Seasonal influenza vaccination in adults

INTRODUCTION — Influenza is an acute respiratory illness caused by influenza A or B viruses. It typically occurs in epidemics every year, mainly during the winter season in temperate climates.

Annual influenza vaccination is an important public health measure for preventing influenza infection [1,2]. Immune pressure within exposed populations, together with high viral mutation rates, lead to new variants which can escape population immunity, resulting in the need for regular updating of vaccine strains [3].

The role of influenza vaccination in the prevention of seasonal influenza will be reviewed here. Issues related to influenza vaccine in children, pregnant patients, health care workers, immunocompromised patients, and individuals with egg allergy are discussed separately:

●(See "Seasonal influenza in children: Prevention with vaccines".)

●(See "Seasonal influenza and pregnancy", section on 'Vaccination'.)

●(See "Immunizations for health care providers", section on 'Influenza vaccine'.)

●(See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Seasonal influenza vaccine'.)

●(See "Immunizations in adults with cancer", section on 'Influenza vaccine'.)

●(See "Immunizations in solid organ transplant candidates and recipients", section on 'Influenza'.)

●(See "Immunizations in hematopoietic cell transplant candidates, recipients, and donors", section on 'Influenza'.)

●(See "Immunizations in persons with HIV", section on 'Influenza vaccine'.)

●(See "Influenza vaccination in persons with egg allergy".)

VACCINE COMPOSITION AND FORMULATIONS

Antigenic composition

●Antigen selection – New influenza vaccines are produced each year, given the capacity of influenza virus for antigenic drift. Vaccine antigens for the Northern Hemisphere are selected by the World Health Organization (WHO) based on global surveillance of influenza virus strains circulating in February for the subsequent influenza season. As a result, there may be mismatches between the antigens selected for vaccine production and circulating strain antigens, leading to diminished vaccine efficacy. A similar process is followed for the Southern Hemisphere, with antigen selection in October. (See "Influenza: Epidemiology and pathogenesis", section on 'Virology'.)

●Switch from quadrivalent to trivalent vaccines for 2024-25 influenza season – The influenza vaccine used in many countries for the past several years has been quadrivalent, containing two type A subtypes (A/H1N1 and A/H3N2) and two type B lineages (B/Victoria and B/Yamagata). Viruses of the B/Yamagata lineage have not been identified globally since March 2020, and the WHO and other public health authorities have recommended that it be removed from the seasonal vaccine [4]. Accordingly, for the 2024-25 season, all influenza vaccines available for administration in the United States will be trivalent, containing a representative strain of A/H1N1, A/H3N2, and the B/Victoria lineage.

For the 2024-25 northern hemisphere influenza season, egg based-influenza vaccines contain hemagglutinin (HA) derived from [5]:

•An influenza A/Victoria/4897/2022 (H1N1)pdm09-like virus

•An A/Thailand/8/2022 (H3N2)-like virus

•An influenza B/Austria/1359417/2021-like virus (B/Victoria lineage)

For the 2024-25 northern hemisphere influenza season, cell culture-based inactivated vaccine (ccIIV3) and recombinant influenza vaccine (RIV3) contain HA derived from [5,6]:

•An influenza A/Wisconsin/67/2022 (H1N1)pdm09-like virus

•An A/Massachusetts/18/2022 (H3N2)-like virus

•An influenza B/Austria/1359417/2021-like virus (B/Victoria lineage)

Formulations — In the United States, available types of seasonal vaccine include several inactivated influenza vaccines (IIVs), a recombinant influenza vaccine (RIV), and a live attenuated influenza vaccine (LAIV) [7]. Available vaccines are summarized and compared in the tables (table 1 and table 2). The approach to vaccine selection for individual patients is discussed below. (See 'Choice of vaccine formulation' below.)

●Inactivated influenza vaccines

•Egg based

-Standard dose, parenterally administered – The standard-dose IIVs in the United States consist of split virion or subunit vaccines that have been inactivated (Fluarix, FluLaval, and Fluzone) and administered intramuscularly. These vaccines contain 15 mcg of each HA per virus and are produced in embryonated chicken eggs. They are approved by the US Food and Drug Administration (FDA) for all adults. (See 'Antigenic composition' above.).

-Standard dose, "needle free" – The inactivated IIV (Afluria) is administered intramuscularly using a jet injector device. It contains 15 mcg of each HA per virus. It is FDA approved for adults 18 to 64 years of age.

-Standard dose, adjuvanted – An adjuvanted (MF59), subunit IIV (Fluad Quadrivalent) is administered intramuscularly. It contains 15 mcg of each HA per virus and is FDA approved for individuals ≥65 years of age [8]. (See 'Patients 65 years and older' below.)

