AHFS Class:

• Vaccines 80:12

Generic Name(s):

• Influenza Virus Vaccine Inactivated

• Influenza Virus Vaccine Inactivated Quadrivalent

• Influenza Virus Vaccine Adjuvanted

Influenza virus vaccine inactivated (IIV) stimulates active immunity to influenza virus infection.104,106,107,108,160,186,190 Seasonal influenza virus vaccine inactivated contains noninfectious, suitably inactivated influenza virus types A and B subunits representing influenza strains likely to circulate in the US during the upcoming influenza season.100,104,106,107,108,160,186,190

Prevention of Seasonal Influenza A and B Virus Infections

Seasonal influenza virus vaccine inactivated is used in adults,104,106,107,108,160,186,190 adolescents,104,106,107,108,190 children,104,106,107,108 and infants ≥6 months of age104,106,107,108 to stimulate active immunity for prevention of seasonal influenza caused by strains represented in the vaccine.100,104,106,107,108,112,160,186,190

The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and other experts recommend routine annual influenza vaccination against seasonal influenza in all adults, adolescents, children, and infants ≥6 months of age using a licensed age-appropriate vaccine, unless contraindicated.100,112,199,200 Vaccination against seasonal influenza is recommended for otherwise healthy individuals as well as those who have medical conditions that put them at increased risk for influenza-related complications.100,112 Seasonal influenza vaccination is particularly important for individuals at increased risk for severe influenza or influenza-related complications and those who live with or care for such individuals (e.g., health-care personnel, household or other close contacts).100

Annual vaccination against influenza is the primary means of preventing seasonal influenza virus infection and its complications.100 Annual influenza vaccination is necessary because immunity declines in the year following influenza vaccination and circulating influenza strains change from year to year.100,104,106,107,160,186,190

Each year, seasonal influenza vaccines are formulated based on specifications of the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) to contain influenza A and B antigens predicted to represent strains of influenza virus likely to circulate in the US during the upcoming (current) influenza season.100

All influenza vaccines available in the US for the 2023-2024 influenza season are quadrivalent vaccines that contain a different influenza A (H3N2) antigen compared with those contained in vaccines used for the 2022-2023 influenza season.100,588 VRBPAC recommended that egg-based inactivated influenza vaccines for the 2023-2024 influenza season contain antigens representing A/Victoria/4897/2022(H1N1)pdm09-like virus, A/Darwin/9/2021 (H3N2)-like virus, B/Austria/1359417/2021 (B/Victoria lineage), and B/Phuket/3073/2013-like virus (B/Yamagata lineage) and that the cell culture-based vaccine contain antigens representing A/Wisconsin/67/2022 (H1N1)pdm09-like virus, A/Darwin/6/2021 (H3N2)-like virus, B/Austria/1359417/2021 (B/Victoria lineage)-like virus, and B/Phuket/3073/2013-like virus (B/Yamagata lineage).100,588 Quadrivalent seasonal influenza vaccines offer broader protection against circulating influenza B than the previously available trivalent vaccines since they contain antigens representing both the B/Yamagata and B/Victoria lineages.100,112,561,562 Influenza B viruses of both the B/Yamagata and B/Victoria lineages have cocirculated during most influenza seasons since the 1980s, including recent influenza seasons.112,510,511,519,520,541,544,545,551,552,557,559,561,562,570,571,575,576,578,582,585

Seasonal influenza vaccines are not effective against all possible strains of influenza virus and provide protection only against those strains of virus from which the vaccine is prepared and possibly closely related strains.100,166 Efficacy (i.e., prevention of illness among vaccinated individuals in controlled trials) and effectiveness (i.e., prevention of illness in vaccinated populations) of seasonal influenza vaccines depend in part on the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains represented in the vaccine and circulating strains.100,166 In addition, the timing of seasonal influenza vaccination programs is an important consideration.100,112

Current information regarding influenza surveillance and updated recommendations for prevention and treatment of seasonal influenza is available from the US Centers for Disease Control and Prevention (CDC) at [Web].

Choice of Influenza Vaccines for Prevention of Seasonal Influenza

Several different types of influenza virus vaccines are commercially available in the US for active immunization against seasonal influenza, including an inactivated virus vaccine (influenza virus vaccine inactivated [IIV]),100,104,106,107,108,160,186,190 an adjuvanted inactivated influenza vaccine (influenza vaccine, adjuvanted [aIIV]),100,186 a recombinant vaccine (influenza vaccine recombinant [RIV]),100,183 and a live attenuated virus vaccine (influenza vaccine live intranasal [LAIV]).100,157 The various vaccine formulations also differ based on method of manufacturer (egg-based versus cell culture-based), dose (standard versus high-dose), and route of administration (e.g., parenteral versus intranasal),100

Influenza virus vaccine inactivated contains inactivated influenza virus subunits (split virus or subvirion) and is administered parenterally.100,104,106,107,108,160,186,190 Seasonal influenza vaccine live intranasal contains attenuated, live influenza virus reassortants and is administered intranasally.100,157 Seasonal influenza vaccine recombinant contains recombinant hemagglutinin proteins from influenza viruses and is administered parenterally.100,183

Standard-dose, nonadjuvanted inactivated influenza vaccines contain 15 mcg of hemagglutinin per vaccine virus in a 0.5-mL dose (7.5 mcg of hemagglutinin per vaccine virus in a 0.25-mL dose).100 For the 2023-24 season, standard-dose, nonadjuvanted inactivated influenza vaccines include 5 different vaccine products, all of which are approved for individuals ≥6 months; 4 of these vaccines are egg-based vaccines (Afluria Quadrivalent, Fluarix Quadrivalent, FluLaval Quadrivalent, Fluzone Quadrivalent) and one is a cell culture-based vaccine (Flucelvax Quadrivalent).100 Two additional inactivated influenza vaccines that will be available for the 2023-24 season are approved for individuals ≥65 years of age and are egg-based: a quadrivalent high-dose inactivated influenza vaccine (Fluzone High-Dose Quadrivalent) and a quadrivalent adjuvanted inactivated influenza vaccine (Fluad Quadrivalent).100

One recombinant influenza vaccine (Flublok Quadrivalent) is expected to be available during the 2023-24 influenza season for use in individuals ≥18 years of age.100 This vaccine contains recombinant hemagglutinin produced in an insect cell line using genetic sequences from cell-derived influenza viruses and is manufactured without the use of influenza viruses or eggs.100

One live attenuated influenza vaccine (FluMist Quadrivalent) is expected to be available during the 2023-24 influenza season for use in individuals 2 through 49 years of age.100

The choice of a specific influenza vaccine should be made based on the age and health status of the individual.100,112 For many individuals, more than one type of influenza vaccine may be appropriate.100,112 ACIP and AAP state that there are no preferential recommendations for any specific vaccine type or trade name when more than one licensed, recommended, and age-appropriate vaccine is available, with the exception of selection of influenza vaccines for individuals ≥65 years of age.100,112 If an age-appropriate vaccine is available and there are no contraindications, vaccination should not be delayed to obtain a specific product.100,112

Influenza Virus Vaccine Inactivated

Influenza virus vaccine inactivated is used for prevention of seasonal influenza in adults, adolescents, children, and infants ≥6 months of age, depending on the specific product.100,104,106,107,108,160,190

Although most inactivated influenza virus vaccines available in the US for use in adults and pediatric patients ≥6 month of age are quadrivalent egg-based vaccines (Afluria^®, Fluarix^®, Flulaval^®, Fluzone^®; IIV4),104,106,107,108 a quadrivalent cell culture-based vaccine (Flucelvax^®; ccIIV4) also is available for use in individuals ≥6 months of age.190 In addition, a quadrivalent egg-based vaccine (Fluzone^® High-Dose; IIV4)160 and quadrivalent adjuvant-containing egg-based vaccine (Fluad^®; aIIV4)186 are available for use only in adults ≥65 years of age.

