Protocol · graded by use, four uses
Influenza vaccination (yearly flu shot), for older adults
Influenza in adults aged 60 and older, standard-dose vaccine against placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received..
At a glance
This is about the yearly flu shot for people 60 and older. In older trials it cut flu over one winter from about 6 in 100 people to about 2 or 3 in 100. Those trials counted flu partly by a blood test, not only by illness. No fair test has shown fewer deaths. A trial that followed people for 25 years found none. A stronger shot prevented more flu than the usual one, but it did not lower hospital stays. Sore arms are common. A rare nerve illness is about 1 or 2 cases per million shots more common.
- What was measured
- Influenza over one winter in adults 60 and older, counted partly by a blood test showing the body had fought the virus.
- How big
- Influenza over one season fell from 6% to 2.4% in older adults given the vaccine.Read from the summary of PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 29388197.
- Who it applies to
- Adults 60 and older living at home, given the standard inactivated flu shot. It does not cover hospital stays or deaths, which the placebo trials did not show.
- Safety
- Sore arms and mild fever are the common side effects. A rare nerve illness, Guillain-Barré syndrome, was about 1 or 2 cases per million shots more common after the 2009 pandemic flu shot.
- Compared with
- A dummy shot of salt water.
- Certainty
- Grade B, resting on: Randomized placebo-controlled trials pooled in a Cochrane review; randomized trials of high-dose against standard-dose vaccine.
- What would change this grade
- Could rise to A with: Large randomized trial of the standard inactivated vaccine against placebo, run independently of any maker. Who: Adults aged 65 and older living in the community. Measured: Hospitalization for influenza confirmed by PCR, or death. Length: At least one full influenza season, at least 10,000 per arm.
- Cost
- No price recorded yet.
- Sources
- 7 studies cited on this record, listed under Sources.
The B belongs to one of the four uses graded on this record. The other three carry their own letters.
This record carries a separate letter for each thing it has been measured on. The headline grade is the best of them, and it does not transfer to the others.
Demicheli et al. (Cochrane Database Syst Rev, 2018; PMID 29388197) pooled 8 placebo-controlled trials in Europe and the USA: influenza over one season 6% against 2.4% (risk ratio 0.42), low certainty because of uncertainty over how influenza was diagnosed; influenza-like illness 6% against 3.5%, moderate certainty. Govaert et al. (JAMA, 1994; PMID 7966893), 1,838 adults aged 60 and older: serological influenza 4% against 9%. Repeated by independent groups, but the outcome is partly a rise in antibodies, a laboratory marker of infection, so B under Rule 06.
Verhees et al. (PLoS One, 2019; PMID 31120943): one season's vaccination did not change survival over 25 years, adjusted hazard ratio How often an event happened in the treated group compared with the control group over the same period. A ratio of 0.80 means 20 percent fewer events. 0.95. Demicheli et al. (Cochrane, 2018; PMID 29388197): the only trial reporting deaths was underpowered, very low certainty. Tested, no benefit shown: D on Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale., with low certainty stated, because no trial large enough to measure deaths against placebo has been run.
DiazGranados et al. (N Engl J Med, 2014; PMID 25119609): laboratory-confirmed influenza with a protocol-defined illness 1.4% against 1.9%, relative efficacy 24.2% (9.7 to 36.5); funded by Sanofi Pasteur, the maker. A disease event confirmed in the laboratory, in one trial: C under Rule 06 until another trial repeats it. The Danish DANFLU-2 trial reported fewer hospital stays for influenza as a secondary outcome, but its plan did not test secondary outcomes after a neutral primary, so it is not counted here as a repeat.
Johansen et al. (N Engl J Med, 2025; PMID 40888720), DANFLU-2: the high-dose vaccine did not significantly lower hospitalization for influenza or pneumonia, the primary outcome. Tested, no benefit on the primary endpoint The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight.: D on Route 2.
The inactivated flu vaccine is one injection each autumn. In placebo-controlled trials in adults aged 60 and older it lowered influenza over one season, but those trials counted influenza partly by a rise in antibodies, and none has shown fewer deaths. A higher-dose vaccine prevented more laboratory-confirmed influenza than the standard dose in one trial, and in a second, much larger trial it did not lower hospital stays for influenza or pneumonia. Graded by use.
Why this letter
Why this gradeThe reasoning, and what the grade does not cover.
Grade B on influenza in adults aged 60 and older: placebo-controlled trials pooled by Cochrane found influenza over one season lowered from 6% to 2.4% (Demicheli et al., 2018; PMID 29388197), and the largest of them, run in Dutch family practices, found it about halved (Govaert et al., 1994; PMID 7966893).