-High dose – A high-dose quadrivalent IIV (Fluzone High-Dose) is administered intramuscularly. It contains 60 mcg of each HA per virus and is FDA approved for individuals ≥65 years of age; [9]. (See 'Patients 65 years and older' below.)

•Cell culture based, standard dose – A non-egg-based IIV produced in cultured mammalian cells (Flucelvax) is approved for individuals ≥6 months of age [7,10]. The vaccine is administered intramuscularly and contains 15 mcg of each HA per virus. (See 'Efficacy of alternatives to egg-based IIVs' below.)

●Recombinant HA influenza vaccine – A recombinant hemagglutinin (HA) influenza vaccine (Flublok), is approved for individuals ≥18 years of age [11]. Unlike the other formulations, which contain both HA and NA antigens, the recombinant vaccine contains only HA antigens. It is administered intramuscularly and contains 45 mcg of each HA per virus. (See 'Efficacy of alternatives to egg-based IIVs' below.)

●Live attenuated influenza vaccine (nasal spray, egg based) – The only intranasally administered influenza vaccine, LAIV (FluMist) is approved for healthy nonpregnant individuals between 2 and 49 years of age. Contraindications to LAIV are summarized in the table (table 3). If LAIV is administered inadvertently to an individual who has close contact with a severely immunosuppressed individual, contact should be avoided for seven days [12]. Pregnant and postpartum people do not need to avoid contact with people who recently received LAIV [12].

LAIV uses a master attenuated cold-adapted donor virus; reassortants are generated with HA and NA antigens from circulating virus at the time the annual vaccine was designed. The vaccine is produced in embryonated chicken eggs.

CLINICAL APPROACH

Whom to vaccinate — We are in agreement with the Advisory Committee on Immunization Practices (ACIP), which recommends annual influenza vaccination for all individuals ≥6 months of age [13].

If vaccine supply is limited, priority groups include individuals at increased risk for complications (table 4), as well as the caregivers and household contacts of these individuals, including [2]:

●Health care personnel who have the potential for exposure to patients and/or to infectious materials

●Household contacts (including children ≥6 months) or caregivers of children <5 years or adults ≥50 years of age, particularly contacts of children <6 months

●Household contacts (including children ≥6 months) or caregivers of persons with medical conditions that put them at increased risk for severe complications of influenza

Among patients in these categories, live attenuated influenza vaccine (LAIV) is contraindicated; the approach to vaccination for immunocompromised patients and health care workers is discussed further separately. (See 'Introduction' above.)

When to vaccinate — A single dose of a seasonal influenza vaccine should be administered to adults annually [7]. We do not recommend more than one dose of seasonal influenza vaccine for adults in a single season as this has not been shown to be of additional benefit [14,15].

The ideal time to begin vaccinating is uncertain, given the importance of balancing the unpredictability of influenza season timing (and minimizing missed opportunities for vaccination) with possible waning of vaccine-induced immunity over the course of the season (figure 1).

From a public health perspective, administration of vaccine in preseasonal campaigns is the most efficient way to achieve high coverage before influenza circulation. In general, vaccination should be administered as soon as it becomes available, prior to onset of influenza activity in the community (typically by the end of October in the northern hemisphere and by April in the southern hemisphere) [7].

The ideal time to begin vaccinating is uncertain and likely differs from year to year, given the importance of balancing the unpredictability of influenza season timing (and minimizing missed opportunities for vaccination) with possible waning of vaccine-induced immunity over the course of the season (figure 1).

Vaccination during July or August is not recommended for most nonpregnant adults because of possible waning of immunity, unless there is concern that vaccination later in the season might not be possible.

In countries near the equator with no distinct peak in influenza activity, timing of annual vaccination may be based on local factors. Issues related to influenza vaccination for travelers are discussed separately. (See "Immunizations for travel".)

The protection afforded by annual vaccination may attenuate over time [15]. In one study including more than 49,000 adults and children who received inactivated influenza vaccine between September 2010 and March 2017, those vaccinated 42 to 69 days prior to testing had 1.3 times the odds of testing positive for influenza compared with those vaccinated 14 to 41 days prior testing (95% CI 1.1-1.6) [16]. The odds ratio for testing positive increased linearly by approximately 16 percent for each additional 28 days since vaccination; it was 2.1 (95% CI 1.7-2.5) for individuals vaccinated ≥154 days prior to testing. Delaying vaccination until there is evidence of increasing influenza circulation in a community can result in missed vaccinations and should not be a routine clinical practice. However, we encourage unvaccinated individuals to receive the vaccine until the end of influenza season.