The quadrivalent cell culture-based vaccine (Flucelvax^®) is produced using Madin Darby Canine Kidney (MDCK) cells (not embryonated chicken eggs).190

The quadrivalent adjuvant-containing egg-based vaccine (Fluad^®) contains MF59C.1 adjuvant (MF59^®), a squalene-based oil-in-water emulsion,186 to increase antibody response.569 FDA approval of the adjuvant-containing influenza vaccine was based on the immune response elicited by the vaccine;186 continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.186

Influenza virus vaccine inactivated has several advantages over the other available influenza vaccines since the various available preparations can be used in the broadest range of patients, including individuals who cannot receive influenza vaccine recombinant (e.g., infants and children 6 months through 17 years of age) and individuals who cannot receive influenza vaccine live intranasal (e.g., infants 6 through 23 months of age, adults 50 years of age or older, pregnant women, individuals with underlying medical conditions that may predispose them to severe disease following influenza infection, children and adolescents receiving long-term aspirin therapy, individuals with altered immunocompetence including those receiving immunosuppressive therapy, individuals who have close contact with severely immunocompromised individuals, individuals who have received other live virus vaccines within the past 4 weeks, individuals receiving antivirals for treatment or prevention of influenza).100,112,134

Influenza Vaccination During the Coronavirus Disease 2019 (COVID-19) Pandemic

CDC and ACIP state that efforts to ensure influenza vaccination for all individuals ≥6 months of age for the upcoming (current) influenza season are of paramount importance to reduce influenza-related morbidity and mortality and reduce the impact of respiratory illnesses in the population and the resulting burdens on the health-care system.100 SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is expected to circulate in the US during the influenza season, although the extent of continued or recurrent circulation of SARS-CoV-2 during the time that influenza viruses are circulating is not known.100 Vaccination against influenza can reduce the prevalence of influenza illness and reduce the incidence of influenza symptoms that might be confused with COVID-19 symptoms (i.e., fever, cough, dyspnea).100 In addition, prevention of influenza and reduction in severity of influenza illness and associated outpatient visits, hospitalizations, and intensive care unit admissions could alleviate stress on the US health-care system.100

ACIP recommends that influenza vaccination should be deferred in symptomatic individuals with moderate or severe COVID-19 until recovery and deferral also may be considered in persons with mild or asymptomatic COVID-19 illness.100

Target Groups for Influenza Vaccination

Routine annual vaccination against seasonal influenza is recommended for all adults, adolescents, children, and infants ≥6 months of age using an age-appropriate seasonal influenza vaccine, unless contraindicated.100,112,199,200 Seasonal influenza vaccination is particularly important for individuals at increased risk for severe influenza and influenza-related outpatient, emergency department, or hospital visits and those who live with or care for such individuals (e.g., health-care personnel, household or other close contacts).100,112 (See Table 1.)

In some individuals, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac diseases) or lead to secondary bacterial pneumonia, sinusitis, otitis media, or primary influenza viral pneumonia and can occur as part of a coinfection with other viral or bacterial pathogens.100,166 Influenza infection also has been associated with encephalopathy, transverse myelitis, Reye's syndrome, myositis, myocarditis, and pericarditis.100,166,560

The risk for complications, hospitalizations, and deaths from seasonal influenza usually is highest among infants and children younger than 5 years of age, adults ≥65 years of age, and individuals of any age who have medical conditions that place them at increased risk for influenza-associated complications.100,166

Health-care Personnel

ACIP recommends annual vaccination against seasonal influenza for health-care personnel, including all paid and unpaid individuals working in health-care settings who have the potential for exposure to patients or to infectious materials.100 This includes, but is not limited to, physicians, nurses, nursing assistants, nurse practitioners, physician assistants, therapists, technicians, emergency medical service personnel, pharmacists, dental personnel, laboratory personnel, autopsy personnel, students and trainees, contractual staff, and other individuals not directly involved in patient care but who might be exposed to infectious agents (e.g., clerical, dietary, housekeeping, laundry, security, maintenance, administrative, billing staff, volunteers).100

Individuals with Chronic Medical Conditions

Individuals with chronic medical conditions that increase the risk of influenza or influenza-related complications should receive annual vaccination against seasonal influenza.100

Groups considered to be at increased risk for influenza-related complications include adults, adolescents, and children with chronic cardiovascular (excluding isolated hypertension), pulmonary (e.g., asthma, cystic fibrosis, chronic asthma), renal, hepatic, hematologic (including sickle cell disease and other hemoglobinopathies) disease, chronic metabolic disorders (including diabetes mellitus), neurologic and neurodevelopmental conditions (e.g., disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, seizure disorders, and stroke), and residents of nursing homes and other chronic-care facilities housing patients of any age with chronic medical conditions.100,105 Other groups considered at increased risk of influenza-related complications include adults, adolescents, and children who are immunocompromised (including those immunosuppressed because of immunosuppressive therapy or human immunodeficiency virus [HIV] infection) and children and adolescents 6 months through 18 years of age who are receiving long-term aspirin- or salicylate-containing therapy and therefore may be at risk of developing Reye's syndrome following influenza infection.100,105,123,287,382

Infants, Children, and Adolescents

Data from several studies indicate that hospitalization rates are higher in young children than among older children when influenza viruses are circulating,100,384,385,386,387,421 and that these increased rates are comparable to those for other high-risk groups.100,421

ACIP and AAP recommend that all infants and children 6 months of age through 4 years of age receive annual vaccination against seasonal influenza.100,112,199 Annual influenza vaccination also is recommended for children and adolescents 5-18 years of age based on accumulated evidence that influenza vaccine is effective and safe for this age group, increased evidence that seasonal influenza has substantial adverse impacts among school-age children and their contacts (e.g., school absenteeism, increased anti-infective use, health-care visits, parental work loss), and an expectation that simplified influenza vaccine recommendations for all school-age children and adolescents will improve vaccine coverage levels among children who already have a risk- or contact-based indication for annual influenza vaccination.100,112

Geriatric Adults

Geriatric adults ≥65 years of age should receive routine annual vaccination against seasonal influenza.100,200 The majority of influenza-associated deaths occur in adults ≥65 years of age.100,153,182,363 The risk increases with age in this population, and those ≥85 years of age are 16 times more likely than those 65-69 years of age to die of an influenza-associated underlying pneumonia and influenza death.421,422 The risk of hospitalization and death attributable to pneumonia and influenza is particularly increased for geriatric adults with underlying chronic lung disease compared with those who do not have an underlying pulmonary or cardiac condition.100,374 Therefore, targeting geriatric individuals for annual influenza vaccination is particularly important.100,136,141,143,146,166,182,362,363,374

ACIP recommends that adults ≥65 years of age receive one of the higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4).100 If none of these vaccines is available at an opportunity for vaccine administration, then any other age appropriate influenza vaccine should be administered.100

An adjuvant-containing influenza vaccine (Fluad^® quadrivalent) is commercially available for use in adults ≥65 years of age.100,186 This vaccine is a standard-dose preparation that contains an adjuvant (i.e., MF59C.1)186 to increase antibody response.569 FDA approval of the adjuvant-containing influenza vaccines was based on the immune response elicited by the vaccines;186 continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.186 Two other vaccines, HD-IIV (Fluzone^® High-Dose quadrivalent) and RIV (Flublok^® quadrivalent), are higher dose vaccines, which contain an increased dose of HA antigen per virus compared with nonadjuvanted SD-IIVs (60 µg for HD-IIV4 and 45 µg for RIV4, compared with 15 µg for standard-dose inactivated vaccines).100

Certain observational studies have reported relative benefit for HD-IIV, RIV, and aIIV in comparison with nonadjuvanted SD-IIVs, particularly in prevention of influenza-associated hospitalizations.100 However, the relative benefit has varied from season to season and is not seen in all studies in all seasons, making it difficult to generalize the findings.100

At this time, studies directly comparing HD-IIV, RIV, and aIIV are few and do not support a conclusion that any one of these vaccines is consistently superior to the others for adults ≥65 years of age across influenza seasons.100 Also, comparisons of quadrivalent formulations introduced in the 2020-21 influenza season, relative to nonadjuvanted SD-IIV4s against laboratory-confirmed influenza outcomes are not yet available.100

Pregnant Women

Because pregnant and postpartum women are at risk for influenza-related complications, ACIP, American College of Obstetricians and Gynecologists (ACOG), and AAP recommend that all women who are pregnant or who might become pregnant during the influenza season should be vaccinated, and such women should receive any licensed, age-appropriate, inactivated influenza vaccine (i.e., influenza virus vaccine inactivated or influenza vaccine recombinant) for prevention of seasonal influenza.100,112,118 This recommendation includes pregnant women without underlying influenza risk factors.100

HIV-infected Individuals

ACIP, AAP, CDC, National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and other experts recommend annual vaccination against seasonal influenza for all HIV-infected adults, adolescents, children, and infants 6 months of age or older since these individuals may be at increased risk of influenza-related complications.100,112,156 Influenza virus is not traditionally classified as an opportunistic pathogen, but vaccination against the virus is important because of the possible risks of secondary bacterial respiratory infections in such patients.100,105,116,146,156,230,232,233

For prevention of seasonal influenza, HIV-infected adults should receive age-appropriate influenza virus vaccine inactivated or influenza vaccine recombinant and HIV-infected children and adolescents should receive age-appropriate influenza virus vaccine inactivated.100,112,156 Influenza vaccine live intranasal should not be used in HIV-infected individuals.100

Immunization against influenza may be less effective in some HIV-infected individuals than in immunocompetent individuals since the antibody response to vaccines may be reduced and inversely correlated with the severity of the disease.100,105,116,156,232,233,310,376 However, adequate antibody responses to influenza virus vaccine inactivated generally are attained in HIV-infected individuals with minimal AIDS-related symptoms and normal or near-normal CD4⁺ T-cell counts.100 In one study, influenza virus vaccine inactivated was most effective in preventing influenza in HIV-infected individuals with CD4⁺ T-cell counts of 100/mm³ or greater and HIV-1 RNA levels less than 30,000 copies/mL.100 There is no evidence that a second dose of influenza vaccine improves the immune response in HIV-infected individuals.100

