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 subsequent 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 [1-5]. The protection provided by influenza vaccines is based upon induction of virus-neutralizing antibodies, mainly against the viral hemagglutinin.

The role of influenza vaccination in the prevention of seasonal influenza will be reviewed here. The use of influenza vaccine in immunocompromised hosts, pregnant women, patients with chronic liver disease, patients with end-stage kidney disease, health care workers, and travelers is discussed separately. (See associated topic reviews.)

The clinical manifestations and diagnosis of influenza in adults, the role of antiviral agents for the prevention and treatment of seasonal influenza, and vaccines against H5N1 and H7N9 avian influenza are also reviewed elsewhere. Seasonal influenza vaccination in children is also presented separately. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Prevention of seasonal influenza with antiviral drugs in adults" and "Seasonal influenza in adults: Treatment" and "Avian influenza vaccines" and "Avian influenza A H7N9: Treatment and prevention", section on 'Vaccine development' and "Seasonal influenza in children: Prevention with vaccines".)

VACCINE COMPOSITION AND FORMULATIONS

Antigenic composition — Influenza virus is remarkable for its high mutation rate, compromising the ability of the immune system to protect against new variants [6]. For this reason, new vaccines are produced each year to match the circulating viruses. Vaccine production takes approximately six months from strain selection to the final vaccine product. Influenza antigens for inclusion in the vaccines is made in advance of the influenza season, based on global surveillance of influenza viruses circulating at the end of the prior influenza season [2]. There may be mismatches between the vaccine strains and the circulating strains, resulting diminished vaccine efficacy.

In February 2021, the World Health Organization (WHO) recommended use of quadrivalent vaccine in the northern hemisphere during the 2021-2022 influenza season [7]. 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) [1].

For the 2021-2022 influenza season, United States egg-based influenza vaccines contain hemagglutinin (HA) derived from [1]:

●An influenza A/Victoria/2570/2019 (H1N1) pdm09-like virus

●An influenza A/Cambodia/e0826360/2020 (H3N2)-like virus

●An influenza B/Washington/02/2019 (Victoria lineage)-like virus

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

For the 2021-2022 influenza season, United States cell culture-based inactivated (ccIIV4) and recombinant (RIV4) influenza vaccines contain HA derived from [1]:

●An influenza A/Wisconsin/588/2019 (H1N1) pdm09-like virus

●An influenza A/ Cambodia/e0826360/2020 (H3N2)-like virus

●An influenza B/Washington/02/2019 (Victoria lineage)-like virus

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

Influenza A viruses undergo periodic changes in the antigenic characteristics of their envelope glycoproteins, hemagglutinin (HA) and neuraminidase [8]. Among the influenza A viruses that infect mammals, three major HA subtypes (H1, H2, and H3) and two neuraminidase subtypes (N1 and N2) commonly cause disease in humans; other subtypes have caused sporadic infections (eg, H5N1, H7N9). Major changes in these glycoproteins are referred to as antigenic shifts, and minor changes are called antigenic drifts. Antigenic shifts are generally associated with pandemics of influenza A. Antigenic drifts are associated with the usual annual epidemics and necessitate annual updating of the vaccine antigen makeup. (See "Influenza: Epidemiology, pathogenesis, and outcomes", section on 'Antigenic drifts' and "Influenza: Epidemiology, pathogenesis, and outcomes".)

Influenza B viruses have a lesser propensity for antigenic changes; only antigenic drifts in the HA have been described. More subtypes of HAs and neuraminidases have been described among avian influenza A viruses compared with the influenza A viruses that cause seasonal influenza infections. (See "Avian influenza: Epidemiology, transmission, and pathogenesis", section on 'Background'.)

Two genetic lineages of influenza B viruses have circulated since the mid-1980s. The potential benefit of using a quadrivalent vaccine is illustrated by a report showing that, during 12 seasonal influenza outbreaks between 1999 and 2012, 42 percent of all influenza B infections were caused by viruses of the genetic lineage that was not included in the trivalent vaccine used during those seasons [9]. Influenza B viruses accounted for 26 percent of all typed viruses.

The current vaccination strategy is vulnerable to the emergence of epidemic or pandemic strains that are not represented in the current vaccines. Ongoing research is focused on developing a universal vaccine that would elicit protective antibodies against conserved viral proteins. (See 'Immunogenicity, efficacy, and safety' below and 'Universal vaccines' below.)

Available 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) [1]. Available vaccines are summarized and compared in the tables (table 1 and table 2). 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 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 also approved for adults 18 to 64 years of age [2].

-Standard dose, adjuvanted – An adjuvanted IIV (Fluad Quadrivalent) is approved for use in individuals ≥65 years of age [10]. It contains 15 mcg of each HA per virus. (See 'Adjuvanted IIV' below.)

-High dose – An intramuscular high-dose quadrivalent IIV (Fluzone High-Dose) is approved for individuals ≥65 years of age; the vaccine contains 60 mcg of each HA per virus [11]. (See 'High dose IIV' 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 [1,12]. The vaccine contains 15 mcg of each HA per virus. (See 'Cell culture based' below and 'Alternative production methods' below.)

●Recombinant HA influenza vaccine – A recombinant HA influenza vaccine (Flublok), produced using recombinant DNA technology, is FDA approved and available for individuals ≥18 years of age [13]. Unlike the other formulations, which contain both HA and neuraminidase antigens, the recombinant vaccine contains only HA antigens. (See 'Recombinant HA vaccine' below and 'Alternative production methods' below.)

●LAIV, egg based, nasal spray – The intranasally administered LAIV (FluMist) is approved for healthy nonpregnant individuals between 2 and 49 years of age.

This vaccine uses a master attenuated cold-adapted donor virus from which reassortants are generated that have HA and neuraminidase antigens from strains that were circulating at the time that the annual vaccine was designed. The vaccine is produced in embryonated chicken eggs.

The Advisory Committee on Immunization Practices recommended against the use of LAIV for the 2016-2017 and 2017-2018 influenza seasons in the northern hemisphere; in the 2018-2019 season, it resumed recommending it as an option [14]. (See 'Live attenuated vaccine (LAIV)' below.)

CLINICAL APPROACH

Indications — The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all individuals ≥6 months of age who do not have contraindications [2,15]. High-risk individuals, their close contacts, and health care workers remain high-priority recipients in vaccination campaigns (table 3). (See 'High-priority groups' below.)

Older adults and individuals with underlying health problems are at increased risk for complications of influenza, including death. Influenza vaccination not only reduces the risk of influenza infection but also reduces the severity of illness in those who are infected [16,17]. Influenza virus usually causes an acute self-limited febrile illness in healthy young adults; vaccination results in fewer influenza infections and fewer missed days from work in such individuals [18].

Widespread immunization of children has appeared to result in herd immunity, with a reduction in influenza infections in unvaccinated children and adults of all ages. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Community ("herd") immunity'.)

High-priority groups — Although annual influenza vaccination is recommended for all individuals ≥6 months of age, when the vaccine supply is limited, those who are at increased risk for complications and household contacts and caregivers of such persons should be the highest priority recipients (table 3) [2]. (See 'Indications' above.)