In countries near the equator with no distinct peak in influenza activity, timing of annual vaccination should follow national public health recommendations. Issues related to influenza vaccination for travelers are discussed separately. (See "Immunizations for travel".)

Choice of vaccine formulation — Vaccine composition and formulations are summarized above (table 1). (See 'Vaccine composition and formulations' above.)

The choice of vaccine formulation depends upon several factors, including age, comorbidities, and risk of adverse reactions (table 2). Contraindications and precautions should be reviewed carefully prior to selection of a vaccine formulation (table 3) [17]. (See 'Contraindications and precautions' below.)

●For healthy nonpregnant adults ≤49 years, any of the inactivated influenza vaccines (IIVs), RIV, or LAIV may be given (table 1).

●For individuals ≤49 years with a contraindication to LAIV (eg, immunosuppression; chronic cardiovascular, pulmonary, or metabolic disease; pregnancy (table 3)), any of the IIVs or RIV may be given.

●For individuals 50 to 64 years of age, any of the IIVs or RIV may be given.

●For individuals ≥65 years of age, we agree with the ACIP which recommends that such individuals receive any one of the following higher dose or adjuvanted influenza vaccines (table 1) [7]:

•Trivalent high-dose inactivated influenza vaccine (HD-IIV3)

•Trivalent adjuvanted inactivated influenza vaccine (aII3)

•Trivalent recombinant influenza vaccine (RIV3)

If these vaccines are not available, standard IIVs are an acceptable alternative.

●For individuals who are needle phobic, alternative formulations include:

•Live attenuated influenza vaccine – The LAIV is administered via single-use intranasal sprayer. Contraindications and precautions are summarized in the table (table 3) and discussed below. (See 'Contraindications and precautions' below.)

•Needle-free intramuscular administration – Intramuscular administration of IIV (Afluria) using a jet injector is approved for individuals 18 to 64 years of age [18]. The jet injector is a device that uses a high-pressure jet of liquid vaccine to penetrate tissue. This method has been associated with a higher frequency of local injection site reactions than use of needle and syringe. (See 'Adverse reactions' below.)

●The approach vaccine selection for other groups, including immunosuppressed patients, pregnant patients, health care workers, and individuals with egg allergy, is discussed separately. (See 'Introduction' above.)

Administration technique — The deltoid muscle is the preferred site for intramuscular influenza vaccine administration in adults. Issues related to administration technique are discussed further separately. (See "Standard immunizations for nonpregnant adults", section on 'Technique'.)

Coadministration with other vaccines

●COVID-19 vaccine – Influenza vaccine may be coadministered with coronavirus disease 2019 (COVID-19) vaccine [7,19-22]. The vaccines should be administered at different anatomic sites to reduce the risk of local reactions with coadministration [7].

This approach is supported by a trial including more than 600 adults previously immunized with a single dose of COVID-19 vaccine (ChAdOx1 or BNT162b2) randomly assigned to receive concomitant administration of influenza vaccine (cellular quadrivalent, recombinant quadrivalent, or MF59C adjuvanted trivalent) or placebo along with their second dose of COVID-19 vaccine [23]. There were no safety concerns, most systemic reactions to vaccination were mild or moderate, and the immune response to both vaccines was preserved. COVID-19 vaccine may also be administered with high-dose influenza vaccine [24].

●Respiratory syncytial virus (RSV) vaccine – Influenza vaccine may be coadministered with RSV vaccine [25]; given evolving data, consult current CDC guidance for the latest information.

●Pneumococcal vaccine – Influenza vaccine may be coadministered with 15-valent or 20-valent pneumococcal conjugate vaccines (PCV15 or PCV20) or with 23-valent pneumococcal polysaccharide vaccine [26]; given evolving data, consult current CDC guidance for the latest information.

●Coadministration of influenza vaccine with other vaccines

•Inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV) – IIV or RIV may be administered at the same time as (but at a different site from) other vaccines. IIVs and RIV do not interfere with the immune response to other inactivated vaccines or to live virus vaccines [27].

Given limited data on the safety of simultaneous administration vaccines containing nonaluminum adjuvants, selection of a nonadjuvanted influenza vaccine should be considered in situations in which influenza vaccine and another vaccine containing a nonaluminum adjuvant are to be administered concomitantly [2].

•Live attenuated influenza vaccine (LAIV) – LAIV can be administered at the same time as other live virus vaccines or inactivated vaccines. However, if it is not administered on the same day as other live virus vaccines (such as zoster vaccine), it should be administered at least four weeks later, since the immune response to one live virus vaccine may be impaired if administered within four weeks of another live virus vaccine.