Travelers

The risk of exposure to seasonal influenza during travel varies depending on the time of year and destination.100 In temperate climate regions of the Northern and Southern Hemispheres, influenza activity is seasonal, typically occurring during colder winter months (i.e., October to May in the Northern Hemisphere and April to September in the Southern Hemisphere).100 In the tropics, influenza can occur throughout the year.100 Travelers may be exposed to influenza when traveling to an area where influenza is circulating or when traveling as part of large tourist groups (e.g., on cruise ships) that include individuals from areas of the world where influenza is circulating.100,329,334,335,395,551

Unvaccinated travelers who want to reduce their risk for influenza should consider vaccination against seasonal influenza, preferably at least 2 weeks before travel.100 Individuals living in the US who are at higher risk for influenza complications and were not vaccinated against influenza during the Northern Hemisphere fall or winter should consider vaccination before departure if they plan to travel to the tropics, travel to the Southern Hemisphere during the Southern Hemisphere influenza season (April to September), or travel with organized tourist groups or on cruise ships to any location.100 Revaccination is not recommended for individuals who received influenza vaccine during the fall and will be traveling during the summer.100 Individuals at higher risk for influenza complications should consult their health-care provider to discuss the risk for influenza or other travel-related diseases before traveling during the summer.100

Pandemic Influenza

Influenza viruses can cause seasonal epidemics and, occasionally, pandemics during which rates of illness and death from influenza-related complications can increase dramatically worldwide.100,166,437,513,521

The most recent influenza pandemic occurred during 2009 and was related to a novel influenza A strain, influenza A (H1N1)pdm09.100,166,513,535,536 Prior to 2009, the 3 most recent influenza pandemics were the 1918 Spanish flu pandemic (H1N1; originated in China and caused 20-50 million deaths worldwide including about 500,000 deaths in the US), the 1957 Asian flu pandemic (H2N2; originated in China and caused 1-4 million deaths worldwide including about 70,000 deaths in the US), and the 1968 Hong Kong flu pandemic (H3N2; originated in Hong Kong and caused 1-4 million deaths worldwide including about 34,000 deaths in the US).166,437,521

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asian and other countries that has been occurring since 2003 may represent a future pandemic threat.147,437,485 If the avian influenza virus reassorts with a human influenza virus (e.g., H3N2) in a dually infected individual or nonhuman mammal or if virus mutations that foster transmission occur, the resulting new virus variant could be capable of sustained human-to-human transmission.437 The World Health Organization (WHO) states that the risk of a pandemic related to avian influenza A (H5N1) is great, but unpredictable in terms of timing and severity; all conditions for the start of a pandemic are in place except a change in the H5N1 virus that would make the virus contagious among humans.446

Although vaccination is the primary strategy to reduce the impact of an influenza pandemic,437,521 available seasonal influenza virus vaccine provides protection only against those strains from which the vaccine is prepared and closely related strains and would not provide protection against new influenza subtypes, including avian influenza strains.312,437 Therefore, US and global influenza surveillance is necessary to provide warning signals regarding emerging new strains and allow time to manufacture an appropriate vaccine.241,312,316,317,318,437,521

Avian Influenza A Virus Infections

Influenza vaccines used for the prevention of seasonal influenza are not expected to provide protection against infection with avian influenza A viruses, including avian influenza A (H5N1).115,149 Although not commercially available, several different inactivated influenza A (H5N1) monovalent vaccines have received FDA approval and are stored in the US Strategic National Stockpile (SNS).470,471,472,473

Avian influenza A virus refers to influenza A subtypes that occur mainly in birds but also have rarely caused infection in humans (H5N1, H5N6, H5N8, H7N2, H7N4, H7N3, H7N7, H7N9, H9N2, H10N8).115,149,150,171,445,562,576 Experience to date indicates that avian influenza A viruses are not easily transmitted from wild or domestic birds, water fowl, or poultry to humans, but human infections can occur and have been linked to contact with live or dead infected birds or poultry, uncooked poultry products, or surfaces contaminated with infected poultry feces or respiratory secretions.115,147,149,150,312,316,316,317,318,445,485,487,540,552,559,565

Worldwide, most avian influenza viruses isolated in wild birds, water fowl, or poultry have been designated as low pathogenic strains; however, various highly pathogenic avian influenza (HPAI) strains have been detected.149,150 Reported human cases of avian influenza A generally have involved highly pathogenic strains.115,147,149,312,316,316,317,318,445,485,487,540,552,571

Vaccination with the current seasonal influenza virus vaccine has been recommended for individuals involved in poultry culling operations who have direct contact with poultry potentially infected with avian influenza.149,434,448 Although seasonal influenza vaccines are not expected to provide protection against avian influenza A viruses, including avian influenza A (H5N1),115,149,449 they might reduce the risk of coinfection149,434,449 and thereby reduce the potential for human-avian reassortment of genes in an individual simultaneously infected with a human and avian strain.434,449 If reassortment occurs, the likelihood that an avian influenza A virus (e.g., H5N1) could be readily transmitted from person to person increases.432,449

Information regarding treatment and prevention of avian influenza A infections is available from CDC at [Web] and WHO at [Web].

Avian Influenza Type A (H5)

A panzootic outbreak of HPAI type A (H5N1) virus infection in poultry and wild birds in Asia, Africa, Eastern Europe, and the Middle East has been ongoing for more than 15 years.115,147,149,150,433,445,451,457,467,485,552,559,562 There also have been sporadic severe and fatal human cases of infection with HPAI type A (H5N1) in these countries, primarily among individuals in direct or close unprotected contact with infected or dead birds.115,147,149,312,316,316,317,318,445,485,487,540,552,571 Since 2003, WHO has received reports of 861 human cases of avian influenza A (H5N1) infection (including 455 fatalities).150

Some other HPAI type A (H5) subtypes (H5N2, H5N6, H5N8) also have been reported in poultry or wild birds in Asia, Europe, and North America.150,435,436,438,579 Human cases of avian influenza A (H5N6), including some fatalities, have been reported in China.435,579

In the US, HPAI type A viruses (H5N1, H5N2, H5N8) have been reported in wild birds, water fowl, and/or domestic poultry (commercial or backyard flocks) in various states (e.g., Alaska, Arkansas, California, Idaho, Iowa, Minnesota, Missouri, Nebraska, North Dakota, Oregon, South Dakota, Utah, Washington, Wisconsin) since December 2014.149,436,563,564,566 Although CDC states that the risk of human infection with these HPAI type A (H5) viruses is considered low in the US at this time, human infection is possible since other closely related HPAI type A (H5) viruses in Asia and other countries have caused sporadic cases of human respiratory illness.149,563,564 The HPAI type A (H5N1) strain reported in poultry outbreaks in the US is a reassortant virus that is genetically different from the HPAI Asian strain of influenza A (H5N1) that has caused human infections in Asia and other countries and has been associated with a high mortality rate.149,563

Sustained person-to-person transmission of avian influenza viruses, including avian influenza A (H5N1), has not been reported to date,115,147,149,540,552,559,562,571,576,579 but clusters of human cases of avian influenza A (H5N1) indicating the possibility of person-to-person transmission of the virus have been reported in a few countries (Indonesia, Vietnam, China, Thailand).147

Variant Influenza Virus Infections

Influenza viruses that circulate in swine are called swine influenza viruses when isolated from swine, but are called variant influenza viruses when isolated from humans.570,572 Human infections caused by influenza A (H1N1) variant (H1N1v), influenza A (H1N2) variant (H1N2v), and influenza A (H3N2) variant (H3N2v) have been detected in the US.150,570,572,576,587

Information regarding variant influenza virus infections is available from CDC at [Web].