WHY NOT Athose trials counted influenza partly as a fourfold rise in antibodies between two blood samples, a laboratory marker of infection rather than a confirmed illness, and Cochrane rates the result low certainty for that reason; a marker caps the letter at B under Rule 06. Grade D, tested, on death from any cause: the one trial in the Cochrane review that reported deaths was too small to show a difference (PMID 29388197), and 25 years of follow-up of the Dutch trial found no difference in survival (Verhees et al., 2019; PMID 31120943). Grade C on laboratory-confirmed influenza with the high-dose vaccine against the standard dose: one maker-funded trial, 24% fewer cases (DiazGranados et al., 2014; PMID 25119609), not repeated with that endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score.. Grade D, tested, on hospitalization for influenza or pneumonia with the high-dose vaccine: the Danish trial of 332,438 older adults found no significant difference (Johansen et al., 2025; PMID 40888720).
WHAT THIS GRADE DOES NOT COVERhospitalization for influenza against no vaccine, which no placebo-controlled trial in older adults has reported; people with heart failure or other specific illnesses, who were not the populations graded here; the adjuvanted and recombinant vaccines; and children or adults under 60.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
Who responds: this record's trial reading reports no subgroup that identifies who responds.
Evidence notes: randomized trial, meta-analysis A study that pools the numbers from several trials into one combined estimate., independently replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away., industry-sponsored
Endpoint graded: Influenza in adults aged 60 and older, diagnosed partly by a rise in antibodies on blood tests (surrogate)
Last reviewed: November 2026
The trial that would change this grade.
Positive trials of this shape from independent research groups would move this entry to A.
Why the current trials fall short
The B rests on placebo trials from 1965 to 2000 that diagnosed influenza partly by antibody rise (PMIDs 29388197, 7966893). A modern placebo trial with a confirmed hard outcome, repeated by a second group, is what would move the letter to A.
ClinicalTrials.gov, the public registry run by the U.S. National Library of Medicine, lists studies that are recruiting volunteers. The link below searches it for Influenza Vaccine among studies recruiting now. EBL has no relationship with any listed study and receives no payment for this link.
Search recruiting studies of Influenza Vaccine on ClinicalTrials.gov
Dose, form and timing
Measured outcome in the graded trials: influenza over one season, diagnosed by laboratory test, by a fourfold rise in antibodies between blood samples, or both, in the placebo trials; influenza confirmed by laboratory test in the high-dose trial; hospital admissions coded for influenza or pneumonia in the Danish trial.
As studiedDose, form, population and duration for every use.
A grade describes the intervention that was tested. Where the product on the shelf differs from it, this says so.
Safety
Side effects are usually mild. In the placebo-controlled trials pooled by Cochrane, fever followed vaccination in 2.5% against 1.6% on placebo and nausea in 4.2% against 2.4%, with wide uncertainty (Demicheli et al., 2018; PMID 29388197). Guillain-Barré syndrome, a nerve disorder that causes weakness, was measured after the 2009 pandemic flu vaccines in about 23 million vaccinated people: about 1.6 extra cases per million vaccinated, a level the authors call consistent with earlier estimates after seasonal flu vaccines (Salmon et al., Lancet, 2013; PMID 23498095). VAERS, the US Vaccine Adverse Event Reporting System, received 12,320 reports after the high-dose flu vaccine in adults aged 65 and older from 2011 to 2019; 5.9% were classed serious, 55 reported a death, and record review confirmed 61 reports of Guillain-Barré syndrome (Moro et al., Vaccine, 2020; PMID 32709434). Anyone can file a VAERS report, reports are not verified, and the system does not know how many people were vaccinated, so a report does not show that the vaccine caused the event and the counts are not rates. Its role is to raise signals, which studies with a known number of vaccinated people then measure. The reports can be searched at the system's public site, vaers.hhs.gov.
Cautions documented in human studies. Each caution on this record, sorted by what it rests on.
- Fever after vaccination 2.5% against 1.6% on placebo in pooled trials, wide uncertainty (PMID 29388197)
- Guillain-Barre syndrome: about 1.6 extra cases per million people vaccinated with the 2009 pandemic vaccines (PMID 23498095)
- VAERS: 12,320 reports after the high-dose vaccine, 2011 to 2019, 5.9% serious, 55 death reports, unverified and not rates or proof of cause (PMID 32709434)
None recorded.
None recorded.
Does not apply: human harm data are listed above.
Grade history
How this letter has changedLatest: No. 418 · November 2026 · First graded.
