Trivalent mRNA Flu Shot More Effective Than Standard Vaccines

An investigational mRNA-based vaccine against three strains of influenza outperformed standard flu shots among adults ages 50 and older in the Fluent randomized trial.

Reverse transcriptase-polymerase chain reaction-confirmed illness from influenza A or B was observed in 2% of participants who received the trivalent mRNA-1010 compared with 2.8% of those who received approved standard-dose vaccines through the end of the flu season, for a relative vaccine efficacy of 26.6% (95% CI 16.7-35.4), with one-sided P<0.001 for noninferiority, superiority, and higher-level superiority.

The novel shot carried a substantially higher risk of solicited adverse events compared with standard vaccines, including injection-site pain (65.8% vs 29.8%), fatigue (45.1% vs 20.3%), headache (37.8% vs 18.0%), and myalgia (35.4% vs 11.6%), reported Grace Huang, MD, of Moderna in Cambridge, Massachusetts, and co-authors in the New England Journal of Medicine.

However, most reactions were mild to moderate and transient. Serious adverse events were “infrequent and similar in the two groups,” according to the authors, with rates of 2.2% in mRNA-1010 recipients (three events considered vaccine-related) versus 1.9% in the comparator group (two events considered vaccine-related).

That safety profile could mean “balancing assessment of temporary vaccine-induced reactogenicity events with the magnitude of protection against influenza,” Huang and team suggested. “These findings support the role of mRNA-1010 in improving influenza prevention.”

A research summary published alongside the study touted the benefits of an mRNA approach to vaccination including capacity for rapid updates, as proven in the COVID-19 era, compared with “time-consuming egg-based production” for most licensed vaccines, a difference “which might improve protection.”

Developer Moderna publicly sparred with the FDA over the trial earlier this year. While not raising any safety concerns, the agency initially refused to consider Moderna’s application for the new flu vaccine made with Nobel Prize-winning mRNA technology, faulting the trial for not including another vaccine brand specifically recommended for people 65 and older as a comparator.

After the company shared additional comparison data from a separate trial that used a high-dose shot for older people, a compromise was reached in which Moderna agreed to seek full approval for the vaccine’s use in adults ages 50 to 64 and accelerated approval for those 65 and older, with an additional study once the shot is on the market.

Among more than 19,000 adults ages 65 and older in the Fluent trial, “a population particularly susceptible to severe influenza,” the relative vaccine efficacy of mRNA-1010 was 27.4% (95% CI 12.1-40.0), “which suggests benefits similar to those of enhanced (high-dose, adjuvanted, or recombinant-based) influenza vaccines in older adults,” Huang and colleagues noted.

The phase III trial randomly assigned 40,703 adults 50 and older (mean age 64, 57% women) to receive trivalent mRNA-1010 (37.5 μg, which includes 12.5 μg each of A/H1N1, A/H3N2, and B/Victoria) or a licensed standard-dose trivalent or quadrivalent comparator.

The relative vaccine efficacy of mRNA-1010 appeared to be generally consistent across the three influenza strains and across subgroups defined by age, sex, race, body mass index, comparator vaccine (trivalent or quadrivalent), geographic region, baseline risk status, frailty, and flu vaccination status during the previous flu seasons.

In exploratory analyses, medically attended influenza-associated outcomes across all healthcare settings occurred in 80 participants in the mRNA-1010 group and 120 in the standard-dose comparator group, which corresponded to a relative vaccine efficacy of 33.7% (95% CI 12.0-50.0).

Among the 64 participants who sought higher-level care, hospitalization, emergency department, or urgent care encounters occurred in 22 recipients of mRNA-1010 and 42 recipients of the standard-dose comparator, which corresponded to a relative vaccine efficacy of 47.9% (95% CI 12.8-68.9).

“The consistency of relative vaccine efficacy across these many outcomes suggests that mRNA-1010 efficacy is broadly applicable across diverse populations and the spectrum of influenza disease,” the researchers concluded.

Adverse events of special interest considered by the investigator to be vaccine-related occurred in two cases in each group: thrombocytopenia and cardiomyopathy (not considered by the independent cardiac event adjudication committee to be myopericarditis) occurred 84 days and 95 days after vaccination with mRNA-1010. With the standard vaccines, one recipient had pericarditis 60 days after vaccination and one developed Bell’s palsy. No cases of acute myocarditis, myopericarditis, or pericarditis occurred with mRNA-1010 within what the researchers called the conservative risk window of 42 days after vaccination.

A decision on FDA approval is expected by Aug. 5, and Moderna said it hoped to make the vaccine available later this year.

A quadrivalent mRNA flu vaccine in development by Pfizer has likewise shown superior efficacy against standard vaccines. In a randomized trial published last year, the quadrivalent mRNA shot had 34.5% greater relative efficacy versus a standard inactivated quadrivalent influenza vaccine in people ages 18 to 64, meeting the criteria for both noninferiority and superiority.

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