Administration

Inactivated influenza virus vaccines are administered parenterally.104,106,107,108,160,186,190

Afluria^® (quadrivalent), Fluad^® (quadrivalent), Fluarix^® (quadrivalent), Flucelvax^® (quadrivalent), Flulaval^® (quadrivalent), Fluzone^® (quadrivalent), and Fluzone^® High-Dose (quadrivalent) are administered only by IM injection.104,106,107,108,160,186,190

Inactivated influenza virus vaccines for IM injection should not be administered intradermally,104,106,107,190 IV,104,106,107,160,190 or subcutaneously.104,106,107,190

If prefilled syringes are not available, the appropriate volume can be administered from a single-dose or multidose vials.100

As an alternative to IM injection using a needle and syringe, Afluria^® (quadrivalent) may be administered IM using a PharmaJet^® Stratis^® needle-free injection system only in adults 18 through 64 years of age.108,543 Other commercially available inactivated influenza virus vaccines should not be administered IM using a jet injector.543

Influenza virus vaccine inactivated should be inspected visually for particulate matter and discoloration prior to administration.104,106,107,108,160,186,190 The vaccine should be discarded if it contains particulates, appears discolored, or cannot be resuspended with thorough agitation.104,106,107,160,190

Influenza virus vaccine inactivated should not be mixed with any other vaccine or solution.104,134,160,186,190

Syncope (vasovagal or vasodepressor reaction; fainting) may occur following vaccination; such reactions occur most frequently in adolescents and young adults.134 Appropriate measures should be taken to decrease the risk of injury if a patient becomes weak or dizzy or loses consciousness (e.g., vaccinees should sit or lie down during and for 15 minutes after the vaccination).134 If syncope occurs, the patient should be observed until symptoms resolve.134

Influenza virus vaccine inactivated may be administered concurrently with other vaccines during the same health-care visit.100,134 When multiple vaccines are administered during a single health-care visit, each parenteral vaccine should be given using separate syringes and different injection sites.134 Injection sites should be separated by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.134

Timing of Influenza Vaccination

Seasonal influenza vaccine should be administered every year before exposure to seasonal influenza.100 The optimal time for annual vaccination against seasonal influenza cannot be predicted because the onset, peak, and decline of influenza activity varies for each influenza season and more than one outbreak might occur in a given community during a single year.100 In the US, localized outbreaks indicating start of the annual influenza season can occur as early as October and peak influenza activity (which often is close to the midpoint of influenza activity for the season) usually occurs in January or February or later.100

ACIP recommends that health-care providers offer influenza vaccination by the end of October, if possible, and continue to offer vaccination as long as influenza viruses are circulating and unexpired vaccine is available.100 Although influenza vaccination by the end of October is recommended, vaccination in December or later (even if influenza activity has already begun) is likely to be beneficial in the majority of influenza seasons.100

When 2 doses of influenza vaccine are required in children 6 months through 8 years of age, the first dose should be given as soon as possible after the vaccine becomes available since this allows the second dose to be administered by the end of October.100 For children and adults requiring only a single dose of influenza vaccine, there is evidence that early vaccination (i.e., in July or August) is likely to be associated with suboptimal immunity (waning immunity) before the end of the influenza season, particularly in older adults.100 Community vaccination programs should balance maximizing the likelihood of persistence of vaccine-induced protection through the season with avoiding missed opportunities for vaccination or vaccinating after influenza circulation has already started, especially in individuals ≥65 years of age.100

IM Administration

Prefilled single-dose syringes containing influenza virus vaccine inactivated for IM administration should be shaken before administering the dose.104,106,107,108,160,186,190

Single- and multiple-dose vials containing influenza virus vaccine inactivated for IM administration 104 should be shaken before withdrawing a dose.104,108,190

Depending on patient age, IM injections should be made into the anterolateral muscles of the thigh or deltoid muscle of the arm.134

In infants 6 months through 11 months of age, IM injections should preferably be made in the anterolateral thigh.100,104,106,107,134 In certain circumstances (e.g., physical obstruction at other sites and no reasonable indication to defer the vaccine dose), IM injections can be made into the gluteal muscle using care to identify anatomic landmarks prior to injection.134

In infants and children 1 through 2 years of age, the anterolateral thigh is preferred;134 alternatively, IM injections can be made into the deltoid muscle if muscle mass is adequate.134

In adults, adolescents, and children 3 years of age or older, IM injections should preferably be made into the deltoid muscle;100,104,106,107,108,134,160,186,190 alternatively, IM injections can be made into the anterolateral thigh.134

Influenza virus vaccine inactivated should not be administered into the gluteal region or any area where there may be a major nerve trunk.104,106,107,160,186,190

To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin using a needle length appropriate for the individual's age and body mass, thickness of adipose tissue and muscle at the injection site, and injection technique.134 Anatomic variability, especially in the deltoid, should be considered and clinical judgment should be used to avoid inadvertent underpenetration or overpenetration of muscle.134

Jet Injector (Afluria®)

Afluria^® (quadrivalent) may be administered IM using a PharmaJet^® Stratis^® needle-free injection system in adults 18 through 64 years of age.108 The jet injector should not be used to administer Afluria^® (quadrivalent) in individuals younger than 18 years of age or geriatric adults ≥65 years of age.108

For specific information on how to administer Afluria^® using the PharmaJet^® Stratis^® needle-free injection system, the manufacturer's information for the jet injector should be consulted.108

Dosage

Dose and dosing schedule (i.e., number of doses) of influenza virus vaccine inactivated for prevention of seasonal influenza depend on the individual's age, vaccination history, and specific product administered.100,104,106,107,108,112,160,186,190

Inactivated influenza vaccines are approved in different dose volumes for very young children than for older children and adults.100 Care should be taken to administer an age-appropriate vaccine at the approved dose volume for each required dose.100

Pediatric Dosage

Infants and Children 6 through 35 Months of Age (Afluria®)

If Afluria^® (quadrivalent) is used for prevention of seasonal influenza in infants and children 6 through 35 months of age, reduced doses of 0.25 mL should be used.100,108,112

Infants and children 6 through 35 months of age who have not previously received any doses or have an uncertain history of influenza vaccination should receive two 0.25-mL doses of Afluria^® (quadrivalent) administered IM at least 1 month (4 weeks) apart.100,106,112

ACIP and AAP state that infants and children 6 through 35 months of age who did not receive a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season should receive two 0.25-mL doses of Afluria^® administered IM at least 4 weeks apart.100,112

A single 0.25-mL dose of Afluria^® (quadrivalent) can be used for prevention of seasonal influenza in infants and children 6 through 35 months of age who received a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season.100,112

Infants and Children 6 through 35 Months of Age (Fluarix®, Flulaval®)

For prevention of seasonal influenza in infants and children 6 through 35 months of age who have not previously received any doses of any seasonal influenza vaccine or have an uncertain history of influenza vaccination, two 0.5-mL doses of Fluarix^® (quadrivalent) or Flulaval^® (quadrivalent) should be administered IM at least 1 month (4 weeks) apart.100,106,107,108,112

ACIP and AAP state that infants and children 6 through 35 months of age who did not receive a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season should receive two 0.5-mL doses of Fluarix^® or Flulaval^® administered IM at least 4 weeks apart.100,112

A single 0.5-mL dose of Fluarix^® or Flulaval^® can be used for prevention of seasonal influenza in children 6 through 35 months of age who received a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season.100,112

Infants and Children 6 through 35 Months of Age (Fluzone®)

If Fluzone^® (quadrivalent) is used for prevention of seasonal influenza in infants and children 6 through 35 months of age, reduced doses (0.25 mL; prefilled syringes 0.25mL no longer available) or standard doses (0.5 mL) may be used.100,104,112

The manufacturer states that infants and children 6 through 35 months of age who have not previously received any doses of any seasonal influenza vaccine or have an uncertain history of influenza vaccination should receive two 0.25-mL doses, two 0.5-mL doses, or one 0.25- and one 0.5-mL dose of Fluzone^® (quadrivalent) administered IM at least 1 month (4 weeks) apart.100,104,112

ACIP and AAP state that infants and children 6 through 35 months of age who did not receive a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season should receive two 0.25-mL doses or two 0.5-mL doses of Fluzone^® administered IM at least 4 weeks apart.100,112

A single 0.25- or 0.5-mL dose of Fluzone^® can be used for prevention of seasonal influenza in children 6 through 35 months of age who received a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season.100,112

Children 6 months through 8 Years of Age (Flucelvax®)

If Flucelvax^® is used for prevention of seasonal influenza in children 6 months through 8 years of age who have not previously received any doses of any seasonal influenza vaccine or have an uncertain history of influenza vaccination, two 0.5-mL doses should be administered IM at least 1 month (4 weeks) apart.100,112,190

ACIP and AAP state that children 6 months through 8 years of age who did not receive a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season should receive two 0.5-mL doses administered IM at least 4 weeks apart.100,112

A single 0.5-mL dose can be used for prevention of seasonal influenza in children 2 through 8 years of age who received a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season.100,112,190

Children 3 through 8 Years of Age (Afluria®, Fluarix®, Flulaval®, Fluzone®)

For prevention of seasonal influenza in children 3 through 8 years of age (Afluria^® quadrivalent, Fluarix^® quadrivalent, Flulaval^® quadrivalent, Fluzone^® quadrivalent) who have not previously received any doses of any seasonal influenza vaccine or have an uncertain history of influenza vaccination, two 0.5-mL doses should be administered IM at least 1 month (4 weeks) apart.100,104,112,106,107,108

ACIP and AAP state that children 3 through 8 years of age who did not receive a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season should receive two 0.5-mL doses administered IM at least 4 weeks apart.100,112

A single 0.5-mL dose can be used for prevention of seasonal influenza in children 3 through 8 years of age who received a total of 2 or more doses of any seasonal influenza vaccine before July 1 of the summer prior to the upcoming (current) influenza season.100,112

Children and Adolescents 9 through 17 Years of Age (Afluria®, Fluarix®, Flucelvax®, Flulaval®, Fluzone®)