The yearly flu shot now has its own record, graded by use and shown with its harms. Placebo trials pooled by Demicheli et al. (Cochrane Database Syst Rev, 2018; PMID 29388197) and Govaert et al. (JAMA, 1994; PMID 7966893) found influenza over one season lowered in adults aged 60 and older; influenza was diagnosed partly by antibody rise, so B. Verhees et al. (PLoS One, 2019; PMID 31120943) found no difference in deaths over 25 years: D, tested. The high-dose vaccine prevented more laboratory-confirmed influenza in one trial, DiazGranados et al. (N Engl J Med, 2014; PMID 25119609): C; and did not lower hospital stays for influenza or pneumonia in DANFLU-2, Johansen et al. (N Engl J Med, 2025; PMID 40888720): D, tested. Harms: Guillain-Barre syndrome, Salmon et al. (Lancet, 2013; PMID 23498095), and VAERS reports, Moro et al. (Vaccine, 2020; PMID 32709434), with their limits stated.PMID 29388197 PMID 7966893 PMID 31120943 PMID 25119609 PMID 40888720 PMID 23498095 PMID 32709434
Every change to a letter on this site is dated and published. The full evidence log →
Sources
- Citations
- Every paper cited on this page is matched to its PubMed record on every build.
- Retractions
- None of these papers is retracted or under a journal expression of concern. PubMed is checked again on every build.
- Read against the papers
- November 2026. By a language model (AI-assisted reading), not yet reviewed by a clinician.
- Outside review
- Not yet done. No reviewer outside EBL has checked this record.
What each of these checks can and cannot show: evidence integrity.
The evidence, in fullSeven papers, each linked to its PubMed record.
Demicheli et al. (Cochrane Database Syst Rev, 2018; PMID 29388197): 8 randomized trials, over 5,000 adults aged 65 and older, 1965 to 2000; influenza over one season 6% against 2.4% with vaccine (risk ratio 0.42, 95% CI 0.27 to 0.66, low certainty because of how influenza was diagnosed); influenza-like illness 6% against 3.5% (0.59, 0.47 to 0.73, moderate certainty); deaths 3 of 522 against 1 of 177 in the one trial that reported them, very low certainty; no hospitalization data. Govaert et al. (JAMA, 1994; PMID 7966893): 1,838 adults aged 60 and older in Dutch family practices, vaccine or saline placebo, 1991-1992; serological influenza 4% against 9% (relative risk The risk in one group expressed as a share of the risk in another. It can make a small absolute difference look large. 0.50), clinical influenza 2% against 3%. Verhees et al. (PLoS One, 2019; PMID 31120943): 25-year follow-up of that trial, all-cause mortality adjusted hazard ratio 0.95 (0.85 to 1.05). DiazGranados et al. (N Engl J Med, 2014; PMID 25119609): 31,989 adults aged 65 and older, high-dose against standard-dose vaccine, double-blind; laboratory-confirmed influenza 1.4% against 1.9%, relative efficacy 24.2% (9.7 to 36.5); funded by Sanofi Pasteur, the maker. Johansen et al. (N Engl J Med, 2025; PMID 40888720): DANFLU-2, 332,438 adults aged 65 and older in Denmark, open-label, high-dose against standard-dose over three seasons; hospitalization for influenza or pneumonia 0.68% against 0.73%, relative effectiveness 5.9% (-2.1 to 13.4), not significant; funded by Sanofi. Harms: Demicheli 2018 (PMID 29388197), fever 2.5% against 1.6%; Salmon et al. (Lancet, 2013; PMID 23498095), 2009 pandemic flu vaccines in about 23 million vaccinated people, Guillain-Barré syndrome incidence rate ratio 2.35, about 1.6 extra cases per million vaccinated; Moro et al. (Vaccine, 2020; PMID 32709434), VAERS reports after the high-dose vaccine in adults 65 and older, 2011 to 2019, 12,320 reports, 5.9% serious, 55 death reports, 61 reports of Guillain-Barré syndrome confirmed by record review.
How EBL searched for the trials (1 search)
The search that was run, what it returned, and what was left out and why, so the absence of evidence can be checked as well as its presence.
influenza vaccin*[tiab] AND placebo[tiab] AND (elderly[tiab] OR "older adults"[tiab] OR aged[tiab]) AND (mortality[tiab] OR death[tiab] OR hospitali*[tiab]) AND randomized controlled trial[pt]PubMed watch: does a new study change the grade? (nothing new)
No new paper matching the search behind this grade has been added to PubMed since November 2026.
Last run November 2026. A letter on EBL moves only after a logged review. A new paper never moves a letter by arriving: it is read, the answer is written here, and any change to the letter is published in the evidence log.
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