Individuals who are at increased risk for influenza complications include those at the extremes of age, pregnant women, immunocompromised hosts, those with certain chronic diseases, and others; the groups at high risk for influenza complications are presented in the following table (table 4) [2]. Although there are no data regarding the risk for severe or complicated influenza among asplenic individuals, influenza is a risk factor for secondary bacterial pneumonia, which can be severe in such patients. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Pregnancy — Given that influenza infection is associated with excess complications and death in pregnant women, we are in agreement with the ACIP which recommends influenza vaccination for pregnant women with inactivated vaccine. Influenza vaccination in pregnant women is discussed in detail separately. (See "Immunizations during pregnancy", section on 'Inactivated influenza vaccine'.)

Immunocompromised patients — The ACIP recommends the inactivated influenza vaccine for immunocompromised patients, including HIV-infected individuals, patients with cancer, and transplant recipients [2]. Live attenuated influenza vaccine (LAIV) is contraindicated in immunocompromised individuals. Influenza vaccination in the setting of immunocompromise is discussed in detail separately. (See 'Choice of vaccine formulation' below and "Immunizations in adults with cancer", section on 'Influenza vaccine' and "Immunizations in solid organ transplant candidates and recipients", section on 'Influenza' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Influenza' and "Immunizations in patients with HIV", section on 'Influenza vaccine'.)

Close contacts of immunocompromised patients — Vaccination is particularly important for individuals who might transmit influenza to persons at high risk for complications; such individuals include health care workers, workers at chronic health care facilities, providers of home care to persons at high risk, and household contacts of persons in high-risk groups (table 3) [2].

Health care workers and household contacts who have close contact with severely immunocompromised persons who require a protective environment should receive IIV rather than LAIV; if LAIV is given, the health care worker or household contact should avoid contact with severely immunocompromised patients for seven days after receipt [2,19].

Vaccination of health care workers is discussed in greater detail separately. (See "Immunizations for health care providers", section on 'Influenza vaccine'.)

Choice of vaccine formulation — The choice of vaccine formulation depends upon several factors, including age, comorbidities, and risk of adverse reactions (table 2) [2]. Contraindications and precautions should be reviewed carefully prior to selection of a vaccine formulation (table 5) [2]. (See 'Contraindications and precautions' below.)

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

●For individuals between 50 and 64 years of age and for individuals ≤49 years of age who have a contraindication to receiving LAIV (eg, immunocompromise; chronic cardiovascular, pulmonary, or metabolic disease; pregnancy (table 5)), any of the IIVs may be given.

●For individuals ≥65 years of age, we suggest the high-dose IIV (Fluzone High-Dose) where available, rather than a standard-dose IIV, particularly in those taking a statin. The ACIP has not stated a preference for this vaccine over other influenza vaccines in older adults, although several studies have shown that the high-dose vaccine is more effective than the standard-dose vaccine in older adults (including a mortality benefit). 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 'High dose IIV' below.)

An alternative is the recombinant HA vaccine (Flublok Quadrivalent), which is more effective than the standard-dose inactivated vaccine for preventing influenza; however, it has not been compared directly with the high-dose IIV. (See 'Recombinant HA vaccine' below.)

An adjuvanted vaccine is another option for this age group according to the ACIP, but we do not favor it at this time, as there are no reported clinical trials evaluating the efficacy of this vaccine in older adults.

●Individuals who are needle phobic may prefer to receive one of the following formulations:

•LAIV – The LAIV is administered via single-use intranasal sprayer. Contraindications and precautions are summarized in the table (table 5) and discussed below. (See 'Contraindications and precautions' below.)

The ACIP recommended against the use of LAIV for the 2016-2017 and 2017-2018 influenza seasons in the northern hemisphere; it began recommending it again as an option beginning in the 2018-2019 season [14]. (See 'Live attenuated vaccine (LAIV)' below.)

•Needle-free intramuscular administration – Intramuscular administration of IIV (Afluria) using a jet injector has been approved for individuals between 18 and 64 years of age. 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. Adverse reactions are discussed below. (See 'Inactivated vaccines' below.)

In a noninferiority trial, 1250 healthy adults between the ages of 18 and 64 years were randomly assigned to receive one dose of a trivalent inactivated influenza vaccine given either intramuscularly with a needle-free jet injector or with needle and syringe [20]. The immune response to influenza vaccine given with the jet injector device was comparable with the immune response to influenza vaccine given with needle and syringe.

●Recommendations for health care workers are presented separately. (See "Immunizations for health care providers", section on 'Influenza vaccine'.)

●Recommendations for individuals with egg allergy are presented separately. (See "Influenza vaccination in individuals with egg allergy" and 'Available formulations' above.)

Schedule — A single dose of an influenza vaccine should be administered to adults annually. Annual immunization is necessary even if the previous year's vaccine contained one or more of the antigens to be administered, since immunity declines during the year following vaccination [2,21]. (See 'Waning immunity' below.)

We do not recommend more than one dose of influenza vaccine for adults in a single season; the safety of additional vaccines is not known [22].

Ideally vaccination should be offered before the onset of influenza activity in the community (by the end of October in the northern hemisphere and by April in the southern hemisphere) [2].

Influenza vaccination may be administered at any time during the influenza season, the length of which varies from year to year. Evidence of significant influenza activity in the community should be used to determine how late in the season vaccination should be offered. (See "Influenza: Epidemiology, pathogenesis, and outcomes".)

In the tropics, influenza occurs throughout the year [23]. In addition, summertime outbreaks of influenza have occurred on cruise ships in the northern and southern hemispheres and during pandemics. Repeat vaccination is not necessary in those who received routine vaccination at the appropriate time in the previous fall or winter. (See "Immunizations for travel", section on 'Influenza vaccine'.)

Coadministration with other vaccines

●COVID-19 – Influenza vaccine may be coadministered with coronavirus disease 2019 (COVID-19) vaccine; providers should check for updates on coadministration as there is limited experience to date [1,24]. To reduce the risk of local reactions with coadministration of these vaccines, they should be administered at different anatomic sites [1].

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

●IIVs – IIVs do not interfere with the immune response to other inactivated vaccines or to live virus vaccines [2,26]. Therefore, an IIV may be administered at the same time as (but at a different site from) other recommended vaccines. The deltoid muscle is the preferred site for intramuscular influenza vaccine administration in adults.

●LAIV – LAIV can be administered at the same time as other live virus vaccines or inactivated vaccines [2]. However, if it is not administered on the same day as other live virus vaccines (eg, 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 vaccines can be given to individuals with minor respiratory illnesses, in the presence or absence of fever [27]. In patients with moderate or severe acute illness, with or without fever, influenza vaccination should be delayed until symptoms have resolved, to avoid confusion between the underlying illness and adverse effects of the vaccine.

We avoid administration of the live attenuated influenza vaccine (LAIV) (which is administered nasally) in patients with upper respiratory tract infection, given concern for inadequate virus replication and/or inadequate antigen exposure [2]. (See 'Live attenuated vaccine (LAIV)' below.)

For patients with COVID-19, influenza vaccination should be deferred until the illness has resolved to avoid confusing postvaccination reactions with COVID-19 symptoms [1]. To date, there is limited information on immune response to the influenza vaccine in those who with SARS-CoV-2 infection.  

Improving vaccination rates — The Healthy People 2020 adult influenza vaccination target is 70 percent [28]. Despite the accessibility of influenza vaccine, vaccine uptake among adults 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 [29]. 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.

General issues related to improving vaccination rates are discussed further separately. (See "Standard immunizations for nonpregnant adults", section on 'Increasing immunization rates'.)