For prevention of seasonal influenza infection in children and adolescents 9 through 17 years of age, 0.5 mL of Afluria^® (quadrivalent), Fluarix^® (quadrivalent), Flucelvax^® (quadrivalent), Flulaval^® (quadrivalent), or Fluzone^® (quadrivalent) should be administered IM as a single dose.100,104,106,107,108,112,190

Adult Dosage

Adults 18 Years of Age or Older (Afluria®, Fluarix®, Flucelvax®, Flulaval®, Fluzone®)

The usual dosage of Afluria^® (quadrivalent), Fluarix^® (quadrivalent), Flucelvax^® (quadrivalent), Flulaval^® (quadrivalent), or Fluzone^® (quadrivalent) for prevention of seasonal influenza infection in adults 18 years of age or older is 0.5 mL administered IM as a single dose.100,104,106,107,108,190

Adults 65 Years of Age or Older (Fluad®, Fluzone® High-Dose)

The usual dosage of Fluad^® standard-dose adjuvant-containing vaccine (quadrivalent) for prevention of seasonal influenza infection in adults 65 years of age or older is 0.5 mL administered IM as a single dose.186

The usual dosage of Fluzone^® High-Dose (quadrivalent) for prevention of seasonal influenza infection in adults 65 years of age or older is 0.7 mL administered IM as a single dose.160

Local Effects

The most frequent adverse effects of seasonal influenza virus vaccine inactivated are local effects.100,104,106,107,108,136,139,160,162,190,243,244,246

Pain or soreness at the injection site has been observed in 10-69% of individuals receiving seasonal influenza virus vaccine inactivated by IM injection.106,107,108,160,186,190 Erythema, swelling, and induration also have been reported.104,106,107,190 Local reactions generally are mild to moderate in severity, persist less than 2 days, and rarely interfere with normal activities.100

Systemic Effects

The most frequent systemic adverse effects of seasonal influenza virus vaccine inactivated are fever, malaise, fatigue, myalgia, and headache.100,104,106,107,108,160,186,190 These systemic reactions have been reported in up to 40% of patients,104,106,107,108,160,190 generally are self-limited, and subside after 1 or 2 days.100 Such systemic reactions occur most frequently in individuals who have not been exposed previously to the influenza virus antigens contained in the vaccine (e.g., young children).100

GI manifestations (e.g., nausea, vomiting) have been reported in 2-15% of individuals following administration of influenza virus vaccine inactivated.104,106,107,108,190 Loss of appetite has been reported in up to 32% of vaccinees.104,106,107,190

Febrile seizures have been reported rarely following administration of influenza virus vaccine inactivated.100,104,108,160

Rarely, administration of seasonal influenza virus vaccine inactivated has been associated temporally with the development of angiopathy,179,203,209 microscopic polyangiitis (vasculitis),179,203,209 uveitis,163,180 dermatomyositis,195 or arthritis195,213 or other rheumatic complications.213 It is unclear whether patients with rheumatoid arthritis are at increased risk of arthritis flare following influenza vaccination.169,193,194,214 At least one case of acute symmetrical polyarthropathy, orbital myositis, and posterior scleritis was postulated as being a sensitivity reaction to the vaccine.273 Although a causal relationship has not been established, the onset of Gianotti-Crosti syndrome (a papular acrodermatitis) in a hepatitis B virus-infected woman249 and of erythromelalgia (palmar and plantar erythema, burning pain, and increased skin temperature) in a child274 were associated temporally with administration of seasonal inactivated influenza virus vaccine.

Because the timing of seasonal influenza immunization programs coincides with peak periods for other respiratory illnesses, many patients who develop a respiratory illness following influenza vaccination incorrectly conclude that the respiratory illness resulted from the vaccine itself, and then often avoid future influenza vaccination.131,146,262,263 Confusion between lay and medical use of the term “flu” may contribute to patient misconceptions.131 Patients should be advised that influenza virus vaccine inactivated contains only inactivated influenza viruses and cannot cause influenza infection.100,104,106,107,108,160,190

Sensitivity Reactions

Allergic or immediate hypersensitivity reactions to seasonal influenza virus vaccine inactivated, including urticaria, angioedema, anaphylaxis, anaphylactic shock, serum sickness, and allergic asthma, have been reported rarely.100,104,106,107,108,160,190

Although bronchoprovocation tests have shown increased bronchial reactivity in some asthmatics for several days after vaccination with seasonal influenza virus vaccine inactivated337,338,339,399 and an association between vaccination and asthma exacerbations337,340,341,399 and/or decreased pulmonary function (e.g., peak expiratory flow)337,342,343,399 has been reported occasionally, such studies were poorly designed (e.g., no placebo control)399 and other studies have been unable to confirm such findings.121,151,344,345,346,347,348,349,350,399 One randomized, double-blind, placebo-controlled cross-over study in children and adults 3-64 years of age with asthma found no increase in asthma exacerbations during the 2 weeks after administration of influenza virus vaccine inactivated.100,424 ACIP and AAP state that influenza virus vaccine inactivated is well tolerated in asthmatic children and adults and annual vaccination with a seasonal inactivated influenza vaccine is recommended in asthmatics since such individuals are at increased risk for influenza-related complications.100,105,112

Guillain-Barré Syndrome

There are postmarketing reports of Guillain-Barré syndrome (GBS) following administration of influenza virus vaccine inactivated.104,106,107,108,160,186

A temporal association was noted between administration of the 1976 swine influenza vaccine and GBS.278,279,364,365 Epidemiologic evidence indicated that the associated risk between administration of this vaccine and GBS did not extend beyond 6 weeks after vaccination.191 GBS is characterized by ascending symmetric paralysis that usually begins in the legs and usually is self-limited and reversible.364 Although the immunologic events leading to GBS have not been fully elucidated, the syndrome is mediated through an immune response that results in direct destruction of either the myelin sheath surrounding the peripheral nerves or the axon itself, and it may or may not follow triggering events such as vaccination.364 The rate of GBS that exceeded the background rate of 10-20 cases per 1 million in adults who received the 1976 swine influenza vaccine was slightly less than 10 additional cases per 1 million vaccinees.192,275,276,277,278,279

An increased risk of developing GBS was not clearly evident with subsequent influenza vaccine formulations prepared from other virus strains, but it is difficult to estimate precisely the risk for a condition as rare as GBS.100,192,275,276,277,280 In addition, vaccinees who received the 1976 swine influenza vaccine have not been shown to exhibit an increased risk of GBS with subsequent vaccine formulations.280

In the 1992-1993 and 1993-1994 seasons, an increase to 1.7 of the overall relative risk of GBS adjusted for age, gender, and vaccine season was observed during the 6 weeks after vaccination, with the combined number of GBS cases peaking 2 weeks after vaccination.364 Although there was concern that the increased number of case reports of GBS associated with the 1993-1994 season relative to the 1992-1994 season may have represented an increased GBS risk with the 1993-1994 vaccine, epidemiologic analysis showed that there was no increase in vaccine-associated GBS between these seasons.364 Estimates from these seasons suggest slightly more than one additional case of GBS per 1 million influenza vaccinees.364,365

Even if GBS truly were an adverse effect of influenza virus vaccine inactivated in the years subsequent to 1976, the estimated risk for GBS of approximately 1 additional case per 1 million vaccinees is much less than the 1976 rate and substantially less than the risk for severe influenza, which can be prevented by vaccination in all age groups, particularly for those 65 years of age and older and for individuals who have medical indications for vaccination.152,364,365

The risk of developing GBS is increased substantially in individuals with a history of GBS.100 Therefore, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among those with a history of GBS than among those without such a history.365

Other Neurologic Effects

Although a causal relationship was not necessarily established, there have been postmarketing reports of other neurologic disorders (not defined as GBS) following vaccination with seasonal influenza virus vaccine inactivated.104,106,107,108,160,190 These adverse effects include encephalopathy, encephalomyelitis, seizures (including febrile seizures), transverse myelitis, facial palsy (Bell's palsy), facial or cranial nerve paralysis, neuritis or neuropathy (including optic neuritis), brachial neuritis, neuralgia, paresthesia, hypoesthesia, hypokinesia, limb paralysis, tremor, somnolence, syncope, presyncope, and dizziness.104,106,107,108,160,190

A placebo-controlled study of seasonal influenza immunization in patients with multiple sclerosis found no association between the rate of neurologic exacerbation of the disease postvaccination nor a change in disease progression over the subsequent 6 months of follow-up.351 In another study that surveyed patients with multiple sclerosis who were identified through a registry of the disease, no deleterious effect from vaccination was observed in patients with primary progressive multiple sclerosis, and the neurologic exacerbation rate was substantially greater following influenza illness than following vaccination in patients with relapsing multiple sclerosis.360

Fever and Febrile Seizures

Febrile seizures have been reported rarely in individuals who received seasonal influenza virus vaccine inactivated100,104,108,160 alone or concurrently with other vaccines.100

