High-dose flu vaccine extends benefit to adults aged 50–64 years

A modified double-blind study shows the immunological superiority of high-dose (HD) over standard-dose (SD) inactivated influenza vaccine (IIV) in adults aged 50–64 years.

“[HD IIV] is approved for use in adults aged ≥65 years in the US. This study was designed following FDA guidance to support the extension of [its indication] to adults aged 50–64 years,” said Dr Rachna Gupta from Sanofi, Morristown, New Jersey, US, at IDWeek 2025. “This phase III age-extension study achieved all primary [noninferiority and] secondary superiority endpoints.”

Seroconversion rates (SCR) were higher with HD vs SD 28 days after vaccination for all three influenza strains: A/H1N1 (74.5 percent vs 56 percent; difference, 18.46 percent, 95 percent confidence interval [CI], 12.90–23.86), A/H3N2 (82.1 percent vs 64.8 percent; difference, 17.31 percent, 95 percent CI, 12.16–22.33), and B/Victoria (77 percent vs 64.8 percent, difference, 12.23 percent, 95 percent CI, 6.90–17.47).

According to Gupta, the lower limits of the CIs all exceed the prespecified -10 percent noninferiority criterion for SCR. [IDWeek 2025, abstract 409]

There were also robust antibody responses favouring HD over SD as reflected by the geometric mean titre (GMT) ratios. The lower bounds of all CIs exceed the noninferiority margin of 0.67 and the prespecified superiority margin of 1 (1.34, 1.8, and 1.36 for A/H1N1, A/H3N2, and B/Victoria, respectively). The respective GMT ratios were 1.55, 2.08, and 1.55.

When using a higher threshold (98.3 percent CI), the lower limit of the CI also exceeded the superiority margin of 1.5 for at least one of the three strains (1.75 for A/H3N2).

Safety

Injection-site pain was most frequent with both HD and SD (27.8 percent and 16.3 percent), with similar grade 3 events between groups (0.2 percent for both). The most common systemic solicited reactions were fatigue (18.2 percent and 15 percent), headache (19.4 percent and 17.4 percent), and myalgia (17.8 percent and 15 percent).

“Overall, HD had the expected reactogenicity profile, with severity comparable to SD,” noted Gupta.

Both groups had similar frequencies of unsolicited and medically attended adverse events (AEs), with no immediate unsolicited AEs, AEs of special interest (eg, anaphylaxis, new-onset Guillain-Barré syndrome, encephalitis/myelitis, neuritis, thrombocytopenia, vasculitis), or deaths reported during the study.

There were three serious AEs in the HD group and eight in the SD group, but none were deemed vaccine-related by the investigator.

Substantial burden

“The clinical burden of influenza in adults aged 50–64 years remains substantial compared with individuals aged 18–49 years,” noted Gupta. In one study, the former group had a threefold higher rate of hospitalization and a ninefold higher rate of mortality attributable to influenza. [Open Forum Infect Dis 2022;10:ofac664]

Gupta and colleagues randomized 1,180 participants 1:1 to receive a single dose of HD or SD IIV. Of these, 1,171 (mean age 57 years, 54.9 percent women) were vaccinated by visit 1, and 91.1 percent completed the 6-month safety follow-up. About a third of participants had received an influenza vaccine in the previous season.

Robust, superior immune responses for three influenza strains

“In this study, HD IIV demonstrated robust immune responses that were noninferior to SD for all three vaccine-matched strains based on both GMT and SCR [and] a superior immune response over SD for all three vaccine-matched strains based on GMT,” said Gupta.

HD IIV also met the stringent superiority criteria for the A/H3N2 strain. A GMT ratio with a lower bound above 1.5 indicates that the HD produces H3N2 antibody levels that are more than 50 percent higher than those with SD, she added.

“HD IIV had an acceptable and comparable safety profile to SD. The improved immune responses with HD relative to SD were consistent with prior data in this age group and fit well with what we have seen in the older age group,” Gupta concluded.