CONTRAINDICATIONS AND PRECAUTIONS — Contraindications and precautions for use of influenza vaccines are summarized in the table (table 5) [1]. Influenza vaccination is contraindicated in patients who have had 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 individuals with egg allergy".)

It seems prudent to withhold influenza immunization from individuals who developed Guillain-Barré syndrome within six weeks after a previous influenza immunization [2]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

Inactivated influenza vaccines do not appear to exacerbate chronic neurologic diseases, such as multiple sclerosis, and therefore can be given to individuals with such conditions [30,31].

It appears that patients receiving an oral anticoagulant (eg, warfarin) can safely receive the influenza vaccine by intramuscular injection [32-34]. Nevertheless, steps should be taken to minimize the risk of significant hematoma in such patients. Such measures include using 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 [27].

ADVERSE REACTIONS

Inactivated vaccines — The inactivated influenza vaccines are generally well tolerated, with the most common side effect being arm soreness at the injection site (in 64 percent of vaccine recipients) [35].

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

In clinical trials, serious adverse events have been reported rarely. A slightly increased risk of Guillain-Barré syndrome has been associated with the inactivated influenza vaccine during certain influenza seasons, but this added risk appears to be substantially less than the overall health risk posed by naturally occurring influenza [37]. This topic is discussed in greater detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

Immediate immunoglobulin (Ig)E-mediated hypersensitivity reactions have been reported rarely following influenza vaccination [2]. Oculorespiratory syndrome, an acute self-limited reaction, was first described during the 2000 to 2001 influenza season in Canada and has been reported occasionally within 24 hours of administration of the inactivated influenza vaccine [38]. It is typically mild and is characterized by bilateral conjunctivitis, facial edema, and/or respiratory symptoms (eg, cough, wheezing). It is not thought to be IgE mediated, and a causal link to influenza vaccination has not been established. However, after changes to the manufacturing process to the vaccine formulation associated with oculorespiratory syndrome, the incidence dropped substantially.

Mild to moderate local reactions are more common with the high-dose inactivated influenza vaccine (Fluzone High-Dose) than the standard-dose vaccine [39]. During the first year of postmarketing surveillance of the high-dose vaccine, a greater proportion of gastrointestinal complaints (especially vomiting) was reported to the Vaccine Adverse Event Reporting System (VAERS) among recipients of the high-dose vaccine than among recipients of the standard-dose vaccine [40]. However, in a large randomized trial, rates of serious gastrointestinal effects were no greater among high-dose vaccine recipients than in standard-dose vaccine recipients [41].

Needle-free intramuscular administration — Use of an inactivated influenza vaccine with a jet injector device is associated with a higher frequency of local injection site reactions than the use of needle and syringe [20]. These include pain, tenderness, itching, redness, swelling, and bruising.

Live attenuated vaccine — Live attenuated vaccine (LAIV) is generally well tolerated, with the most common side effects in adults being rhinorrhea, nasal congestion, headache, and sore throat [42].

Out of 2.5 million people who received LAIV, the following serious adverse events have been reported to VAERS: possible anaphylaxis (seven), Guillain-Barré syndrome (two), Bell's palsy (one), and asthma exacerbation among individuals with a history of asthma (eight) [43].

IMMUNOGENICITY, EFFICACY, AND SAFETY — Because influenza vaccines produced in eggs take approximately six months to manufacture, they necessarily contain antigens from strains that circulated during the previous year. The protective efficacy of the vaccine is largely determined by the relationship (closeness of "fit" or "match") between the strains in the vaccine and viruses that circulate in the outbreak. A study that compared the effectiveness of the inactivated influenza vaccine (IIV) during influenza seasons with differing degrees of vaccine match illustrates the importance of the fit between circulating influenza virus strains and the vaccine [44]. During the 2014 to 2015 influenza season in the United States, influenza A H3N2 viruses predominated and more than half of these viruses contained H3N2 antigen that was antigenically different (drifted) from that included in that season's influenza vaccines [45]. The adjusted overall vaccine effectiveness for the 2014 to 2015 influenza season was 19 percent; for H3N2-associated illness, the vaccine effectiveness was only 6 percent [46]. A meta-analysis of observational studies showed that influenza vaccines are less effective against H3N2 influenza A than against H1N1 influenza A and influenza B [47].

Other factors that likely contribute to variability in influenza vaccine effectiveness include gain or loss of glycosylation at key antigenic sites, early childhood imprinting, epitope specificity, mutations in virus antigens grown in eggs, and the individual immune landscape generated by prior influenza vaccination or infection [48-52].

A repeated finding in various studies is that vaccination produces a greater reduction in serologically confirmed influenza than in clinically diagnosed influenza. Universal influenza vaccination in Ontario, Canada, has also been shown to reduce the number of antibiotic prescriptions during periods of peak influenza activity [53].

The primary means of assessing serum antibody responses to influenza vaccination is the serum hemagglutination (HA)-inhibition assay; in addition to the HA antibody response, other immune mechanisms that contribute to protection against influenza include mucosal immunity, antibodies to neuraminidase (NA), virus-specific CD4 and CD8 T cells, and possibly antibodies to minor envelope protein 2 (M2) and the structural nucleoprotein [4].

Healthy adults — A number of studies have evaluated the efficacy or immunogenicity of various influenza vaccines in different populations.

Inactivated influenza vaccines (IIVs)

Egg based — Although many studies evaluating the efficacy of influenza vaccines in healthy adults have been published and efficacy is often estimated to be between 70 and 90 percent, a 2012 comprehensive review suggested that efficacy may be considerably lower [54]. In a 2012 meta-analysis (performed by the same group that did the comprehensive review) that included eight randomized trials of the inactivated influenza vaccines in adults aged 18 to 64 years over nine influenza seasons, vaccine efficacy for preventing laboratory-confirmed influenza was 59 percent (95% CI 5167 percent) [55]. Of note, higher rates of efficacy and effectiveness have been reported in trials that used serologic endpoints; such trials were excluded from this meta-analysis because using serologic endpoints is likely to lead to an overestimation of benefit.

In a 2018 meta-analysis of randomized controlled trials or quasi randomized controlled trials, inactivated influenza vaccination reduced influenza in healthy adults (0.9 percent with vaccination versus 2.3 percent without vaccination; risk ratio [RR] 0.41, 95% CI 0.36-0.47), corresponding to a number needed to vaccinate (NNV) of 71 [31].

The match between the antigens included in the influenza vaccines and circulating influenza strains would be expected to have an important influence on the efficacy of the vaccines. In the 2014 meta-analysis described above, inactivated vaccines were 16 percent effective (95% CI 9 to 23 percent) in preventing influenza-like illness when strains contained in the vaccine antigenically matched circulating strains [56]. On the other hand, inactivated vaccines were not protective against influenza-like illness when the degree of matching between the vaccine and circulating influenza strains was absent or unknown. In contrast, the efficacy of inactivated vaccines for preventing laboratory-confirmed influenza was similar when the match was good and when the match was absent or unknown (62 versus 55 percent, respectively). Nevertheless, even when vaccine efficacy is suboptimal because of antigen mismatch, reductions in influenza-related morbidity and mortality can still be substantial [57].