There were postmarketing reports of increased rates of fever and febrile seizures in infants and children 6 months through 4 years of age and an increased incidence of fever in children 5 through 8 years of age who received a 2010 Southern hemisphere parenteral inactivated influenza vaccine100,534 that was antigenically equivalent to and produced by the same manufacturer as one of the 2010-2011 seasonal parenteral inactivated influenza vaccines marketed in the US (i.e., Afluria^®; CSL).534 Subsequent laboratory investigation by the manufacturer into the potential etiology of these reactions concluded that the 2010 Southern Hemisphere formulation induced a stronger inflammatory cytokine response than that associated with previous formulations of the vaccine or with other inactivated influenza virus vaccines and this may have been mediated by higher concentrations of residual lipid and RNA remaining in the vaccine.100

Oculorespiratory Syndrome

During the 2000-2001 influenza vaccination season, an oculorespiratory syndrome (ORS) was reported in at least 960 individuals who received seasonal influenza virus vaccine inactivated in Canada.100,293,419,491 The syndrome was defined as the presence of bilateral red eyes and/or at least one of several respiratory symptoms (i.e., cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat) and/or facial edema occurring within 24 hours after influenza vaccination and resolving within 48 hours.293,419,491 The syndrome generally was mild and self-limited.100,419 Although the pathophysiologic mechanism for ORS is unknown,100,419,491 studies suggest the reaction was not an IgE-mediated allergy.100,491 Most reported cases (96%) occurred following receipt of one specific seasonal influenza virus vaccine inactivated preparation (Fluviral^® S/F; not commercially available in the US).100,419 To further evaluate the risk of ORS, controlled studies were done in Canada the following year using the 2001-2002 Fluviral^® S/F preparation in adults with or without a history of ORS following influenza vaccination the previous year.419 Results in adults without a prior history of the adverse effect indicated that the risk of developing ORS, defined as onset of bilateral red eyes, respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat), and/or facial swelling within 2-24 hours after vaccination, was 6.3% in those who received Fluviral^® S/F and 3.5% in those who received placebo.419 However, the study in those with a prior history of ORS was terminated early because the vaccine-attributable risk of the syndrome exceeded 10% in these individuals.419

Approximately 5-34% of patients who previously experienced ORS have a recurrence attributable to seasonal influenza vaccine, but most recurrences are less severe than the previous episode.491 Individuals who have a recurrence of ORS following subsequent vaccination do not necessarily experience further episodes with future vaccinations.491

Precautions and Contraindications

The patient and/or the patient's parent or guardian should be informed of the benefits and risks of immunization with seasonal influenza virus vaccine inactivated and should be provided with a copy of the appropriate Vaccine Information Statement (available at the CDC website [Web]).104,106,107,108,160,186,190,477 Patients and/or the patient's parent or guardian also should be instructed to report any severe or unusual adverse reactions to their health-care provider.104,106,107,108,160,186,190 Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].104,106,107,108,160,186,190

Sensitivity Reactions

Seasonal inactivated influenza virus vaccines are contraindicated in individuals with a history of severe hypersensitivity reaction (e.g., anaphylaxis) to a previous dose of any influenza vaccine.104,106,107,108,112,160,186

The manufacturers state that egg-based inactivated influenza virus vaccines (Afluria^®, Fluad^®, Fluarix^®, Flulaval^®, Fluzone^®) are contraindicated in individuals with a history of severe hypersensitivity reaction (e.g., anaphylaxis) to any component of the vaccine, including egg protein.104,106,107,108,112,160,186,190 However, ACIP states that all persons aged ≥6 months with egg allergy should receive influenza vaccine with any influenza vaccine (egg-based or nonegg-based) that is otherwise appropriate for the recipient's age and health status.100

Cell culture-based influenza vaccine inactivated (Flucelvax^®) is contraindicated in individuals with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine.190

Prior to administration of seasonal influenza virus vaccine inactivated, the patient's immunization history regarding possible sensitivity reactions to the vaccine or vaccine components, including egg protein, and vaccination-related adverse effects should be reviewed to identify any contraindications and assess the risks and benefits of the vaccine.100,106,107,112

Influenza virus vaccine inactivated should be administered in a setting where appropriate medical treatment and supervision are available to manage possible anaphylactic reactions if they occur.100,104,106,107,108,112,134,160,186,190

ACIP states that cell culture-based influenza vaccine inactivated (Flucelvax^®) should not be used in individuals who have had a severe allergic reaction (e.g., anaphylaxis) to any trivalent or quadrivalent cell culture-based influenza vaccine or to any component of the vaccine.100 However, ACIP states that a history of severe allergic reaction (e.g., anaphylaxis) to any other trivalent or quadrivalent type of influenza vaccine (egg-based influenza vaccine inactivated, influenza vaccine recombinant, influenza vaccine live intranasal) is a precaution to use of the cell culture-based vaccine.100 If Flucelvax^® is used in an individual with such a history, the vaccine should be administered in an inpatient or outpatient medical setting supervised by a health-care provider able to recognize and manage severe allergic reactions.100 Consultation with an allergist should be considered to help identify the vaccine component responsible for the prior reaction.100

When assessing whether a patient who experienced ocular and respiratory symptoms following administration of influenza virus vaccine inactivated should receive further doses, ACIP states that clinicians should consider whether any concerning signs and symptoms of IgE-mediated immediate hypersensitivity were present.100 Consultation with an allergist/immunologist is recommended if it is unclear whether ocular and respiratory symptoms reported or observed after receipt of influenza vaccine represent an IgE-mediated hypersensitivity immune response.100

Egg Allergy

Most currently available quadrivalent seasonal influenza virus vaccines (Afluria^®, Fluad^®, Fluarix^®, Flulaval^®, Fluzone^®, Fluzone^® High-Dose) are egg-based and produced using embryonated chicken eggs;104,106,108,112,160,186 these vaccines can contain residual egg protein (ovalbumin).100,106,107,108,186 Flucelvax^® influenza virus vaccine inactivated (quadrivalent) is cell culture-based and prepared using virus propagated in Madin Darby Canine Kidney (MDCK) cells (not embryonated chicken eggs).190

The manufacturers of egg-based inactivated influenza vaccines state that these vaccines are contraindicated in individuals who have had a severe allergic reaction (e.g., anaphylaxis) to egg protein.104,106,107,108,160,186

ACIP states that all individuals aged ≥6 months with egg allergy should receive influenza vaccine with any influenza vaccine (egg-based or nonegg-based) that is otherwise appropriate for the recipient's age and health status.100 ACIP no longer recommends that persons who have had an allergic reaction to egg involving symptoms other than urticaria should be vaccinated in an inpatient or outpatient medical setting supervised by a health care provider who is able to recognize and manage severe allergic reactions if an egg-based vaccine is used.100 Egg allergy alone necessitates no additional safety measures for influenza vaccination beyond those recommended for any recipient of any vaccine, regardless of severity of previous reaction to egg, as all vaccines should be administered in settings in which personnel and equipment needed for rapid recognition and treatment of acute hypersensitivity reactions are available.

A previous severe allergic reaction to influenza vaccine, regardless of the component suspected of being responsible for the reaction, is a contraindication to future receipt of influenza vaccine.100,112

Neomycin and/or Polymyxin B Allergy

Afluria^® (quadrivalent) contains neomycin sulfate (81.8 ng or less per 0.5-mL dose) and polymyxin B (14 ng or less per 0.5-mL dose).108

Fluad^® (quadrivalent) may contain trace amounts of neomycin (0.02 mcg or less by calculation per 0.5-mL dose) and kanamycin (0.03 mcg or less by calculation per 0.5-mL dose).186

Neomycin hypersensitivity usually manifests as a delayed-type (cell-mediated) contact dermatitis.134 ACIP states that a history of delayed-type allergic reaction to neomycin is not a contraindication to administration of vaccines containing trace amounts of neomycin; however, individuals with a history of anaphylactic reaction to neomycin should be evaluated by an allergist before receiving a neomycin-containing vaccine.134

Thimerosal Allergy

All multiple-dose vials of seasonal influenza virus vaccine inactivated (Afluria^®, Flucelvax^®, Fluzone^®) contain thimerosal as a preservative.104,108,190

Single-dose vials104 and prefilled single-dose syringes104,106,107,108,190,160,186 of seasonal influenza virus vaccine inactivated are preservative-free and do not contain thimerosal.104,106,107,108,160,186,190

Hypersensitivity reactions to thimerosal have been reported in some individuals.140,498,500 These reactions usually manifest as local, delayed-type hypersensitivity reactions (e.g., erythema, swelling),134,140,427 but a generalized reaction manifested as pruritus and an erythematous, maculopapular rash on all 4 extremities has been reported rarely.500 Even when patch or intradermal tests for thimerosal sensitivity are positive, most individuals do not develop hypersensitivity reactions to thimerosal administered as a component of vaccines.134,140

ACIP states that a history of local or delayed-type hypersensitivity to thimerosal is not a contraindication to use of vaccines that contain thimerosal.134

