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Seasonal influenza vaccination in adults

Seasonal influenza vaccination in adults
Literature review current through: Sep 2023.
This topic last updated: Sep 19, 2023.

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. Influenza viruses change their antigenic characteristics frequently, and their spread depends upon the susceptibility of the population to viruses with novel antigens.

Annual influenza vaccination is an important public health measure for preventing influenza infection [1,2].

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 and recipients".)

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

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

VACCINE COMPOSITION AND FORMULATIONS

Antigenic composition — New 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. (See "Influenza: Epidemiology and pathogenesis", section on 'Virology'.)

The quadrivalent influenza vaccines available in the United States contain two influenza A antigens and two influenza B antigens; they are summarized in the table (table 1) [3].

For the 2023 to 2024 northern hemisphere influenza season, egg-based influenza vaccines contain hemagglutinin (HA) derived from [4]:

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

An influenza A/Darwin/9/2021 (H3N2)-like virus

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

An influenza B/Phuket/3073/2013-like virus (B/Yamagata lineage)

For the 2023 to 2024 northern hemisphere influenza season, cell culture-based inactivated (ccIIV4) and recombinant (RIV4) influenza vaccines contain HA derived from [4]:

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

An influenza A/Darwin/6/2021 (H3N2)-like virus

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

An influenza B/Phuket/3073/2013-like virus (B/Yamagata lineage)

Formulations — In the United States, available types of quadrivalent vaccine include several inactivated influenza vaccines (IIVs), one recombinant influenza vaccine, and one live attenuated influenza vaccine (LAIV) [3]. 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). They are approved by the US Food and Drug Administration (FDA) for intramuscular injection in all adults. These vaccines contain 15 mcg of each HA per virus and are produced in embryonated chicken eggs. (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 IIV (Fluad Quadrivalent) is FDA approved for use in individuals ≥65 years of age [5]. It contains 15 mcg of each HA per virus. (See 'Patients 65 years and older' below.)

-High dose An intramuscular high-dose quadrivalent IIV (Fluzone High-Dose) is FDA approved for individuals ≥65 years of age; the vaccine contains 60 mcg of each HA per virus [6]. (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 [3,7]. The vaccine contains 15 mcg of each HA per virus. (See 'Alternatives to egg-based inactivated influenza vaccines' below and 'Alternatives to egg-based production' below.)

Recombinant HA influenza vaccine – A recombinant hemagglutinin (HA) influenza vaccine (Flublok), is approved for individuals ≥18 years of age [8]. Unlike the other formulations, which contain both HA and neuraminidase antigens, the recombinant vaccine contains only HA antigens. (See 'Alternatives to egg-based inactivated influenza vaccines' below and 'Alternatives to egg-based production' below.)

Live attenuated influenza vaccine (nasal spray, egg based) – The intranasally administered 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 [9].

The Advisory Committee on Immunization Practices recommended against use of LAIV in the northern hemisphere for the 2016-2017 and 2017-2018 influenza seasons; it resumed including it as an option in the 2018-2019 season [10].

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 [11].

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 ≤59 months (<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 an influenza vaccine should be administered to adults annually [3]. We do not recommend more than one dose of influenza vaccine for adults in a single season; the safety of this approach is unknown [12].

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).

In general, in the northern hemisphere, vaccination should be offered during September or October (during March or April in the southern hemisphere) [3]. If vaccination is not completed by October, it may continue to be offered throughout the influenza season, so long as influenza viruses continue circulating and unexpired vaccine is available.

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; development of a more nuanced approach to optimize protection for the duration of influenza season warrants further investigation. 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) [13]. 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.

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) [14]. (See 'Contraindications and precautions' below.)

For healthy nonpregnant adults ≤49 years, any of the inactivated influenza vaccines (IIVs) 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 may be given.

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

For individuals ≥65 years of age, we agree with the ACIP which recommends that for the 2023 to 2024 season, such individuals receive any one of the following higher dose or adjuvanted influenza vaccines (table 1) [3]:

Quadrivalent high-dose inactivated influenza vaccine (HD-IIV4)

Quadrivalent adjuvanted inactivated influenza vaccine (aIIV4)

Quadrivalent recombinant influenza vaccine (RIV4)

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 [15]. 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 [3,16,17]. The vaccines should be administered at different anatomic sites to reduce the risk of local reactions with coadministration [3].

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 [18]. There were no safety concerns, most systemic reactions to vaccination were mild or moderate, and the immune response to both vaccines was preserved.

Inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV) – IIVs and RIVs 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 [19].

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].

For respiratory syncytial virus vaccine, consult current CDC guidance for evolving data informing simultaneous administration with influenza vaccines.

Live attenuated influenza vaccine– 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 fever [20].

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 moderate or severe COVID-19, IIV or RIV should be deferred until symptoms of COVID-19 infection have resolved [3].

For patients with mild or asymptomatic COVID-19, deferral should be considered to avoid confusion of adverse vaccine effects with COVID-19 symptoms.

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 [14].

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 [3]:

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 [21].

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 [22]. 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 [23]. 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) [3].

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 [24,25]. 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 [20].

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 [26,27]. (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) [28]. 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) [29].

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 [3]. 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) [30].

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) [31].

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 [15].

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 [32]. 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) [33].

EFFICACY — Vaccine effectiveness is influenced by a number of factors; these include age, baseline health, immune function, and the degree of match between vaccine antigens and circulating virus strains [1].

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 [34].