Because inactivated influenza vaccines are thought to provide nonsterilizing immunity, influenza vaccination might have a greater effect on reducing illness severity than on preventing infection [58]. In a case-control study in which hospitalized patients with laboratory-confirmed influenza infection were matched against outpatients with laboratory-confirmed influenza and outpatient controls, vaccine effectiveness was 75 percent for preventing outpatient influenza cases, 60 percent for preventing influenza-associated hospitalizations, and 89 percent for preventing severe influenza [16]. Among hospitalized patients with influenza, those who had been vaccinated against influenza were less likely to have severe influenza than those who had not been vaccinated (adjusted odds ratio [aOR] 0.42, 95% CI 0.22-0.80).

In a population-based study in the United States that assessed the effect of influenza vaccination on disease severity among hospitalized patients during the 2013 to 2014 influenza season (a season in which vaccine viruses were antigenically similar to circulating viruses), influenza vaccination was associated with a reduction in the odds of in-hospital death among patients aged 18 to 49 years of age and 50 to 64 years of age [59]. Influenza vaccination also reduced intensive care unit (ICU) admission among patients aged 18 to 49 years and shortened ICU and hospital length of stay among those 50 to 64 years of age. The effect on patients ≥65 years of age is discussed below. (See 'Older adults' below.)

Influenza vaccination also appears to reduce the risk of influenza pneumonia. A multicenter case-control study of adults and children hospitalized for community-acquired pneumonia (CAP) estimated that influenza vaccine effectiveness for preventing influenza-associated pneumonia was 57 percent (95% CI 32 to 73 percent) [60].

Some studies have shown an association between acute respiratory tract infections and acute myocardial infarction (see "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Cardiac complications'). A case-control study in adults 40 years or older found that influenza vaccination was associated with a reduction in the rate of first acute myocardial infarction (aOR 0.81, 95% CI 0.77-0.85) [61].

Many of the studies related to inactivated vaccines were performed using trivalent vaccines. A meta-analysis that included five randomized trials showed that the quadrivalent inactivated vaccine was as immunogenic as the trivalent inactivated vaccine for the antigens included in both vaccines [62]. The quadrivalent vaccine was more immunogenic than the trivalent vaccine for the influenza B strain included only in the quadrivalent vaccine. There were no differences for aggregated local and systemic adverse effects and there were no vaccine-related serious adverse effects for either vaccine. However, injection site pain was more common with the quadrivalent vaccine than with the trivalent vaccine (pooled risk ratio 1.18, 95% CI 1.03-1.35).

Cell culture based — The US Food and Drug Administration (FDA) has approved a quadrivalent inactivated influenza vaccine produced in cultured mammalian cells (Flucelvax) for individuals ≥6 months of age [2,12,63]. Several other randomized trials have demonstrated that the immunogenicity and efficacy of influenza vaccines produced using mammalian cell lines are comparable to vaccines produced using embryonated eggs [17,64-67].

Benefits of cell-based vaccines (eg, faster production time) are discussed below. (See 'Alternative production methods' below.)

Recombinant HA vaccine — The FDA has approved a quadrivalent recombinant HA influenza vaccine (Flublok Quadrivalent) for individuals 18 years of age or older; the vaccine is produced using recombinant DNA technology and a baculovirus expression system that produces virus-like particles [13].

This vaccine was shown to be safe and immunogenic in randomized trials that included adults between 18 and 49 years of age [68,69].

In a randomized trial that included 4648 adults 18 to 49 years of age, Flublok was approximately 45 percent effective against all circulating influenza strains, despite substantial antigenic mismatch between the vaccine antigens and circulating viruses; 96 percent of influenza viruses isolated from trial participants contained antigens that differed from the vaccine antigens [70]. Adverse events were similar to those that occur with conventional egg-based IIVs [13].

The efficacy of the recombinant HA vaccine in older adults is discussed below. (See 'Recombinant HA vaccine' below.)

Live attenuated vaccine (LAIV) — The Advisory Committee on Immunization Practices (ACIP) continues to recommend live attenuated influenza vaccine (LAIV), as it has since the 2018-2019 season [2,12,14].

Previously the ACIP recommended that LAIV not be used during the 2016-2017 or 2017-2018 influenza seasons, given low effectiveness against H1N1 influenza among children during the 2013-2014 and 2015-2016 seasons. The manufacturer subsequently changed the H1N1 strain, which had been found to have poor replicative fitness during the seasons in which LAIV was poorly effective. Data from the manufacturer indicate that the H1N1 strain used in the newer vaccine has improved replicative fitness and induces higher antibody responses than the earlier strain [14]. Seroconversion rates to the newer strain are comparable with those obtained in response to H1N1 strains used in LAIV during seasons in which the vaccine was observed to be effective against influenza A H1N1 influenza viruses. This is discussed in greater detail separately. (See "Seasonal influenza in children: Prevention with vaccines", section on 'IIV versus LAIV'.)

A randomized trial compared the LAIV preparation with placebo in 4561 healthy, employed adults followed through an influenza season [18]. Vaccination was associated with significant reductions in severe febrile illnesses (19 percent), febrile upper respiratory tract illnesses (24 percent), and days of work lost for febrile upper respiratory tract illnesses (28 percent). The vaccine was well tolerated and appeared to protect against the prevailing strain of influenza A that season, despite the virus showing considerable drift from the vaccine strain.

In a 2014 meta-analysis of randomized trials and observational studies in healthy adults, LAIV had an overall effectiveness of 10 percent for preventing influenza-like illness, corresponding to a NNV of 46 [56]. Overall efficacy for preventing laboratory-confirmed influenza was 53 percent, corresponding to a NNV of 39.

Studies in adults have shown that the inactivated vaccine is either equivalent to or more effective than LAIV [71-75].

Comparisons of inactivated and live attenuated vaccines have shown the following:

●A randomized trial compared the intramuscular inactivated vaccine and LAIV in 5210 healthy individuals over five years of age [71]. For preventing culture-positive influenza A infection, the inactivated and live attenuated vaccines were 76 and 85 percent effective against H1N1 influenza and 74 and 58 percent effective against H3N2 influenza, respectively. The differences between the two vaccines were not statistically significant.

●A randomized trial compared the inactivated vaccine to LAIV in 1247 healthy adults during the 2004 to 2005 influenza season [72]. Both vaccines had similar efficacy against culture-proven influenza A infection (74 percent), despite the fact that most circulating viruses were dissimilar to those included in the vaccines. In contrast, the inactivated vaccine was superior to LAIV against culture-confirmed type B influenza infections (80 versus 40 percent efficacy).

●In another randomized trial that included 1952 adults vaccinated during the 2007 to 2008 influenza season, the inactivated vaccine was superior to LAIV against influenza infection as detected by viral culture, real-time polymerase chain reaction, or both (68 versus 36 percent absolute efficacy) [73]. During the same influenza season, 90 percent of isolates were influenza A H3N2 and 9 percent of isolates were influenza B. The absolute efficacy against the influenza A strain was 72 percent for the inactivated vaccine compared with 29 percent for LAIV.

●In a large surveillance study of United States military personnel during three influenza seasons between 2004 and 2007, immunization with the inactivated vaccine was associated with lower rates of health care visits for pneumonia and influenza compared with LAIV (8.6 versus 19.4 per 1000 person-years in 2004 to 2005, 7.8 versus 10.9 per 1000 person-years in 2005 to 2006, and 8.0 versus 11.7 per 1000 person-years in 2006 to 2007) [74]. However, among individuals who had not been immunized the previous year, the effect of LAIV was comparable with the inactivated vaccine during the 2005 to 2006 and 2006 to 2007 seasons. Whether these results can be generalized to other populations is uncertain.

