high dose flu vaccine in elderly is best

 A recent Danish study found that elderly patients given the high-dose influenza vaccine had reduced incidence of cardiorespiratory hospitalizations when compared to those given the standard-dose vaccine (see influenza vaccine high-dose helps in elderly JAMACardiol2025 in dropbox, or doi:10.1001/jamacardio.2025.3460)

Details:

--332,438 participants at least 65-year-old were assessed through a prespecified secondary analysis of the DANFLU-2 study, a pragmatic, open-label, individually randomized clinical trial using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 Influenza seasons

-- patients were randomized to receiving a high-dose inactivated influenza vaccine (HD-IIV) versus the standard-dose IIV (SD-IIV)

-- severe cardiovascular outcomes were prespecified secondary and exploratory endpoints in the DANFLU-2 trial, when occurring at least 14 days after vaccination and through May 31 of the following year

-- there were no formal exclusion criteria to being in the study

-- mean age 73.7 years, 51% male,

-- prior history of cardiovascular disease 27%:  31,000 (9.4%) with ischemic heart disease, 9400 (2.8%) with a history of MI, 10,400 (3.1%) with a history of heart failure, and 34,000 (10.3%) with atrial fibrillation; cerebrovascular disease was present In 8000 (18%); peripheral arterial disease in 1500 (3%)

-- diabetes in 15%, chronic kidney disease in 18%, cancer in 14%, chronic lung disease in 9%, COPD in 5%, immunodeficiency in 4%

    -- those with a prior history of cardiovascular disease or these comorbidities were more likely to have been older (mean age 75.3% versus 73.1%) and male (63.4% versus 46.9%)

 -- coadministration with COVID vaccine in 61%, with 97% having had the COVID vaccine at some time during the same season

-- Primary endpoints: 

    -- the relative vaccine efficacy (rVE) of HD-IIV vs SD-IIV against the prespecified end-points of hospitalization for any cardiovascular (CV) disease, respiratory disease, MI, heart failure, atrial fibrillation, stroke, and major adverse CV events (MACE, a composite of MI, stroke, or all-cause death)

        -- these results were also assessed according to whether the condition was present at baseline vs new-onset disease, in order to differentiate whether the condition was worsening of preexisting disease or a new one

    -- prespecified sensitivity analysis focused on aspects of the follow-up period

 Results:

-- high-dose influenza vaccine (HD-IIV) did not significantly reduce the overall trial's primary endpoint of hospitalizations for pneumonia or influenza vs SD-IIV, both by 5.9% (-2.1% to 13.4%)

-- the incidence for hospitalization for any cardiorespiratory disease:

    -- HD-IIV: 3735 participants (2.25%)

    -- SD-IIV: 3962 participants (2.38%)

        --relative vaccine efficacy (rVE), lower in HD-IIV group by 5.7% (1.4%-9.9%)

        -- absolute difference: -0.13 (-0.24 to -0.03) percentage points, number needed to vaccinate (NNV) 732 to prevent one additional event

            -- No difference in the rVE by history of prior cardiovascular disease

-- the incidence for hospitalization for cardiovascular disease:

    -- HD-IIV: 2156 participants (1.30%)

    -- SD-IIV: 2323 participants (1.40%)

        --relative vaccine efficacy (rVE), lower in HD-IIV group by 7.5% (1.5%-12.5%)

        -- absolute difference: -0.10 (-0.18 to -0.02) percentage points, NNV 995

            -- No difference in the rVE by history of prior cardiovascular disease

-- the incidence for hospitalization for MACE (I am including those with heart failure):

    -- HD-IIV: 1158 participants (0.7%)

    -- SD-IIV: 1224 participants (0.74%)

        --relative vaccine efficacy (rVE), lower in HD-IIV group by 5.4% (-2.6 to 12.8)

        -- absolute difference: -0.04 (-0.10 to 0.02) percentage points, NNV 2519, though not statistically significant

            -- No difference in the rVE by history of prior cardiovascular disease

-- the incidence for hospitalization specifically for heart failure (chosen because it had the highest benefit):

    -- HD-IIV : 214 participants(0.13%)

    -- SD-IIV: 266 participants (0.16%)

        --relative vaccine efficacy (rVE), lower in HD-IIV group by 19.5% (3.3%-33.1%)

        -- absolute difference: -0.03 (-0.06 to -0.01) percentage points, NNV 3197

            -- no difference in the rVE by age, sex, presence of cardiovascular disease, ischemic heart disease, heart failure, atrial fibrillation, diabetes, chronic kidney disease

            -- there was more benefit in those receiving HD-IIV who had coadministration of COVID-19 vaccine, almost statistically significant

-- hospitalization for any respiratory disease: not statistically significant

-- sensitivity/ analyses:

    -- the rVE for hospitalization for any cardiorespiratory disease and hospitalization for heart failure were increased during periods with substantial influenza circulation

    -- hospitalization for heart failure differences were independent of whether patients had pre-existing heart failure or not

 Commentary:

-- influenza is well-known to be associated with increased risk of atherosclerotic cardiovascular events overall, as well as heart failure and atrial fibrillation

