.)
Moderna’s Phase III trial had 30 severe cases of COVID-19 starting at 14 days after dose 2, all of which were in the placebo group, giving the vaccine an estimated 100% efficacy against severe disease. This included 11 cases of severe COVID-19 at the time of the interim secondary efficacy analyses.
FDA broke down Moderna’s data by interim and final analyses, noting that its review of the final scheduled efficacy analysis data was not independently verified by the agency to the same extent as the interim efficacy analysis due to timing of the submission. FDA also noted it’s possible one severe COIVD-19 case may have occurred in the vaccine arm of Moderna’s trial, but the case did not meet the protocol-specific case definition.
In comparison, a final analysis of Pfizer’s Phase III study identified five participants that had severe COVID-19 at least seven days after Dose 2, including one subject in the vaccine arm and four who received placebo for an estimated 75 percent efficacy rate.
Moderna Suggests Infection Prevention; FDA Is Silent
Another area where Moderna may have bested Pfizer is in data it collected on its vaccine’s efficacy against asymptomatic infection. The company provided some data to suggest the vaccine may start preventing some asymptomatic infections after the first dose, however, this data was among the data provided after the initial EUA filing and was not addressed at all by FDA in the agency’s briefing documents.
Moderna conducted nasal swabs on trial participants ahead of dose 1 and dose 2 of the vaccine and compared the number of swabs positive for the virus ahead of vaccine dose two in baseline seronegative participants. Their descriptive summary found 14 trial participants in the vaccine group and 38 participants in the placebo group had evidence of SARS-CoV-2 infection before the second dose without evidence of COVID-19 symptoms, meaning that two-thirds fewer swabs were positive in the vaccine group as compared to the placebo group.
“Additional evaluations will be needed to assess the effect of the vaccine in preventing asymptomatic infection, including data from clinical trials and from the vaccine’s use post-authorization,” FDA’s briefing documents said, which was nearly identical to the agency’s take on Pfizer’s vaccine’s ability to prevent asymptomatic disease.
The agency has speculated that it is possible that asymptomatic infections may not be prevented as effectively as symptomatic ones based on how some other vaccines work. Preventing asymptomatic infections is seen as key to being able to curb transmission of the virus.
Pfizer did not provide any data on its vaccine’s impact on asymptomatic disease for its EUA, but said it plans to gather data from its ongoing Phase III trial on efficacy of the vaccine against asymptomatic infection “in the months ahead.” (Also see "Pfizer Rose To The COVID-19 Challenge And The Stars Aligned" - Pink Sheet, 11 Dec, 2020.)
FDA’s Center for Biologics Evaluation and Research Director Peter Marks said 14 December that the US National Institutes of Health is contemplating a study to determine whether COVID-19 vaccines can prevent transmission by routinely testing for asymptomatic disease. (Also see "NIH Considering Trial of COVID-19 Vaccines and Asymptomatic Transmission" - Pink Sheet, 14 Dec, 2020.)
The National Institutes of Allergy and Infectious Diseases at NIH told the Pink Sheet that it is not presently supporting trials in this area “but recognizes this is an important question for public health to address.”