Vaccination in setting of concomitant illness

●Inactivated influenza vaccine or recombinant influenza vaccine

•Non-COVID-19 respiratory illness – For individuals with minor non-COVID-19 respiratory illnesses, IIV or RIV may be administered, in the presence or absence of a low-grade fever [28].

For individuals with moderate or severe acute respiratory illness (with or without fever) IIV or RIV should be deferred until symptoms have resolved, to avoid confusion between the underlying illness and adverse vaccine effects.

•COVID-19 – Specific data concerning the optimal timing of influenza vaccination of persons with COVID-19 illness are not available.

For patients with COVID-19, IIV or RIV should be deferred until symptoms of COVID-19 infection have resolved and the period of quarantine has ended [7].

●Live attenuated vaccine − For patients with upper respiratory tract infection, we avoid administration of LAIV (which is administered nasally), given concern for inadequate virus replication and/or inadequate antigen exposure [17].

Vaccination in setting of concomitant antivirals — Administration of IIV or RIV to individuals receiving influenza antiviral medications for treatment or chemoprophylaxis of influenza is acceptable. However, influenza antiviral medications may mitigate the benefit of LAIV, since this vaccine contains live influenza virus; the potential influence of antiviral agents on vaccine effectiveness may vary depending on drug half-life.

For individuals who received antiviral medications and LAIV during the time windows outlined below, revaccination with IIV or RIV is warranted [7]:

●Oseltamivir or zanamivir – Between 48 hours before and 14 days after LAIV

●Peramivir – Between 5 days before and 14 days after LAIV

●Baloxavir – Between 17 days before and 14 days after LAIV

Improving vaccination rates — The Healthy People 2020 adult influenza vaccination target is 70 percent [29].

Influenza vaccine uptake remains suboptimal. In a retrospective study including more than 31 million Medicare beneficiaries >19 years of age in the United States during the 2018 to 2019 influenza season, vaccination claims were filed for only 50 percent of individuals [30]. Vaccination uptake was higher among White beneficiaries than Black or Hispanic beneficiaries (53, 35, and 30 percent, respectively), and was higher for those with high-risk conditions than for those without (56 versus 27 percent, respectively). Among unvaccinated beneficiaries overall, 77 percent visited a provider during influenza season.

Several strategies for improving immunization rates have been proposed; these are outlined separately. (See "Standard immunizations for nonpregnant adults", section on 'Increasing immunization rates'.)

Use of electronic letters has been proposed as a strategy for improving annual influenza vaccination rates. In a study including more than 960,000 Danish citizens ≥65 years of age prior to the 2022 to 2023 influenza season, participants were randomly assigned to receive no letter or one of nine letters that included a behavioral nudge [31]. Vaccination rates were higher among two groups; those who received letters highlighting cardiovascular disease protection (81.00 versus 80.12 percent; difference 0.89 percentage points [99.55% CI 0.29-1.48]; relative risk [RR] 1.011 [99.55% CI 1.004-1.019]), and those who received a standard electronic letter repeated at 14 days (80.85 versus 80.12 percent; difference 0.73 percentage points [0.13-1.34]; RR 1.009 [1.002-1.017]). Although the observed effects were modest, a difference of 0.89 percent across the entire cohort would amount to vaccination of more than 8500 additional individuals – a meaningful increase for a low-cost, scalable intervention.

CONTRAINDICATIONS AND PRECAUTIONS — Contraindications and precautions for use of influenza vaccines are summarized in the table (table 3) [7].

●Allergy − Influenza vaccination is contraindicated in patients with prior history of a severe allergic reaction (eg, anaphylaxis) to an influenza vaccine.

The approach to influenza vaccination in individuals with egg allergy is discussed separately. (See "Influenza vaccination in persons with egg allergy".)

●Patients on anticoagulation − Patients receiving an oral anticoagulant may receive the influenza vaccine by intramuscular injection [32,33]. Measures should be taken to minimize the risk of hematoma; these include use of a small-gauge needle (eg, 23 gauge or smaller) when possible and applying firm pressure (without rubbing) to the vaccination site for at least two minutes following vaccination [28].

●Guillain-Barré syndrome – For individuals with risk for influenza complications, the small risk of vaccine-associated Guillain-Barré syndrome (GBS) is likely outweighed by the benefits of influenza vaccination; furthermore, influenza vaccination may reduce the small risk for GBS that can be triggered by influenza virus infection [34,35]. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Central nervous system involvement'.)

