Moderna Vaccine Shows Significant COVID-19 Prevention Efficacy in Phase 3 Data

Peer-reviewed interim phase 3 data from the COVE Study Group confirmed that mRNA-1273, from Moderna, has shown 94.1% efficacy in preventing coronavirus 2019 (COVID-19) among adult trial participants at high risk for SARS-CoV-2 infection or its complications.

The findings, published to The New England Journal of Medicine, come 2 weeks following the vaccine’s Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA), and well into the initial pandemic vaccine distribution stage which has seen first-prioritized adults receive their first dose of mRNA-1273.

“Within 1 year after the emergence of this novel infection that caused a pandemic, a pathogen was determined, vaccine targets were identified, vaccine constructs were created, manufacturing to scale was developed, phase 1 through phase 3 testing was conducted, and data have been reported,” investigators wrote.

Study Makeup

The COVE Study Group reported results from the ongoing, randomized, observer-blind, placebo-controlled trial underway in 99 centers throughout the US. At the time of publication, 30,420 volunteers had been randomly enrolled 1:1 to either intramuscular two-dose 100mcg vaccine or placebo (n = 15,210 each).

Investigators assessed for a primary endpoint of preventing COVID-19 illness with onset at least 14 days post-second injection in participants previously not infected with SARS-CoV-2.

Mean participant age was 51.4 years old, with 47.3% being female. About one-fourth (24.8%) were ≥65 years old, while 16.7% were <65 years old with predisposing medical conditions which would indicate risk of severe COVID-19, including obesity, diabetes, heart disease, and pulmonary conditions. All demographics were consistent across both treatment arms.

Despite numerous calls from experts, advocates, and communities to assure minority representation in COVID-19 vaccine assessments—particularly due to the heightened burden of the virus on minority groups in the US—the COVE trial reported 79.2% white patients, only 10.2% black or African-American patients, and 20.5% Hispanic or Latino patients.

Previous SARS-CoV-2 infection, per RT-PCR testing, was presented at baseline in 2.3% of mRNA-1273 group participants, versus 2.2% of placebo group participants.

Efficacy

Through November 25, investigators diagnosed a total of 196 COVID-19 cases. Just 11 cases occurred in patients who received two-dose mRNA-1273, for an incidence rate of 3.3 cases per 1000 person-years (95% CI, 1.7-6.0). The remaining 185 cases occurred in placebo patients, for a 17-fold incidence rate of 56.5 per 1000 person-years (95% CI, 48.7-65.3).

The prevention of symptomatic SARS-CoV-2 infection with mRNA-1273 versus placebo was observed at 94.1% efficacy (95% CI, 89.3-96.8; P <.001).

Efficacy of prevention was even greater in patients diagnosed with SARS-CoV-2 started 14 days after the first dose: 11 cases for mRNA-1273 participants versus 225 cases for placebo participants (95.2%; 95% CI, 91.2-97.4).

In preventing severe COVID-19, investigators observed 30 such cases among placebo participants, versus none in the mRNA-1273 group.

Investigators additionally observed consistent mRNA-1273 efficacy across subgroups stratified by age, sex, race and ethnic groups. Participants positive for SARS-CoV-2 at baseline were completely prevented from COVID-19 in the vaccine group. A small subset of patients (n = 15) who received mRNA-1273 were positive for SARS-CoV-2 by RT-PCR at their second dose visit but had no COVID-19 symptoms.

Safety

Solicited injection-site adverse events were far more frequent at both the first (84.2%) and second dose (88.6%) of mRNA-1273, versus placebo (19.8% and 18.8%, respectively). That said, vaccine-associated injection-site events were mostly grade 1 or 2 in severity and lasted approximately 3 days after each dose, investigators wrote.

The most common injection-site event was pain (86%).

Solicited systemic adverse events occurred more often in the mRNA-1273 doses (54.9% and 79.4%) than placebo doses (42.2% and 36.5%). As with injection-site adverse events, systemic adverse events were more common among younger participants versus older participants. They were also less common in participants positive for SARS-CoV-2 at baseline.

Investigators reported 3 deaths in the placebo group, and 2 in the vaccine group—one from cardiopulmonary arrest and one by suicide. Both treatment arms reported similarly low frequency of grade 3 adverse events and serious adverse events (0.6% in both groups).

As was discussed during the mRNA-1273 Vaccines and Related Biologic Products Advisory Committee (VRBPAC) meeting this month, Bell’s palsy occurred in 3 participants administered mRNA-1273 In the 28 days post-administration.

“Adverse events that were deemed by the trial team to be related to the vaccine or placebo were reported among 4.5% of participants in the placebo group and 8.2% in the mRNA-1273 group,” investigators wrote. “The most common treatment-related adverse events in the placebo group and the mRNA-1273 group were fatigue and headache.”

Conclusion

Investigators stressed the significance of the preliminary COVE Study findings—having been accompanied in Moderna’s EUA application earlier this year, and representing historic outcomes for an mRNA vaccine designed in mere days to respond to a pandemic.

What’s more, its current 94.1% efficacy mark is borderline historic in the context of respiratory virus prevention. Time may show that number was inflated.

“The magnitude of mRNA-1273 vaccine efficacy at preventing symptomatic SARS-CoV-2 infection is higher than the efficacy observed for vaccines for respiratory viruses, such as the inactivated influenza vaccine against symptomatic, virologically confirmed disease in adults, for which studies have shown a pooled efficacy of 59%,” investigators wrote. “This high apparent efficacy of mRNA-1273 is based on short-term data, and waning of efficacy over time has been demonstrated with other vaccines.”

Investigators likened the reported efficacy outcomes to that of BNT162b2, the mRNA COVID-19 vaccine from Pfizer and BioNTech which was granted EUA only a week before the Moderna product.

With a two-year duration of planned follow-up, investigators stressed the need to better understand a litany of outcomes not possible with these current data:

• The efficacy of single-dose vaccine versus two-dose
• The efficacy of the vaccine over changes of time and epidemiologic conditions
• The anecdotal risk of Bell’s palsy in patients
• The long-term risk of enhanced disease in vaccinated persons
• The risk of asymptomatic or subclinical SARS-CoV-2 infection, and viral shedding

Nonetheless, they concluded with praise for the rapid progression of pandemic response which led to a viable vaccine candidate being borne, researched, manufactured, and distributed within a calendar year of a global pandemic—a victory, if there has been any, during the COVID-19 era.

“This process demonstrates what is possible in the context of motivated collaboration among key sectors of society, including academia, government, industry, regulators, and the larger community,” investigators wrote. “Lessons learned from this endeavor should allow us to better prepare for the next pandemic pathogen.”