-- influenza vaccine has been found to decrease cardiovascular disease in a large Danish study of adults followed 3.7 years, with increasing benefit in those individuals having annual vaccination as well as getting a greater cumulative number of vaccinations (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036788). other studies have found similar results when including patients after a myocardial infarction receiving standard-dose IIV, decreasing the risk of all cause death, myocardial infarction, or stent thrombosis by 28% (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057042)

-- the concern with the elderly is that several studies have found that SD-IIV often does not elicit an adequate immune response:

    -- prior randomized clinical trials have documented lower risk of major adverse cardiovascular events through influenza vaccination, including with SD-IIV (but less so than with HD-IIV)

    -- the high-dose vaccine does elicit a higher antibody response, which with standard-dose vaccine tends to be lower in older people as well as in those with known cardiovascular disease

        -- high-dose influenza vaccine has 4 times the amount of hemagglutinin, and large randomized clinical trials have found reduced laboratory-confirmed symptomatic influenza in the elderly by 24.2% (eg see https://www.nejm.org/doi/full/10.1056/NEJMoa1315727?query=featured_home , or https://www.thelancet.com/journals/lanres/article/PIIS2213-2600%2817%2930235-7/fulltext )

-- there was another study (the INVESTED trial) that did not find significant clinical benefit for cardiovascular disease by the higher-dose vaccine, though this trial was quite flawed per my review: http://gmodestmedblogs.blogspot.com/2020/12/high-dose-vs-standard-dose-influenza.html

-- hence the importance of the current secondary analysis of the large DANFLU-02 study

-- this current study found impressive relative benefit of HD-IIV over SD-IIV (heart failure hospitalizations, for example, found relative vaccine efficacy close to 20%), but with only small absolute benefit, though:

    -- these results were consistent over the major cardiovascular subgroups

    -- the absolute benefit in the above study was relatively small; however, this should be interpreted in the perspective of a vaccine that protects against a very prevalent, highly contagious virus with lots of significant severe consequences in the elderly 

    -- and, of course, the comparison of HD-IIV vs SD-IIV includes many elderly patients who would still have some benefit from SD-IIV (i.e., this was not a placebo control, which very likely would have shown a much greater benefit of HD-IIV)

        -- In fact, the World Health Organization estimates that 850 million doses of influenza vaccine are administered yearly, with the HD-IIV comprising only 10% of these doses; the mathematics here suggest that even with an NNV of 732 as found above, this would translate to more than a million additional averted cardiorespiratory hospitalizations worldwide if using HDIIV consistently

    -- both new-onset and recurrent heart failure were apparently protected by HD-IIV, though the number of patients showing benefit was small (though many patients with heart failure may not have been symptomatic enough to require hospitalization)

    -- this trial also found that there was a dose-response curve, with those having had more influenza shots, or those hospitalized with influenza infections at peak times of influenza circulation (who had more virus exposure) had more adverse cardiovascular events, including heart failure

    -- although the numbers of Americans who typically die from influenza is usually in the 12,000 to 56,000 person, but this can be much higher. A CDC report on the 2017-2018 flu epidemic reported that 80,000 people died in the US from influenza: http://gmodestmedblogs.blogspot.com/2018/10/80000-died-in-2017-18-flu-epidemic-in-us.html

-- this current study brings up lots of issues:

    -- one big one is that the identification of the influenza types likely to circulate subsequently and therefore included in the vaccine is fraught and may well be inaccurate (though there may still be some benefit from the non-perfect types included). the current development of the vaccine requires scouring around the world for the early variants well in advance, a necessity given the long time-frame necessary to produce adequate quantities of the vaccine for the next outbreak

    -- and, the anti-vax orientation of the US government (and some others) has led to important impediments here: one of the remarkable benefits of the mRNA vaccines is that there is a very short (a few month) time-frame to produce a more targeted vaccine, since the short time-frame would undoubtedly improve our ability to incorporate the actually circulating virus types into the vaccine

        -- BUT, the anti-vax, anti-science US "Health and Human Services" (in quotes because of this being such a drastic misnomer now) imperative is to "wind down mRNA vaccine development: https://www.hhs.gov/press-room/hhs-winds-down-mrna-development-under-barda.html

    -- though we may not be privy to accurate statistics in the future, a recent CDC report noted the highest flu season hospitalization rate in 2024-2025 since 2010-2011 (the 2024-2025 season happened to coincide with more popular vaccine hesitancy)(https://jamanetwork.com/journals/jama/fullarticle/2839724)

        -- there were 127 influenza-related hospitalizations per 100,000 population in 2024-2025 (1.8-2.8 times higher than any year since 2011)

        -- 17% of these hospitalized patients were in ICUs and 6% had mechanical ventilation, 3% died in the hospital