For individuals with prior history of GBS who are at risk for influenza complications (table 4), we favor proceeding with influenza vaccination. Many defer vaccination ≥12 months after onset of GBS. For those who are not at risk for influenza complications, it is reasonable to forgo influenza vaccination. (See "Guillain-Barré syndrome in adults: Treatment and prognosis", section on 'Subsequent immunizations'.)

It is uncertain whether influenza vaccination increases risk for GBS. In a 2015 systematic review including 22 observational studies of seasonal influenza vaccine between 1981 and 2014, the relative risk of GBS was 1.22 (95% CI 1.01-1.48) [36]. In a 2020 systematic review including 22 epidemiologic studies between 1981 to 2019, no risk of vaccine-associated GBS was observed (effect size 1.15, 95% CI 0.97-1.35); conversely, an increased risk of GBS among patients with previous influenza-like illness was observed (pooled effect size 9.6, 95% CI 4.0-23.0) [37].

ADVERSE REACTIONS

●Inactivated vaccines − The inactivated influenza vaccines are generally well tolerated; adverse effects are outlined below.

•Local injection site reaction − The most common adverse effect is soreness at the injection site for about two days [7]. Low-grade fever, myalgia, headache, and fatigue are less common and may last one to two days.

In a randomized trial including more than 3800 adults ≥65 years, adverse reactions occurred more frequently among those who received high-dose compared with standard-dose vaccine; these included pain (36 versus 24 percent), erythema (15 versus 11 percent), and swelling (6 versus 4 percent) [38].

•Shoulder bursitis − Vaccination in the deltoid muscle can trigger shoulder bursitis (involving the subdeltoid and/or subacromial bursa). In a cohort study including more than 2,940,000 individuals who received inactivated influenza vaccine during the 2016-2017 influenza season, 257 cases of postvaccination shoulder bursitis were observed; 16 developed within 3 days (calculated attributable risk 7.78 excess cases per million people vaccinated), while 51 cases occurred during a "control" period (30 to 60 days further out from vaccination); 190 had symptom onset in neither prespecified interval [39].

Vaccination technique may play a role in shoulder injury. (See "Standard immunizations for nonpregnant adults", section on 'Technique'.)

•Guillain-Barré syndrome − It is uncertain whether influenza vaccination increases risk for Guillain-Barré syndrome (GBS). (See 'Contraindications and precautions' above.)

•Allergic reaction − Anaphylaxis or severe allergic reaction associated with influenza vaccination is rare, even among individuals with egg allergy [1]. Issues related to allergic reactions associated with influenza vaccine are discussed separately. (See "Allergic reactions to vaccines", section on 'Influenza' and "Influenza vaccination in persons with egg allergy".)

●Needle-free intramuscular vaccine − Administration of inactivated influenza vaccine with a jet injector device has been associated with a higher frequency of adverse event (localized tenderness, itching, redness, swelling, or bruising) than use of needle and syringe (47 versus 17 percent); these symptoms generally resolve within three days [18].

●Live attenuated vaccine − Live attenuated vaccine (LAIV) is generally well tolerated; the most common side effects in adults include rhinorrhea, nasal congestion, headache, and sore throat [40]. Among 2.5 million people who received LAIV, serious adverse events include: possible anaphylaxis (seven), GBS (two), Bell's palsy (one), and asthma exacerbation among individuals with asthma history (eight) [41].

EFFICACY

General principles

●Factors influencing vaccine efficacy – Influenza vaccine efficacy is influenced by a number of factors; these include age, baseline health, immune function, as well as vaccine characteristics such as vaccine type, antigen dose, presence of adjuvants, and the degree of match between vaccine antigens and circulating virus strains [1].

●Clinical assessment – Vaccine efficacy is assessed in clinical trials, which strive to evaluate vaccine performance under optimal circumstances for product licensure. In this section, we discuss relevant data on influenza vaccine performance from clinical trials (efficacy) and observational studies (effectiveness).

•Clinical trials – Absolute vaccine efficacy data are limited except when a vaccine is initially approved; clinical trial designs with placebo controls can measure absolute vaccine efficacy, but may be considered unethical in settings where annual influenza vaccination is the standard of care.

•Observational studies – Observational studies evaluating vaccine efficacy are increasingly common, with networks in multiple regions conducting studies annually. While this approach to study design is more prone to bias and confounding, advances in study design and analysis have resulted in improved estimates of influenza vaccine effectiveness.

The United States Centers for Disease Control and Prevention (CDC) conducts annual influenza vaccine effectiveness studies within the United States. Vaccines are also evaluated for effectiveness in other countries. Vaccine effectiveness varies from year to year; the CDC estimates that typically it has been between 40 percent and 60 percent against medically-attended, laboratory-confirmed influenza illness in the general population (adults and children combined), with lower effectiveness at the extremes of age and when the vaccine virus strain does not match well with circulating virus [42]. Vaccine effectiveness estimates are similar against hospitalized, laboratory-confirmed influenza illness [43].