Older adults — More than 90 percent of seasonal influenza-related deaths occur among people over 60 years of age [76], and older adult patients also have increased morbidity from the disease.

Inactivated influenza vaccines (IIVs)

Standard dose IIVs

Efficacy — The efficacy of IIVs in older adult patients has been evaluated in a few randomized trials [77-79] and multiple observational studies, both in the community and in long-term care facilities [80-90] as well as in sicker patients such as those with chronic lung disease [91-93], with conflicting results.

In a 2018 meta-analysis of randomized trials, IIV of older individuals resulted in less influenza over a single season than placebo (2.4 versus 6 percent; risk ratio [RR] 0.42, 95% CI 0.27-0.66) [94]. The authors rated the evidence as low certainty due to uncertainty about how influenza was diagnosed. One multicenter study suggested that influenza vaccine effectiveness decreases in older adults as frailty increases [95].

A 2008 case-control study evaluated 1173 cases and 2346 controls among community-dwelling older individuals during three pre-influenza periods and influenza seasons, periods when there was good antigenic match between the influenza vaccine and circulating viruses [86]. This study found that influenza vaccination did not reduce the risk of pneumonia (including those who did not require hospitalization), after adjusting for the presence and severity of comorbidities. In contrast, in a 2012 cohort study of community-dwelling older individuals that evaluated 12.6 million person-influenza seasons, vaccination was associated with a reduction in the composite endpoint of hospitalization (for pneumonia and influenza) and death during influenza season (aOR 0.86, 95% CI 0.79-0.92) [96]. A case-control study also showed that influenza vaccination was associated with a significant reduction in the risk of hospitalization due to laboratory-confirmed influenza among adults aged ≥50 years of age regardless of age group (50 to <65 years; 65 to <75 years; ≥75 years) [97]. In another study of older individuals, vaccination was 58 percent effective at preventing medically attending laboratory-confirmed influenza illness in adults ≥50 years of age as well as in adults ≥65 years of age [98]. Influenza vaccination has also been associated with reduced risk of postoperative pneumonia among patients >66 years of age who underwent major surgery [99].

Even when vaccine efficacy is low, vaccination is likely to prevent hospitalizations in the older adult population. In a modeling study, during the 2012 to 2013 influenza season (a moderate to severe season), among individuals ≥65 years of age in the United States, a vaccine with 10 percent effectiveness and 66 percent coverage would have averted approximately 13,000 hospitalizations and a vaccine with 40 percent effectiveness would have averted approximately 60,000 hospitalizations [100]. In a population-based study in the United States that assessed the effect of influenza vaccination on disease severity among hospitalized patients ≥65 years of age during the 2013 to 2014 influenza season, a season in which vaccine viruses were antigenically similar to circulating viruses, influenza vaccination was associated with reduced risk of ICU admission and in-hospital mortality as well as reduced ICU and hospital length of stay [59].

Since protection against influenza is suboptimal in older adults, it is not surprising that the outbreaks of influenza have occurred in nursing homes where 80 to 98 percent of residents were vaccinated [85].

Vaccinating younger adults appears to provide benefit for older adults in the same community. In a large nationwide sample of Medicare beneficiaries in the United States, vaccination of adults aged 18 to 64 years was inversely associated with influenza-related illness in individuals ≥65 years of age [101].

Effect of statins — Statins are commonly used in older adults with hyperlipidemia and are known to have immunomodulatory effects, which could affect vaccine responses. The observed associations between statin use and reduced vaccine effectiveness in some studies could be due to confounding factors, since patients being treated with statins may be at greater baseline risk of influenza than those not treated with statins. Although these studies raise the possibility that older patients receiving statins are less likely to be protected by the influenza vaccine than those not receiving statins, such individuals should still receive statins, when indicated, as well as an influenza vaccine (preferably the high-dose vaccine) annually. (See 'Choice of vaccine formulation' above.)

In an observational study conducted in the context of a randomized trial that evaluated influenza vaccines in individuals >65 years of age, hemagglutination inhibition (HAI) geometric mean titers to various influenza strains were 38 to 67 percent lower in those receiving chronic statin therapy than in those not receiving it [102]. In addition, in a large retrospective cohort study conducted over nine influenza seasons in the United States, statin use was associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness [103]. In an adjusted analysis, influenza vaccine effectiveness against medically attended acute respiratory illness was lower among statin users than statin nonusers during periods of local (14.1 versus 22.9 percent; mean difference 11.4 percent, 95% CI -1.7 to 26.1 percent) and widespread (12.6 versus 26.2 percent; mean difference 18.4 percent, 95% CI 2.9-36.2 percent) influenza virus circulation. In a prospective study, statin use reduced the effectiveness of influenza vaccination against laboratory-confirmed H3N2 influenza A but not against H1N1 influenza A or influenza B [104]. In contrast, in a retrospective cohort study of 2.8 million Medicare beneficiaries in the United States, statin use around the time of high-dose or standard-dose vaccination did not substantially affect the risk of influenza-related visits or influenza-related hospitalizations [105]. In a large observational study over six influenza seasons, influenza vaccine effectiveness was not affected by statin use [106].

Effect on mortality — It has been difficult to demonstrate an improvement in survival after influenza vaccination in older adult patients in randomized trials because mortality is a rare endpoint. Some studies have observed a significant reduction in death from influenza or pneumonia [107], but some experts have suggested that frailty selection bias in cohort studies has led to an overestimation of any mortality benefit of influenza vaccination in older adults [108]. The following studies illustrate the range of findings and some of the limitations in study design:

●A pooled cohort study demonstrated a small but significant reduction in mortality in vaccinated older individuals (1.0 versus 1.6 percent in unvaccinated individuals) [81]. A sensitivity analysis was performed to detect unmeasured confounders. Even when a higher rate of confounders was assumed, there was still a significant reduction in mortality. Other studies have supported this finding [109].

●The difficulty of using observational data to evaluate the effect of influenza vaccine on mortality is illustrated by a prospective case-control study of patients (mostly over the age of 65) with CAP. The study assessed the impact of influenza vaccination on in-hospital mortality in patients admitted during the off-season for influenza [110]. A significant mortality reduction was observed in vaccinated patients (odds ratio [OR] 0.49, 95% CI 0.30-0.79). However, when adjustments were made to address confounding factors (eg, functional and socioeconomic status), the mortality benefit became nonsignificant (aOR 0.81, 95% CI 0.35-1.85). This study shows that the presence of bias may overestimate the mortality benefit of influenza vaccination [111].

●A large cohort study of community-dwelling older individuals did not detect a mortality benefit from influenza vaccination [96]. An important limitation of this study was the likely underreporting of vaccination status, which could have contributed to the vaccine appearing ineffective [112].

●In a population-based study in the United States, influenza vaccination was associated with reduced risk of in-hospital death among individuals ≥65 years of age [59].

●In a matched cohort study of patients >66 years of age in Taiwan, those who received the influenza vaccine and later underwent major surgery had lower in-hospital mortality than unvaccinated patients (OR 0.46, 95% CI 0.39-0.56) [99].

