The high-dose flu vaccine’s advantage over the standard shot in people aged 65 and older got larger as frailty got worse, though every estimate in that pattern was loose enough to be nothing at all, according to a prespecified analysis of the DANFLU-2 trial published in The Lancet Healthy Longevity. Among 332,438 Danish adults randomly assigned to one shot or the other across three flu seasons, the high-dose vaccine prevented essentially nothing extra in the least frail group.
For most readers that changes very little. If you are healthy for your age, the standard shot on the pharmacy shelf is a fine shot, and getting a flu vaccine at all matters far more than which vial it came from. If you are frail, meaning several chronic conditions or a recent run of hospital stays, this is worth one question at your next appointment rather than a decision you make alone.
Whether the high-dose shot does anything for the aging brain as well as the lungs is a separate question, and one large analysis of older adults took it on.
Key takeaways
- In the least frail seniors, the high-dose flu shot performed the same as the standard shot against hospitalization for flu or pneumonia.
- The frailest participants were hospitalized for flu or pneumonia 8.2 times as often as the least frail, no matter which vaccine they received.
- The researchers call the frailty pattern exploratory, and Sanofi, which makes the high-dose vaccine, funded the trial.
What the study found
DANFLU-2 randomly assigned 332,438 Danes aged 65 or older, average age 73.7, to the high-dose or standard-dose inactivated flu vaccine during the 2022-23, 2023-24 and 2024-25 seasons. Frailty was scored from hospital diagnosis codes in the previous 10 years. Most participants, 276,173, landed in the low-frailty group. Only 3,861 scored high.
Baseline risk tracked frailty steeply. Hospitalization for flu or pneumonia hit 0.5% of the low-frailty group, 1.5% of the intermediate group and 4.2% of the high-frailty group, an 8.2-fold gap between the extremes.
The vaccine comparison ran the other way. The high-dose shot’s relative effectiveness was 0.2% in the low-frailty group, meaning no measurable benefit, with the true value very likely between 11% worse and 10% better. It was 13.1% better at intermediate frailty (very likely between no benefit and 25% better) and 19.9% better at high frailty, an estimate loose enough to include anything from 10% worse to 42% better.
Treated as a sliding score, frailty did modify the effect. Treated as the three prespecified categories, it did not, with roughly a 1 in 6 chance of coincidence. Serious side effects were similar between the two vaccines in every frailty group.
Dr. Kumar’s take
The parent trial, published in the New England Journal of Medicine, was negative. This frailty analysis runs on the same participants and counts hospitalization for influenza or pneumonia as one combined outcome, split three ways by frailty score.
So the frailty finding is a hypothesis sliced out of a trial that missed its main target, and the authors say so themselves. Sanofi makes the high-dose vaccine and funded the trial. The earlier DANFLU-1 frailty analysis, from the same research group, concluded the opposite, that the high-dose shot may be preferred no matter how frail a person is. Two trials pointing different directions is what an unsettled question looks like.
The part that holds up on arithmetic alone is baseline risk. A 20% cut off a 4.2% risk removes far more admissions than a 20% cut off a 0.5% risk. Even if the true benefit is identical in everyone, it cashes out bigger in people already being admitted eight times as often. That is a reason to weigh frailty when supply is tight, not evidence that the shot works differently in frail bodies.
What it means for you
If you are 65 or older and in good shape for your age, take whichever flu vaccine is in front of you. Nothing here supports skipping an appointment or calling around town for the high-dose version.
If you are frail, with multiple chronic conditions or recent hospitalizations, ask your doctor or pharmacist whether the high-dose vaccine makes sense for you this season. That conversation belongs with someone who knows your history, and this analysis is a reason to raise it, not an answer on its own.
The flu shot is not the only vaccine older adults get offered each fall, and the shingles vaccine carries its own surprising data on the brain.