Overall efficacy

●Vaccination is associated with a reduced incidence of influenza:

•In a 2018 meta-analysis including 52 trials and more than 80,000 healthy adults, influenza vaccination reduced the incidence of influenza from 2.3 to 0.9 percent (risk ratio [RR] 0.41, 95% CI 0.36-0.47), corresponding to a number needed to vaccinate of 71 [44].

•In a 2018 meta-analysis including eight trials and more than 5000 adults ≥65 years, influenza vaccination reduced the incidence of influenza from 6 to 2.4 percent (RR 0.42, 95% CI 0.27-0.66) [45].

●Among vaccinated individuals with breakthrough influenza virus infection, vaccination is associated with reduced mortality and attenuated disease severity [46]:

•Among five observational studies of adults with influenza-associated hospitalization, vaccination was associated with 31 percent mortality reduction (odds ratio [OR] 0.69, 95% CI 0.52-0.92).

•Among eight studies of adults with influenza-associated hospitalization, vaccination was associated with 26 percent reduction in odds of intensive care unit admission (OR 0.74, 95% CI 0.58-0.93).

Efficacy of alternatives to egg-based IIVs — Alternatives to egg-based inactivated influenza vaccines (IIVs) include recombinant vaccine, cell culture-derived inactivated vaccine, and live attenuated egg-based vaccine (table 1):

●Recombinant vaccine – Recombinant influenza vaccine (RIV) may confer better protection than standard dose-IIV:

•In a cluster-randomized observational study including more than 675,000 adults age 50 to 64 years (279,400 in the recombinant-vaccine group and 395,852 in the standard-dose group) during the 2018–2019 and 2019–2020 influenza seasons, fewer cases of influenza were observed in the recombinant-vaccine group (559 versus 925 participants; 2.00 versus 2.34 cases per 1000); the relative vaccine effectiveness was 15.3% (95% confidence interval 5.9 to 23.8) [47].

•In a randomized trial including more than 8600 adults ≥50 years of age (mean 63, range 50 to 96 years) randomly assigned to receive recombinant quadrivalent influenza vaccine or a standard-dose quadrivalent inactivated influenza vaccine (IIV), the attack rate of polymerase chain reaction (PCR)-confirmed influenza was 30 percent (95% CI 10-47) lower among those who received recombinant vaccine compared to standard dose-IIV (2.2 versus 3.2 percent); safety profiles were comparable [48,49].

●Cell culture-derived inactivated vaccine − The efficacy of cell culture-derived inactivated influenza vaccine (ccIIV) is comparable to that of egg-based IIV. In a randomized trial including more than 11,400 adults vaccinated with ccIIV, egg-based IIV, or placebo, vaccine efficacy was 69.5 versus 63 percent, respectively; adverse effects were comparable [50].

●Live attenuated egg-based vaccine – The efficacy of live attenuated influenza vaccine (LAIV) is comparable to that of IIV. In a randomized trial including more than 41,000 individuals over three influenza seasons, there was no difference in influenza-like illness by vaccine type [51].

Effect of virus type and antigen match — There may be mismatches between vaccine strains and the circulating strains, leading to diminished efficacy. Mismatches may occur when the selected vaccine strain does not match with circulating influenza viruses. Additional mismatches can occur when vaccine strain viruses undergo antigenic changes as part of viral adaptations to growth in eggs [52]. (See 'Antigenic composition' above and "Influenza: Epidemiology and pathogenesis".)

●Vaccine effectiveness is lower for A(H3N2) relative to A(H1N1)pdm09 and type B [53]:

•In a meta-analysis including 56 studies of vaccine effectiveness among outpatients between 2004 and 2015, the overall vaccine effectiveness was 33 percent for A(H3N2), 54 percent for influenza B, and 61 percent for A(H1N1)pdm09 [54].

For adults ≥60 years, pooled effectiveness was 24 percent for A(H3N2), 63 percent for influenza, and 62 percent for A(H1N1)pdm09.

●Vaccination is associated with reduced hospitalization risk for influenza A(H1N1)pdm09 infection, but not for influenza A(H3N2) infection:

•In a review including more than 2800 adults (mean age 63 years), vaccination halved the risk of influenza A(H1N1)pdm09-associated hospitalizations (95% CI 25-68 percent) but conferred no protection against influenza A(H3N2)-associated hospitalizations [55].