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) [35].

Among vaccinated individuals with breakthrough influenza infection, vaccination is associated with reduced mortality and attenuated disease severity [36]:

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).

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

Recombinant vaccine – Recombinant influenza vaccine (RIV) may provide better protection than SD-IIV among adults ≥50. In a randomized trial including more than 8600 adults ≥50 years of age, the attack rate of polymerase chain reaction (PCR)-confirmed influenza was 30 percent (95% CI 10-47) lower among those who received recombinant vaccine (2.2 versus 3.2 percent); safety profiles were comparable [37,38].

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 [39].

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 [40].

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 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 (SD-IIV; relative vaccine efficacy 11.7 percent, 95% CI 7.0-16.1 percent) [41]. 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 [42]. 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, relative benefit of quadrivalent RIV (RIV4) over quadrivalent standard dose inactivated vaccine for prevention of PCR-confirmed influenza was observed (relative efficacy 30 percent, 95% CI 10-47 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) [37].

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) [43].

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) [44].

In a 2021 trial including more than 2500 patients with recent myocardial infarction randomly assigned to receive influenza vaccine or placebo, 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) [45].

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 [46].

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 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) [47].

Effect of statins — Some studies have suggested that statin use may reduce efficacy of influenza vaccine (via immunomodulatory or other mechanisms) [48-50], while others suggest no effect of statin use on vaccine efficacy [51,52]. A potential effect of statin use on vaccine efficacy may be attributable to confounding factors, since patients being treated with statins may be at greater baseline risk of influenza.

In a retrospective study including more than 1.4 million patients, statin use around the time of vaccination did not substantially affect the risk of influenza-related medical encounters among older adults. For statin users compared with nonusers, the adjusted relative risk was 1.086 (95% CI 1.025-1.150) for influenza-related visits and 1.096 (95% CI 1.013-1.185) for influenza-related hospitalizations [51].

Effect of virus type and antigen match — There may be mismatches between vaccine strains and the circulating strains, leading to diminished efficacy. (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 [47].

INVESTIGATIONAL AND ALTERNATIVE APPROACHES — Important drawbacks of traditional influenza vaccines include the need to design new vaccines each year to match circulating strains and the fact that the production process takes several months when embryonated eggs are used.

Alternatives to egg-based production — Influenza vaccines have been developed that do not use embryonated eggs as a vehicle for production. Non-egg-based methods are attractive because they are less laborious, have a shorter production time, and are not dependent on egg supply [56].

Thus far, commercially available vaccine formulations include a cell culture-based vaccine and a recombinant vaccine (table 1).

Non-egg-based vaccine production methods include:

Cell culture-based vaccine − Mammalian cell line-based vaccines preserve the structure of the antibody-combining sites on the hemagglutinin (HA) antigen (in contrast to egg-based influenza viruses), which may result in more robust antibody responses [57]. Mammalian cells are also more permissive of influenza virus replication; certain influenza viruses (such as avian H5N1 viruses) do not replicate well in eggs.

Recombinant vaccine − The US Food and Drug Administration has approved a quadrivalent recombinant HA influenza vaccine for individuals ≥18 years; it is produced using recombinant deoxyribonucleic acid (DNA) technology and a baculovirus expression system that produces virus-like particles [8].

In a trial including more than 9000 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), those who received the recombinant vaccine had a lower attack rate of polymerase chain reaction-confirmed influenza (2.2 versus 3.1 percent), and the probability of influenza-like illness was 30 percent lower among recombinant vaccine recipients than among IIV recipients (95% CI 10-47) [37].

Plant-based vaccine − Plant-based vaccine production has been proposed to address some limitations of egg-based and other vaccines. In a trial including more than 10,000 adults 18 to 64 years of age randomly assigned to receive a plant-derived recombinant quadrivalent virus-like particle (QVLP) influenza vaccine or placebo, the absolute vaccine efficacy was 35 percent, which did not meet the study’s primary endpoint of 70 percent for prevention of respiratory illness but nonetheless provided substantial protection [58]. In a second trial including more than 12,000 adults ≥65 years of age randomly assigned to receive QVLP or egg-derived quadrivalent inactivated vaccine, the primary noninferiority endpoint was met. The QVLP vaccine was well tolerated, and no major safety issues were observed. These findings raise promise for further development of plant-based vaccines for prevention of influenza and other infections.

Issues related to influenza vaccine for individuals with egg allergy are discussed separately. (See "Influenza vaccination in persons with egg allergy".)

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 [59,60]. This is an area of ongoing study [61,62].

Intradermal vaccine delivery — Intradermal administration 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 [63,64].

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 5th to 6th 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 10th to 12th 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 infection. (See 'Introduction' above.)

Antigenic composition − New 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. (See 'Antigenic composition' above.)

Formulations − Available formulations of quadrivalent vaccine in the United States include several inactivated influenza vaccines (IIVs), one live attenuated influenza vaccine (LAIV), and one recombinant vaccine (table 1 and table 2). (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 − A single dose of an influenza vaccine should be administered to adults annually. Ideally, vaccination should be administered when 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). However, vaccination may be administered at any time during 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 or LAIV may be given.

For individuals ≤49 years with a contraindication to LAIV (table 3), any of the IIVs may be given.

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

For individuals ≥65 years of age, we suggest the quadrivalent high-dose IIV, quadrivalent adjuvanted inactivated vaccine, or quadrivalent recombinant influenza vaccine 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.)

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References

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