●Annual revaccination has been associated with a reduction in mortality in older adults. A report from the Netherlands of over 26,000 community-dwelling older individuals evaluated the association between the number of consecutive annual influenza vaccinations and all-cause mortality [113]. After adjustment for age, sex, and comorbidities, the following findings were noted:

•A first vaccination was associated with a nonsignificant annual reduction in mortality risk of 10 percent, while revaccination was associated with a significant 24 percent reduction in mortality overall and a 28 percent reduction during epidemics. There was also a trend toward further benefit with each consecutive vaccination.

•Vaccination interruption was associated with a strong and significant increase in mortality risk (adjusted hazard ratio [HR] 1.25, 95% CI 1.10-1.42), an effect that was reversed with restarting annual vaccination.

The impact of the high-dose vaccine on mortality is discussed below. (See 'High dose IIV' below.)

High dose IIV — A high-dose quadrivalent IIV, Fluzone High-Dose Quadrivalent, was approved by the FDA for individuals ≥65 years of age in November 2019. It contains 60 mcg of hemagglutinin (HA) per strain, whereas the standard-dose vaccine contains 15 mcg per strain. (See 'Choice of vaccine formulation' above.)

The high-dose inactivated trivalent vaccine formulation has been shown to be more immunogenic and effective than the standard-dose trivalent inactivated vaccine (including a mortality benefit) in older patients, but it has not been compared directly to the standard-dose quadrivalent inactivated vaccine.

In a multicenter trial that included more than 31,000 adults ≥65 years of age, the trivalent high dose Fluzone was modestly more effective than standard-dose trivalent Fluzone [114]. In the intention-to-treat analysis, 228 individuals in the high-dose group (1.4 percent) and 301 in the standard-dose group (1.9 percent) had laboratory-confirmed influenza associated with an influenza-like illness (relative efficacy 24.2 percent, 95% CI 9.7-36.5 percent). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥1:40) were higher in the high-dose group. At least one serious adverse event was reported in 8.3 percent of individuals who received the high-dose vaccine compared with 9.0 percent of those who received the standard-dose vaccine. Three recipients of the high-dose vaccine had serious adverse events classified as related to vaccination (cranial nerve VI palsy starting one day after vaccination; hypovolemic shock associated with diarrhea starting one day after vaccination; acute disseminated encephalomyelitis starting 117 days after vaccination); all three events resolved before study completion. Continued postmarketing surveillance will be necessary to detect potential rare but serious adverse events. The incidence of mild to moderate local reactions was not reported.

A study of >6 million United States Medicare beneficiaries ≥65 years of age who received either the high-dose or the standard-dose trivalent influenza vaccine during the 2012 to 2013 or 2013 to 2014 influenza seasons evaluated the comparative effectiveness (CE) of the two vaccines; the vaccines were well-matched to the circulating strains during both seasons [115]. The primary outcome was death during the 30 days following an inpatient or emergency department encounter listing an influenza diagnostic code. The mortality rate was 0.028 per 10,000 person-weeks for the high-dose vaccine compared with 0.038 per 10,000 person-weeks for the standard-dose vaccine; overall CE was 24 percent (95% CI 0.6-42 percent). The high-dose vaccine was more effective than the standard-dose vaccine for preventing postinfluenza death during the 2012 to 2013 influenza season (36.4 percent CE, 95% CI 9-56 percent), a season when circulation of H3N2 influenza A (a strain associated with severe disease) was common. In contrast, it was not more effective for preventing postinfluenza death during the following season (2.5 percent CE, 95% CI -47 to 35 percent), when H1N1 influenza A (a strain associated with mild disease) predominated. It is likely that the difference between the results for the two seasons was due to the fact that it is difficult to demonstrate benefit during a mild influenza season, when death is a rare outcome. The high-dose vaccine was associated with a reduced risk of hospitalization during both seasons (2012 to 2013 CE 22.1 percent, 95% CI 16.6-27.3 percent; 2013 to 2014 CE 12.7 percent, 95% CI 4.9-19.9 percent).

In a cluster-randomized trial that compared the high-dose vaccine to a standard-dose trivalent vaccine in residents ≥65 years of age in 823 nursing homes in the United States, the incidence of respiratory-related hospital admissions was lower in facilities where residents received high-dose vaccine than in those where residents received standard-dose vaccine (adjusted relative risk 0.87, 95% CI 0.78-0.98) [116].

Further, in a retrospective cohort study that evaluated >19 million United States Medicare beneficiaries ≥65 years of age who received either the high-dose or the standard-dose influenza vaccine during six influenza seasons between 2012 and 2018, the high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (influenza-related inpatient stays and emergency department visits) in four of the six influenza seasons evaluated and was at least as effective in the other two seasons [117]. The high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for individuals aged ≥85 years of age. Similarly, the high-dose vaccine was more effective than the standard-dose vaccine at protecting veterans ≥65 years of age in the United States against influenza- or pneumonia-associated hospitalization [118]. In contrast, in another large retrospective cohort study of veterans ≥65 years of age in the United States, the high-dose vaccine was not more effective than standard-dose vaccine in protecting against hospitalization for influenza or pneumonia except in those ≥85 years of age [119].

There is also evidence that the high-dose vaccine is more immunogenic than the standard-dose trivalent vaccine in older adults [39,120,121]. Mild to moderate local reactions are more common in those who receive the high-dose vaccine than the standard-dose vaccine [39].

The high-dose influenza vaccine is more expensive than the standard-dose trivalent vaccine. However, in a cost analysis of data from the trial in individuals ≥65 years of age that found that the high-dose vaccine was effective [114], the high-dose influenza vaccine appeared likely to result in cost savings compared with the standard-dose vaccine [122].

In a randomized trial that compared the high-dose quadrivalent vaccine with the high-dose trivalent vaccine in individuals ≥65 years of age, the quadrivalent vaccine resulted in improved immunogenicity against the added strain without reducing the immunogenicity of the other strains [123]. The proportion of individuals who had injection site pain, myalgia, malaise, or headache was slightly higher in the quadrivalent vaccine group than in the trivalent vaccine group.

The immunogenicity of the high-dose vaccine in HIV-infected individuals is discussed separately. (See "Immunizations in patients with HIV", section on 'Efficacy, immunogenicity, and safety'.)

Adjuvanted IIV — Adjuvants are substances that amplify the immune response to an antigen [124].

In 2015, the first adjuvanted trivalent influenza vaccine (Fluad) was approved by the FDA for use in individuals ≥65 years of age [10]. For the 2021-2022 season, the quadrivalent formulation (Fluad) is available.

The adjuvanted vaccine was first approved in Italy in 1997 and is approved in >35 countries. The vaccine is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil.

In a trial that compared the adjuvanted vaccine with an unadjuvanted trivalent inactivated influenza vaccine in more than 7000 individuals ≥65 years of age, antibody levels were comparable in both groups [10]. No safety concerns were identified among 27,000 individuals [10]. The most common adverse effects were injection site pain and tenderness, myalgias, headache, and fatigue.

However, other studies have shown that MF59-adjuvanted influenza vaccines are more immunogenic than unadjuvanted influenza vaccines [125-127].

To date, there are no reported clinical efficacy trials of this vaccine in older adults.

Recombinant HA vaccine — As noted above, the FDA has approved a quadrivalent recombinant hemagglutinin (HA) influenza vaccine (Flublok Quadrivalent) for individuals 18 years of age or older; the vaccine is produced using recombinant DNA technology and a baculovirus expression system that produces virus-like particles [13]. (See 'Available formulations' above.)