●In some circumstances, diminished vaccine efficacy may be attributable in part to antigen match [53]:

•In a meta-analysis including 56 studies of vaccine effectiveness, when the H3N2 vaccine antigen was well-matched to the circulating A(H3N2) viruses, effectiveness was 33 percent; when antigenic drift was present, effectiveness was 23 percent [54].

•In a meta-analysis including nearly 5000 older adults, the adjusted effectiveness of influenza vaccine for prevention of laboratory-confirmed influenza during well-matched versus poorly matched seasons was 44 versus 20 percent, respectively [56].

Efficacy for specific demographic groups

Patients 65 years and older — Among individuals ≥65 years, data suggest that high-dose inactivated vaccine, adjuvanted vaccine, or RIV confer greater protection against influenza virus infection than standard-dose inactivated vaccine. (See 'Choice of vaccine formulation' above.)

●High-dose vaccine − In a meta-analysis including 15 studies, greater protection against influenza was observed among those vaccinated with high-dose inactivated trivalent influenza vaccine than with standard-dose inactivated influenza vaccine (standard dose -IIV; relative vaccine efficacy 11.7 percent, 95% CI 7.0-16.1 percent) [57]. Reductions in mortality due to pneumonia/influenza (relative vaccine efficacy 39.9 percent, 95% CI 18.6-55.6 percent) and cardiorespiratory causes (relative vaccine efficacy 27.7 percent, 95% CI 13.2-32.0) were also observed. Similar pooled efficacy was observed in both matched and mismatched seasons and in seasons where A/H3N2 or A/H1N1 strains were predominant.

Mild to moderate local reactions are more common with the high-dose vaccine than with standard-dose vaccine, but the incidence of serious adverse events is similar. (See 'Adverse reactions' above.)

●Adjuvanted vaccine − In a meta-analysis including five case-control studies, pooled vaccine efficacy for adjuvanted trivalent influenza vaccine was 51.3 percent (95% CI 39.1-61.1) against influenza- or pneumonia-related hospitalization [58]. The relative vaccine effectiveness of adjuvanted trivalent influenza vaccine compared with trivalent inactivated vaccine for prevention of influenza-related medical encounters was 13.9 percent (95% CI 4.2-23.5).

●Recombinant vaccine − In a randomized trial including more than 9000 individuals age ≥50 years, the probability of influenza-like illness was 30 percent lower among those who received RIV4 than those who received IIV4 (attack rate 2.2 versus 3.1 percent); in addition, relative benefit for prevention of culture-confirmed influenza-like illness among those age ≥65 years was observed (relative efficacy 42 percent, 95% CI 9-65 percent) [48].

Patients with heart or lung disease

●Among patients with cardiovascular disease, vaccination is associated with reduced mortality and major adverse cardiovascular events:

•In a 2022 meta-analysis including six randomized trials and 9001 patients, influenza vaccine was associated with a 34 percent lower risk of composite cardiovascular events (3.6 versus 5.4 percent; RR 0.66, 95% CI 0.53-0.83) [59].

•In a 2021 meta-analysis including more than 237,000 patients with cardiovascular disease, vaccination was associated with a 18 percent reduction in cardiovascular mortality (RR 0.82, 95% CI 0.80-0.84) and a 13 percent reduction in major adverse cardiovascular events (RR 0.87, 95% CI 0.80-0.94) [60].

•In a 2021 trial including more than 2500 patients with recent myocardial infarction randomly assigned to receive influenza vaccine or placebo during influenza season, rates of all-cause mortality was lower among those who were vaccinated (2.9 versus 4.9 percent; hazard ratio [HR] 0.59, 95% CI 0.39-0.89) [61].

●Among patients with high-risk cardiovascular disease, the efficacy of high-dose trivalent influenza vaccine appears to be comparable with that of standard-dose quadrivalent vaccine:

•In a randomized trial including more than 5200 patients with recent acute myocardial infarction or hospitalization for heart failure and at least one additional risk factor who received high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, there was no difference in hospitalization for cardiovascular or pulmonary cause or death from any cause (45 versus 42 per 100 patient-years; HR 1.06, 95% CI 0.97-1.17) for up to three influenza seasons [62].

Thus far, similar comparative studies have not been completed with the high-dose quadrivalent vaccine.

●Among patients with chronic lung disease, vaccination is beneficial for protection against influenza virus infection:

•In a meta-analysis including more than 5000 adults, the adjusted effectiveness of influenza vaccine for prevention of laboratory-confirmed influenza among patients with chronic lung disease was 31.2 percent (95% CI 2.4-52.5) [56].