        -- and, as expected, 89% had underlying medical conditions

        -- hospitalizations were most common in those at least 75yo

        -- 2 of every 3 people hospitalized had not been vaccinated

    -- This also brings up the issue noted in prior CDC publications about the timing for influenza vaccination (http://gmodestmedblogs.blogspot.com/2018/09/maybe-we-should-delay-giving-flu-vaccine.html). This blog documents many studies finding that there is significant waning immunity after the influenza vaccine, which varies by the specific influenza type that the patient acquired.  the overall monthly decline in vaccine effectiveness was in the 6-11% range per month after the vaccination, suggesting that getting the vaccine several months prior to the onset of influenza would leave a significant percentage of patients unprotected

-- another very recent open-label study was just published in NEJM finding that community-dwelling adults 65-79yo in Galacia, Spain had fewer hospitalizations for influenza and pneumonia after receiving the high-dose vaccine vs the standard-dose vaccine (https://www.nejm.org/doi/10.1056/NEJMoa2509834)

    -- 2 influenza seasons were assessed: 2023-2034, 2024-2025 were evaluated for hospitalizations for influenza or pneumonia, beginning 14 days after vaccination and up until May 31 of the following year

    -- 103,169 participants were randomized to the 2 doses of influenza vaccine

    -- 174 of 67,093 participants (0.26%) in the high-dose group and 227 of 66,789 (0.34%) in the standard-dose group were hospitalized for influenza or pneumonia, finding a relative vaccine effectiveness with high-dose of 23.7%

    -- effectiveness for hospitalization for influenza decreased by 31.8%, however for hospitalization for pneumonia there was a strong but not statistically significant trend for a decline (overall, there were fewer hospitalizations than expected)

Limitations:

-- as noted by the authors, these results should be considered hypothesis-generating given that the positive results were in the setting of a secondary analysis of a neutral primary analysis of the DANFLU-2 trial (though the current trial was adequately powered to evaluate cardiorespiratory hospitalizations)

-- the results of the study were based on hospitalizations for cardiorespiratory conditions, and there may be many patients with subsequent cardiorespiratory consequences from an influenza infection who were not hospitalized

    --and, in many countries without a sophisticated database (eg, the US) and especially in patients with more remote cardiorespiratory consequences, patients may not be identified who have these influenza-related consequences (and these influenza infections may well not have been very serious ones requiring hospitalization)

    -- and, of course, there may well be many people who had the flu who develop cardiorespiratory events that actually were not related to the influenza infection (hard to determine the actual cause)

-- the trial is open-label (clinicians taking care of the patients with who were hospitalized were not formally part of the study), which can introduce bias

    -- it is conceivable that there was inaccurate information/misclassified data given that these clinicians were not part of the study.

so,

-- the big issue here, of course, is that very prominent political bullies are using their bully pulpit with very strong anti-vaccine rhetoric, reflecting their anti-science approach to medicine (and everything else), creating a hostile environment for extremely important and repeatedly documented medically-necessary immunizations (and lots of other things)

-- It is pretty clear from the above and other studies cited that the influenza vaccine works well, that the high-dose influenza vaccine in elderly seems to have a more profound antibody response and decreased clinical events associated with an influenza infection when the sequelae are measured from 2 weeks to many months after the influenza infection occurred. a recent study on RSV infections similarly found increased cardiovascular disease: http://gmodestmedblogs.blogspot.com/2025/01/adult-rsv-vaccine-effectivenessconcerns.html

-- there is concern about timing of the influenza immunization, which decreases substantially in effectiveness over time. That being said, it seems to me that timing for this immunization should be individualized:

    -- the major concern in waiting for immunization is that patients may not be immunized until too late or not at all. That is the basis, I think, of the global approach by the CDC historically in promoting early immunizations. This has changed some, with the CDC now targeting October vs August, which it used to be. And October is likely a reasonable target for the vast majority of people

    -- Influence activity typically starts in the southern part of the United States (eg see https://www.cdc.gov/fluview/surveillance/usmap.html). So, for home-based patients or clinic  patients who are seen very frequently and reliably for their multiple medical problems, there may be some advantage to waiting until influenza has started in the United States (the vaccine begins to work after about 2 weeks)

-- what are our talking points with patients in this vaccine-hesitancy time?? what points should we focus on?

    -- first, it is always useful to ask patients what they see as the risks of immunization and what are the benefits

    -- it is likely useful to find out where they got their information from about the problems with vaccinations

    -- i have found it useful to discuss the huge numbers of people who get influenza annually (including the 80,000 who died in the 2017-2018 season), which may well be more deaths in the future as fewer people are immunized in the current situation

        -- i think this helps center people who have heard on a couple of adverse anecdotal experiences

        -- also, i think it is likely to help by commenting on the serious complications of influenza (eg cardiac, respiratory), noting that these can emerge many months after the infection as in this study (called "long flu" or "post-viral syndrome")

        -- and i tie into this that it is really important to wear masks, especially when influenza is around since it is so easily transmitted to others

        -- with this approach, i have been able to convince several (but certainly not all) to receive the vaccine

        -- i would add, based on the current study, that it is much better to receive the flu vaccine with the covid vaccine. for those patients who had severe adverse reactions to the mRNA ones, it may make sense to offer the novavax vaccine which is currently available

geoff

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