In a randomized trial that included 9003 adults ≥50 years of age, Flublok Quadrivalent (45 mcg of recombinant HA per strain) was compared with a quadrivalent formulation of a standard-dose inactivated influenza vaccine (15 mcg of HA per strain) [128]. In the modified intention-to-treat population, the polymerase chain reaction (PCR)-confirmed influenza attack rate was 2.2 percent with Flublok Quadrivalent compared with 3.1 percent with the inactivated vaccine. The cumulative incidence of PCR-confirmed influenza-like illness was 30 percent lower with Flublok Quadrivalent than with the inactivated vaccine (hazard ratio [HR] 0.69, 95% CI 0.53-0.90). In a post-hoc analysis, Flublok Quadrivalent had a relative vaccine efficacy of 36 percent against influenza A compared with the inactivated vaccine (HR 0.64, 95% 0.48-0.86), but the two vaccines had similar efficacy against influenza B. Flublok Quadrivalent has not been compared directly with the high-dose inactivated vaccine, which has been found to be more effective than the standard dose inactivated vaccine in older adults. (See 'High dose IIV' above.)

Adults with cardiovascular disease — Individuals with underlying cardiovascular disease are more susceptible to influenza-related complications and adverse clinical outcomes. In a 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 0.59, 95% CI 0.39-0.89) [129].

The approach to choice of vaccine formulation for patients with underlying cardiovascular disease is as described above. (See 'Choice of vaccine formulation' above.)

Patients with cardiovascular disease mount a less robust humoral immune response to standard-dose influenza vaccine than patients without cardiovascular disease, suggesting that a higher-dose vaccine might confer greater protection [130]. However, among more than 5200 patients with recent acute myocardial infarction or hospitalization for heart failure and at least one additional risk factor who were randomly assigned to receive 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 [131], suggesting that the efficacy of high-dose trivalent influenza vaccine appears to be comparable with that of standard-dose quadrivalent vaccine among patients with high-risk cardiovascular disease.

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

Contacts — Vaccination of a population may also be undertaken to protect their contacts. The underpinning for this approach is the concept of "herd immunity," whereby the benefits of immunization may be passed indirectly to vulnerable populations by vaccinating those who may serve as vehicles for disease transmission.

Household contacts — The best data on the effect of influenza vaccination on household contacts come from studies in children, which are discussed in detail elsewhere. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Community ("herd") immunity'.)

Health care workers — The efficacy of influenza vaccination in health care workers is discussed separately. (See "Immunizations for health care providers", section on 'Influenza vaccine'.)

Waning immunity — As discussed above, there is concern that the protection afforded by annual vaccination might attenuate over time, particularly in older individuals, although the data have been variable. Some experts have proposed a more nuanced approach to timing of influenza vaccination that will optimize the duration of protection [132]. Strategies for optimizing the timing of influenza immunization to extend the duration of vaccine efficacy through the risk period require further study. To be effective, such an approach will require improved influenza forecasting.

In one study of healthy adults 18 to 49 years of age participating in a randomized trial of influenza vaccination, HAI and NA inhibition titers decreased slowly over 18 months; a twofold decrease in antibody titer was estimated to take >600 days [133]. Similarly, in another study of healthy adults in the same age range, IIV efficacy decreased slowly over the course of the influenza season and remained efficacious for the majority of the season [134].

A 2008 literature review that included studies of individuals >60 years old found that, after influenza vaccination, seroprotection was maintained for at least four months (and often for longer) in all eight studies that assessed antibody responses to the H3N2 component and in five of seven studies that assessed responses to the H1N1 and B components [135]. Following successful immunization, seroprotection rates of 70 to 100 percent were maintained not just at four months (two studies) but also at five months (two studies) and at >6 months (four studies) for the H3N2 and H1N1 influenza A vaccine components. Seroprotection rates were less consistent for the influenza B vaccine component. An additional study showed a decline in antibody titers six months after vaccination in individuals ≥65 years of age, although the titers still met the levels considered adequate for protection [136]. Low prevaccination HAI titer (<1:40) and advanced age were associated with early decline of HAI titers, falling below presumed seroprotective levels around six months following vaccination. In a 2018 meta-analysis of 14 case-control studies, a significant decline in vaccine effectiveness occurred in the first six months following influenza vaccination [137]. The decline was more pronounced for influenza A H3N2 and influenza B viruses than for influenza A H1N1 virus and was faster among older individuals in the two studies that included a significant proportion of older adults.

The results of the meta-analysis described above are similar to those from a case-positive, control test-negative study of individuals aged 2 to >85 years covered by Kaiser Permanente of Northern California who were vaccinated with inactivated influenza vaccine from September 2010 through March 2017 [138]. PCR tests for influenza and respiratory syncytial virus (negative control) in vaccinees were obtained from the electronic medical record. Compared with individuals vaccinated 14 to 41 days prior to being tested (tests <14 days after vaccination were excluded), those vaccinated 42 to 69 days prior to being tested had 1.3 times the odds of testing positive for influenza (95% CI 1.1-1.6). The odds ratio (OR) increased in linear fashion by approximately 16 percent for each additional 28 days since vaccination; the OR was 2.1 for persons vaccinated ≥154 days prior to being tested (95% CI 1.7-2.5).

Overall, there is a suggestion that older adults are better protected closer to the time of vaccination, but these data do not take into account high-dose influenza vaccination strategies for older adults.

Efficacy of sequential administration — Several studies have shown that influenza vaccination is less effective in individuals who were vaccinated during the current and previous season(s) compared with individuals who were vaccinated during the current season only [139-145]. However, in most of these studies, effectiveness was greater among those who received consecutive seasonal influenza vaccines than those who received influenza vaccine only during the previous season or were unvaccinated [146]. Other studies have not shown a decrease in vaccine efficacy when influenza vaccination is given to people who were vaccinated the previous year [147-150]. In a large surveillance study from 2010 to 2015, vaccination in two consecutive seasons was more effective in preventing hospitalization for confirmed influenza than vaccination in either season alone [151]. Although concerns have been raised about annual immunization over consecutive years contributing to waning antibody titers, most studies indicate that waning is unlikely to impact vaccine efficacy over each individual year [152] and this risk is not a reason to avoid annual immunization.

Some studies have supported the antigenic distance hypothesis to explain the finding of reduced vaccine efficacy in those who were vaccinated during the current and previous season; this hypothesis predicts that negative interference from the prior season's influenza vaccine on the current season's vaccine protection may occur when the antigenic distance is small between the prior and current season's vaccines but large between the prior season's vaccine and the current epidemic strain of influenza [144,153]. As discussed above, annual vaccination continues to be recommended because it is required to protect against newly circulating influenza strains included in the current year's vaccine and because vaccinating the population is likely to provide benefit even if the vaccine has reduced efficacy in those who are vaccinated annually. In an analysis of a hypothetical cohort, over a two-year period, the highest number of cases will occur in the population that remains unvaccinated; a single vaccination is better than no vaccination, and vaccination in both years is likely to prevent more disease than vaccination in a single year [154]. (See 'Schedule' above.)

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.