INVESTIGATIONAL VACCINE APPROACHES — Important drawbacks of traditional influenza vaccines include the need to manufacture new vaccines each year, long production times for egg culture-based manufacturing, and diminished effectiveness in age groups at the greatest risk of severe illness due to influenza.

●Investigational approaches to vaccine development

•mRNA-based vaccine - The efficacy and safety of mRNA-based COVID-19 vaccines and the flexibility of the mRNA platform have sparked research into the development of mRNA seasonal influenza vaccines. These products could be manufactured with shorter timelines than traditional influenza vaccines and avoid the challenges of viral culture. Several mRNA-based influenza vaccines are in human trials [63].

•Universal vaccine development - A universal vaccine capable of eliciting protective antibodies against conserved viral proteins would provide protection against drifting influenza strains as well as against newly emerging pandemic influenza strains [64,65]. This is an area of ongoing study [66,67].

●Investigational modes of vaccine administration

•Intradermal administration - Intradermal administration, including the use of microneedle patches, might be more effective than intramuscular delivery due to stimulation of dendritic cells, which are specialized antigen-presenting cells. An intradermal vaccine was approved in the United States in 2011 but was discontinued due to limited demand. Several trials have shown that a reduced dose of the intradermal vaccine results in similar immunogenicity as standard-dose intramuscular vaccines [68,69].

•Self-administration — Intradermal administration or nasally administered live-attenuated influenza vaccines could have an additional public health benefit of self-administration [70,71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seasonal influenza vaccination".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Flu vaccine (The Basics)" and "Patient education: Flu (The Basics)" and "Patient education: What you should know about vaccines (The Basics)" and "Patient education: Vaccines for adults (The Basics)" and "Patient education: Vaccines and pregnancy (The Basics)")

●Beyond the Basics topics (see "Patient education: Influenza prevention (Beyond the Basics)" and "Patient education: Influenza symptoms and treatment (Beyond the Basics)" and "Patient education: Vaccination during pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction − Influenza is an acute respiratory illness caused by influenza A or B viruses. It occurs in epidemics nearly every year, mainly during the winter season in temperate climates. Annual influenza vaccination is an important public health measure for preventing influenza virus infection. (See 'Introduction' above.)

●Vaccine composition

•Updated influenza vaccines are produced each year, given the capacity of influenza virus for antigenic drift. Vaccine antigens are selected based on global surveillance of influenza viruses circulating at the end of the previous season; however, there may be mismatches between vaccine strains and the circulating strains, leading to diminished efficacy.

•For the 2024-25 season, all influenza vaccines available for administration in the United States will be trivalent, containing a representative strain of A/H1N1, A/H3N2, and the B/Victoria lineage. Viruses of the B/Yamagata lineage have not been identified globally since March 2020, and the WHO and other public health authorities have recommended that it be removed from the seasonal vaccine.

●Vaccine formulations − Vaccine formulations available include several inactivated influenza vaccines (IIVs), one live attenuated influenza vaccine (LAIV), and one recombinant vaccine (table 1 and table 2). IIVs include egg-based and cell culture-based products. (See 'Formulations' above.)

●Whom to vaccinate – We recommend annual influenza vaccination for all adults (Grade 1A), in the absence of contraindications (table 3). If vaccine supply is limited, priority groups include individuals at increased risk for complications (table 4), as well as the caregivers and household contacts of these individuals. (See 'Whom to vaccinate' above.)

●When to vaccinate – Influenza vaccine should be administered as soon as it becomes available, prior to onset of influenza activity in the community (by the end of October in the northern hemisphere and by April in the southern hemisphere). Unvaccinated individuals should be encouraged to receive the vaccine until the end of influenza season. (See 'When to vaccinate' above.)

●Choice of vaccine formulation − The choice of vaccine formulation depends upon several factors, including age, comorbidities, and risk of adverse reactions. (See 'Choice of vaccine formulation' above.)

•For healthy nonpregnant adults ≤49 years, any of the IIVs, RIV, or LAIV may be given.

•For individuals ≤49 years with a contraindication to LAIV (eg, pregnancy, immunocompromise, or chronic cardiovascular, pulmonary, or metabolic disease) (table 3), any of the IIVs or RIV may be given.

•For individuals 50 to 64 years of age, any of the IIVs or RIV may be given.

•For individuals ≥65 years of age, we suggest the high-dose IIV, adjuvanted IIV, or RIV over other influenza vaccines (Grade 2C).

•The approach to vaccine selection for other groups, including immunocompromised patients, pregnant patients, health care workers, and individuals with egg allergy, is discussed separately. (See 'Introduction' above.)