Guillain-Barré Syndrome (GBS) and Other Neurologic Conditions

If Guillain-Barré syndrome (GBS) developed within 6 weeks after previous influenza vaccination, the manufacturers state that a decision to administer influenza virus vaccine inactivated should be based on careful consideration of the potential benefits and risks.104,106,107,108,160,186,190

The 1976 swine influenza vaccine was associated with an elevated risk of GBS.104,106,107,108,160,186,190,278,279,364,365 Investigations to date suggest no large increase in GBS associated with influenza vaccine (other than the 1976 swine influenza vaccine) and, if influenza vaccine does pose a risk, it probably is quite small (i.e., slightly more than 1 additional case of GBS per 1 million vaccinees).104,106,107,108,160,186,190,364,365

ACIP states that, as a precaution, individuals who are not at high risk for severe influenza complications and who developed GBS within 6 weeks of a previous dose of influenza vaccine generally should not receive influenza vaccination.100 As an alternative, ACIP states that clinicians might consider the use of antiviral prophylaxis for such individuals.100 However, ACIP states that the benefits of influenza vaccine may outweigh the risks for certain individuals with a history of GBS within 6 weeks after a previous dose of influenza vaccine who are at high risk for severe complications from influenza.100

Based principally on theoretical concerns, some clinicians have recommended that influenza vaccination probably should be avoided in patients with chronic inflammatory demyelinating polyneuropathy, except in those at substantial risk from influenza complications.365

Individuals with Altered Immunocompetence

Like other inactivated vaccines, seasonal inactivated influenza virus vaccine may be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy;100,105,134,135 however, the possibility that immune response to the vaccine and efficacy may be reduced in these individuals should be considered.100,104,105,106,107,108,134,135,160,186,190

ACIP, AAP, CDC, NIH, IDSA, and other experts state that HIV-infected adults, adolescents, children, and infants 6 months of age or older should receive annual vaccination against seasonal influenza; however, age-appropriate parenteral inactivated influenza vaccine (not the intranasal live vaccine) should be used for prevention of seasonal influenza in HIV-infected individuals.100,156 There is no evidence that use of influenza virus vaccine inactivated in HIV-infected individuals has any clinically important effect on HIV infection or immunocompetence.100 However, antibody response may be reduced in HIV-infected individuals and is inversely correlated with the severity of the disease.100,105,116,232,233,310,376

Inactivated vaccines generally should be administered prior to initiation of immunosuppressive therapy or deferred until immunosuppressive therapy is discontinued.105,134

Hematopoietic stem cell transplant (HSCT) recipients, even if previously vaccinated against influenza, should receive influenza virus vaccine inactivated at least 6 months after HSCT and then annually thereafter.134 Although influenza virus vaccine inactivated can be given as early as 4 months after HSCT, some experts state that a second dose should be considered in this situation.134

Thimerosal Precautions

Although there is no convincing evidence that the low concentrations of thimerosal (a mercury-containing preservative) contained in some vaccines is harmful to vaccine recipients,493,494,499,501,502,503,504,505,506 efforts to eliminate or reduce the thimerosal content in vaccines is recommended as a prudent measure to reduce mercury exposure in infants and children and part of an overall strategy to reduce mercury exposures from all sources, including food and drugs.401,402,403,492

The toxicity of mercury is affected by many variables, including the elemental form and amount of mercury involved in the exposure, route of entry, and age during exposure.403,493 Mercury is ubiquitous in the environment and is found in water, soil, plants, and animals, usually as inorganic mercury salts.403,427,492 Mercury accumulates in the aquatic food chain, principally as methylmercury, and one of the most common environmental exposures to organic mercury is through consumption of predator fish.403,427,492 Methylmercury is less readily eliminated from the body than inorganic mercury and is a known neurotoxin.427,492

Thimerosal is a mercury-containing organic compound (organomercurial) that is used as a preservative in vaccines and other biologicals.427,492,493 Thimerosal is approximately 50% mercury by weight and is metabolized or degraded into ethylmercury and thiosalicylate.427,492,493 Ethylmercury is a different chemical entity than methylmercury.427 Although the toxicologic profile of ethylmercury derived from thimerosal is believed to be similar to that of ethylmercury from other sources, there are little data regarding the comparative toxicities of ethyl- versus methylmercury.403,427,493

As part of an ongoing review of biologic products in response to the FDA Modernization Act of 1997, FDA conducted a comprehensive review of the use of thimerosal in childhood vaccines and evaluated the amount of mercury an infant might receive with the US recommended childhood immunization schedule.427,492 Because there were no existing guidelines for exposure to ethylmercury, FDA used existing guidelines for exposure to methylmercury that suggested that safe exposure levels for methylmercury range from 0.1 mcg/kg daily (Environmental Protection Agency [EPA]) to 0.47 mcg/kg daily (World Health Organization [WHO]).427,492 More recently, some experts have suggested that maximum methylmercury exposure levels of 0.1 mcg/kg daily are scientifically justified for protection of human health.427 Using data regarding the vaccine preparations available at the time of the review (1999), FDA determined that the maximum cumulative exposure to mercury from the multiple vaccines in the recommended childhood immunization schedule was within the acceptable limits for methylmercury exposure set by WHO, FDA, and the US Agency for Toxic Substances and Disease Registry (ATSDR); however, depending on the specific vaccine formulations and the weight of the infant, use of multiple thimerosal-containing vaccines during the first 6 months of life potentially could expose some infants to cumulative levels of mercury that were higher than those recommended by EPA.427,492 As a result, vaccine manufacturers and FDA worked to develop and expedite approval of vaccine formulations that either had no mercury-containing preservatives (thimerosal-free) or greatly reduced concentrations of thimerosal (thimerosal-reduced).401,403,427,492

When thimerosal is used as a preservative in vaccines, it is present in concentrations up to 0.01% (up to 50 mcg of thimerosal per 0.5 mL or up to approximately 25 mcg of mercury per 0.5 mL).427,492 According to FDA, a vaccine is thimerosal-free if no thimerosal can be measured (i.e., thimerosal content is below the limits of detection).427,492 Thimerosal-reduced vaccines do not contain thimerosal as a preservative, but may contain trace amounts (1 mcg or less of mercury per dose) from the manufacturing process.427,492 Therefore, some vaccines may be preservative-free but may have trace amounts of thimerosal remaining from the manufacturing process.427,492 FDA states that these trace amounts are not considered clinically important and would not result in mercury exposure exceeding existing federal guidelines.492

As a result of efforts initiated in 1999 to remove or reduce thimerosal in vaccines and expedite development and approval of preservative-free vaccines, all vaccines included in the US Childhood and Adolescent Immunization Schedule are currently commercially available in the US as preparations that either are thimerosal-free or contain only trace amounts of thimerosal.427,492 However, there are still a few vaccines commercially available in the US that contain thimerosal as a preservative, including some preparations of influenza virus vaccine inactivated.100,427,492

Influenza virus vaccine inactivated is commercially available in prefilled single-dose syringes or single-dose vials as preservative-free formulations for IM injection that do not contain thimerosal.104,106,107,108,160,190,427 Only multiple-dose vials of influenza virus vaccine inactivated for IM injection still contain thimerosal as a preservative (25 mcg or less of mercury per 0.5-mL dose).104,108,190,427

Although it was suggested that thimerosal in vaccines theoretically could have adverse effects in vaccine recipients, there is no conclusive evidence that the low levels of thimerosal contained in vaccines cause harm in vaccine recipients.100,492,493,494,499,501,502,503,504,505,506 A link between thimerosal in vaccines and neurodevelopmental disorders in children (autism, attention deficit/hyperactivity disorder [ADHD], speech or language delay) possibly related to mercury neurotoxicity has been theorized; however, considerable evidence has accumulated that supports the absence of substantial risk for neurodevelopmental disorders or other harm resulting from exposure to thimerosal-containing vaccines.493,494,499,501,502,503,504,505,506 In 2004, the Immunization Safety Review Committee of the Institute of Medicine (IOM) examined the hypothesis that thimerosal-containing vaccines are causally associated with autism and concluded that the body of epidemiologic evidence favors rejection of a causal relationship between these vaccines and autism.506

Analysis of adverse effects reported to VAERS indicates that there is no difference in the incidence of injection site reactions, rash, or infections in infants 6-23 months of age who received preservative-containing (thimerosal-containing) influenza virus vaccine inactivated compared with those who received preservative-free preparations of the vaccine.497 Adverse effects known to be caused by thimerosal contained in vaccines usually have been described as local delayed-type hypersensitivity reactions;134,140,427,493 generalized reactions have been reported rarely.134 There has been no convincing evidence that toxicity has occurred as the result of thimerosal contained in vaccines, but mercury toxicity has been observed in patients who received extremely high overdosage of other thimerosal-containing products (total thimerosal doses ranging from approximately 3 mg/kg to several hundred mg/kg).403,427 There are data indicating that mercury concentrations in blood of infants 2-6 months of age who received thimerosal-containing vaccines are considerably lower than concentrations associated with toxic effects.495,496 AAP states that infants and children who have received thimerosal-containing vaccines do not need to have blood, urine, or hair tested for mercury because the concentrations of mercury would be quite low and would not require treatment.403