Alternative production methods — Influenza vaccines have been developed that do not use embryonated eggs as a vehicle for production. Thus far, commercially available vaccine formulations not produced in eggs include Flucelvax (a cell culture-based vaccine) and Flublok (a recombinant vaccine). (See 'Cell culture based' above and 'Recombinant HA vaccine' above.)

Non-egg-based methods are attractive because they are less laborious, have a shorter production time, and do not depend on a supply of eggs [64,124,155].

Non-egg-based vaccine production methods include:

●Cell-based vaccines − Mammalian cell line-based vaccines preserve the structure of the antibody-combining sites on the HA antigen, unlike egg-adapted influenza viruses; the preservation of the HA may result in more robust antibody responses [156]. Cell-based vaccines may also induce broader immune responses, which might provide better protection against variant strains. Mammalian cells are also more permissive of influenza virus replication; certain influenza viruses, such as avian H5N1 viruses, do not replicate well in eggs.

●Plant-based vaccines − 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 [157]. 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.

●Use of viral vectors or virus-like particles − There has been interest in a modified vaccinia Ankara (MVA) vector-based influenza vaccine because it induces an influenza virus-specific T cell response. In a small study, an MVA vector-based vaccine was safe and immunogenic in healthy individuals and appeared to reduce the incidence of influenza infection following an intranasal challenge compared with unvaccinated individuals [158]. Among vaccinees who developed influenza infection, influenza symptoms were less pronounced and the duration of viral shedding was shorter than in unvaccinated individuals.

Additional vaccines employing other viral vectors (eg, vaccinia virus, adenoviruses, vesicular stomatitis virus) or utilize virus-like particles are being evaluated [124].

Universal vaccines — Ongoing research is focused on developing a universal vaccine that would elicit protective antibodies directed against conserved viral proteins [124,159-170]. Such a vaccine would provide protection against drifting influenza strains as well as against newly emerging pandemic strains [124]. In addition, a universal vaccine might also decrease the emergence of viral escape mutants [171]. Promising targets include the highly conserved external domain of the influenza matrix 2 protein and conserved epitopes from the influenza nucleoprotein, matrix 1 protein, HA protein, and neuraminidase protein [124,168].

Although most influenza vaccines have been designed to elicit a humoral immune response, in a phase I clinical trial, a MVA vector that encodes the influenza nucleoprotein and matrix 1 protein boosted T cell responses, particularly CD8+ T cell responses, to all influenza A subtypes in healthy adults [172]. Such a vaccine has the benefit of being directed at epitopes within the conserved internal proteins of influenza viruses rather than at the highly variable surface proteins [173].

Most neutralizing antibody responses in individuals who were infected with the H1N1 influenza A strain that caused the 2009 to 2010 pandemic were broadly cross-reactive against epitopes in the hemagglutinin stalk and head domain of multiple influenza strains, suggesting that a universal influenza vaccine might be developed using such immunogens [174]. In one study, influenza B infection with either of two strains induced antibodies specific to the HA head and stalk, but only HA stalk-specific antibodies mediated antibody-dependent cellular cytotoxicity efficiently and displayed cross-reactivity with influenza B virus of both lineages [175].

Intradermal delivery — Alternate methods of vaccine administration have been developed to improve immunogenicity, particularly in older adults in whom the immune response may be attenuated. Intradermal administration might be more effective than intramuscular delivery because of stimulation of dendritic cells, which are specialized antigen-presenting cells. An intradermal vaccine was approved in the United States in 2011, but it was subsequently 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 [176-180].

Another way to deliver the inactivated influenza vaccine by the intradermal route is to use a microneedle patch that can be self-administered or administered by a health care worker; in a phase I trial, adults aged 18 to 49 years of age who received the vaccine by microneedle patch had similar neutralizing antibody titers and seroconversion rates as those who received an intramuscular injection [181]. Immunogenicity was also similar in those who self-administered the microneedle patch and those who had it administered by a health care worker. In 50 individuals who received the microneedle patch vaccine, its use was associated with significant rates of pruritus (82 percent), tenderness (66 percent), and erythema (40 percent).

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

●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 (figure 1). Influenza virus is remarkable for its high rate of mutation; this viral evolution compromises the ability of the immune system to protect against new viral variants. As a consequence, new vaccines are produced each year to match the vaccine with the new circulating viruses. The protective efficacy of the vaccine is largely determined by the relationship (closeness of "fit" or "match") between the strains in the vaccine and viruses that circulate in the outbreak. Annual influenza vaccination is an important public health measure for preventing influenza infection. (See 'Introduction' above and 'Antigenic composition' above and 'Immunogenicity, efficacy, and safety' above.)

●Several influenza vaccines are licensed for use in the United States, including inactivated vaccines, which are administered intramuscularly or intradermally, and a live attenuated vaccine, which is administered intranasally (table 1 and table 2). Current influenza vaccines are quadrivalent. The protection provided by influenza vaccines is based upon induction of virus-neutralizing antibodies, mainly directed against the viral hemagglutinin (HA). (See 'Introduction' above and 'Available formulations' above.).

●The United States Advisory Committee on Immunization Practices (ACIP) recommends influenza vaccination for all individuals six months of age and older. High-risk individuals, their close contacts, and health care workers should remain high-priority populations in vaccination campaigns (table 3). (See 'Schedule' above.)

●For healthy nonpregnant adults <65 years of age, we recommend annual influenza vaccination (Grade 1A). For individuals ≥65 years of age and for other individuals at increased risk for severe influenza (eg, immunocompromise; chronic cardiovascular, pulmonary, or metabolic disease; pregnancy) (table 4), we also recommend annual influenza vaccination (Grade 1B). (See 'Indications' above.)

●A single dose of an influenza vaccine should be offered soon after the vaccine becomes available, ideally by October in the northern hemisphere and May in the southern hemisphere. Annual immunization is necessary even if the previous year's vaccine contained one or more of the antigens to be administered because immunity declines during the year following vaccination. (See 'Schedule' above.)

●The choice of vaccine formulation depends on several factors, including age, comorbidities, and risk of adverse reactions (table 1 and table 2 and table 5):

•For healthy nonpregnant adults between 18 and 49 years of age, we use either an inactivated vaccine or the live attenuated influenza vaccine (LAIV); in randomized trials of adults, the inactivated vaccine was either equivalent to or more effective than the live attenuated vaccine.

•We use an inactivated influenza vaccine (IIV) in those patients in whom the safety and/or efficacy of LAIV has not been established, including adults ≥50 years of age; individuals who are immunocompromised or have chronic cardiovascular, pulmonary, or metabolic disease; pregnant women; and those with egg allergy.

•For individuals ≥65 years of age, we suggest the high-dose quadrivalent IIV (Fluzone High-Dose Quadrivalent) when available, rather than a standard-dose quadrivalent IIV (Grade 2C).

An alternative is the recombinant HA quadrivalent vaccine (Flublok Quadrivalent), which is more effective than the standard-dose inactivated vaccine for preventing influenza; however, it has not been compared directly with the high-dose inactivated vaccine.

An adjuvanted trivalent vaccine is also considered an option for this age group by the ACIP, but we do not favor it at this time, as there are no reported clinical trials evaluating the efficacy of this vaccine in older adults.

•Additional guidance regarding the most appropriate formulation for a given patient is provided above. (See 'Available formulations' above and 'Choice of vaccine formulation' above.)

●Recommendations for individuals with egg allergy are presented separately. (See "Influenza vaccination in individuals with egg allergy".)