ACIP, AAP, American Academy of Family Physicians (AAFP), and other experts state that use of vaccines that contain thimerosal is preferable to withholding vaccination since failure to provide protection against vaccine-preventable diseases may represent an immediate threat, especially in infants.401,402,403 AAP states that the benefits of protecting children from influenza outweigh the hypothetical risks associated with the minute amounts of thimerosal contained in some currently available influenza vaccine preparations403 and, therefore, to the extent authorized by state law, children should receive any available age-appropriate formulation of influenza virus vaccine inactivated rather than delaying vaccination while waiting for a thimerosal-free preparation.112

Afluria^® (quadrivalent) is commercially available in 0.25- and 0.5-mL prefilled syringes as a preservative-free formulation (thimerosal was not used in the manufacturing process) and in multiple-dose vials that contain thimerosal as a preservative (12.25 mcg of mercury per 0.25-mL dose; 24.5 mcg of mercury per 0.5-mL dose).108

Fluad^® (quadrivalent) is commercially available in 0.5-mL prefilled syringes as a preservative-free formulation that does not contain thimerosal.186

Fluarix^® (quadrivalent) is commercially available in 0.5-mL prefilled syringes as a preservative-free formulation that does not contain thimerosal.106

Flucelvax^® (quadrivalent) is commercially available in 0.5-mL prefilled syringes as a preservative-free formulation (thimerosal was not used in the manufacturing process) and in multiple-dose vials that contain thimerosal as a preservative (25 mcg of mercury per 0.5-mL dose).190

Flulaval^® (quadrivalent) is commercially available in 0.5-mL prefilled syringes as a preservative-free formulation (thimerosal was not used in the manufacturing process).107

Fluzone^® (quadrivalent) is commercially available in 0.5-mL prefilled syringes as a preservative-free formulation (thimerosal was not used in the manufacturing process).104 Fluzone^® (quadrivalent) also is available in multiple-dose vials in a formulation that contains thimerosal as a preservative (12.5 mcg of mercury per 0.25-mL dose; 25 mcg of mercury per 0.5-mL dose).104

Fluzone^® High-Dose (quadrivalent) is commercially available in 0.7-mL prefilled syringes as a preservative-free formulation.160

Individuals with Bleeding Disorders

Individuals who have bleeding disorders or are receiving anticoagulant therapy and/or their family members should be advised about the risk of hematoma from IM injections.134

ACIP states that IM vaccines may be given to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the preparation can be administered IM with reasonable safety.134 In these cases, a fine needle (23 gauge or smaller) should be used to administer the vaccine, and firm pressure applied to the injection site (without rubbing) for at least 2 minutes.134 In individuals receiving therapy for hemophilia, IM vaccines can be scheduled for administration shortly after a dose of such therapy.134

Concomitant Illness

The decision whether to administer or delay vaccination in an individual with a current or recent acute illness depends on the severity and etiology of the illness.134

ACIP states that mild acute illness generally does not preclude vaccination.134 However, moderate or severe acute illness (with or without fever) is a precaution for vaccination and vaccines should be deferred until the individual has recovered from the acute phase of the illness.134 This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly concluding that a manifestation of the underlying illness resulted from vaccination.134

Individuals with Known or Suspected Coronavirus Disease 2019 (COVID-19)

ACIP states that routine vaccinations, including influenza vaccination, should be deferred in symptomatic individuals with suspected or confirmed COVID-19 until criteria for discontinuance of COVID-19 isolation have been met and the individual is no longer moderately to severely ill.100 Consideration should be given to deferring vaccination until the individual has fully recovered from the acute illness to avoid exposing health-care personnel and other patients to the disease.100 ACIP also states that routine vaccinations, including influenza vaccination, should be deferred in patients with mild or asymptomatic COVID-19 to avoid the inability to discern between COVID-19 symptoms and postvaccination reactions.100 Other considerations include the presence of risk factors for severe influenza illness and the likelihood of being able to vaccinate at a later date.100

Limitations of Vaccine Effectiveness

Following seasonal influenza vaccination, up to 2 weeks may be required to develop antibody protection against infection.100

Seasonal influenza virus vaccine inactivated may not protect all vaccine recipients against influenza.104,106,107,108,160,186,190

Seasonal influenza vaccines are formulated annually to contain influenza A and B antigens predicted to represent strains of influenza virus likely to circulate in the US during the upcoming (current) influenza season.100 Efficacy of seasonal influenza vaccine during any given year depends on how closely viral strains represented in the vaccine match viral strains circulating during the season.100,166

Seasonal influenza virus vaccines are not expected to provide protection against human infection with animal-origin influenza viruses, including avian influenza A viruses (e.g., avian influenza A [H5N1], avian influenza A [H7N9]).115,149

Seasonal influenza vaccines will not provide protection against COVID-19.581

Duration of Immunity

The duration of immunity following vaccination with seasonal influenza virus vaccine inactivated usually is less than 1 year.166 Immunity declines during the year after seasonal influenza vaccination.100,166

Although some available data indicate that early vaccination (e.g., in July and August) might be associated with suboptimal immunity before the end of the influenza season, particularly among older adults, revaccination later in the season is not recommended for individuals who already received influenza vaccine for the current influenza season.100

Annual vaccination with seasonal influenza vaccine is needed because of waning immunity and because circulating strains of influenza virus change from year to year.100,104,106,107,108

Influenza vaccine from a previous influenza season should not be administered during a subsequent influenza season in an attempt to provide protection.100,112

Improper Storage and Handling

Improper storage or handling of vaccines may reduce vaccine potency resulting in reduced or inadequate immune responses in vaccinees.134

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate storage temperature is always maintained.134

Vaccine that has been mishandled or has not been stored at the recommended temperature should not be administered.134

If there are concerns about mishandling, the manufacturer or state or local immunization or health departments should be contacted for guidance on whether the vaccine is usable.134 CDC also can be consulted if necessary.134

Pediatric Precautions

Safety and efficacy of influenza virus vaccine inactivated quadrivalent (Afluria^®, Fluarix^®, Flulaval^®, Fluzone^®) have not been established in infants younger than 6 months of age.104,106,107,108

Safety and efficacy of Flucelvax^® influenza virus vaccine inactivated (quadrivalent) have not been established in children younger than 6 months of age.190

Safety and efficacy of Fluad^® adjuvant-containing influenza vaccine inactivated (quadrivalent) have not been established in pediatric patients.186

Safety and efficacy of Fluzone^® High-dose (quadrivalent) have not been established in pediatric patients.160

Influenza virus vaccine inactivated is less immunogenic in infants younger than 6 months of age than in those 6-18 months of age.295,302,324,325,326 Because seasonal influenza virus vaccine inactivated is not indicated in infants younger than 6 months of age, all household and other close contacts (e.g., day-care providers) of infants younger than 6 months of age should be vaccinated against seasonal influenza using vaccine appropriate for their age and target group since this may provide some protection against seasonal influenza for these young infants.100,105,112

Geriatric Precautions

Clinical studies and other clinical experience with IM seasonal influenza virus vaccine inactivated (Afluria^®, Fluarix^®, Flucelvax^®, Flulaval^®, Fluzone^®) have not revealed any overall differences in safety between geriatric individuals and younger patients;104,106,107,190 however, the vaccine may be less immunogenic in geriatric individuals.100,108,190

Fluad^® adjuvant-containing influenza vaccine (quadrivalent) should only be used in adults 65 years of age or older.100,186 FDA approval of the adjuvant-containing influenza vaccine was based on the immune response elicited by the vaccine;186 continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.186 The safety profile of this standard-dose adjuvant-containing inactivated influenza vaccine is similar to that of standard-dose non-adjuvant-containing inactivated influenza virus vaccine.100 In clinical trials in adults 65 years of age or older, some local and systemic adverse events were reported more frequently with the adjuvant-containing vaccine compared with non-adjuvant-containing vaccine, but most adverse reactions were mild in severity.100

Fluzone^® High-Dose (quadrivalent) should only be used in adults 65 years of age or older.160 Each 0.7 mL of Fluzone^® High-Dose contains 4 times the amount of antigen contained in Fluzone^® (i.e., high-dose formulation contains 60 mcg of hemagglutinin of each of the 4 influenza antigens compared with 15 mcg of hemagglutinin of each antigen in the standard formulation).160 Studies in adults 65 years of age or older indicated that a higher incidence of some injection site reactions and systemic adverse effects was reported with Fluzone^® High-Dose trivalent (no longer available in the US) compared with standard-dose Fluzone^®.100 There is some evidence that the high-dose formulation elicits higher antibody titers and higher seroconversion rates than the standard-dose formulation in adults 65 years of age or older.100

ACIP states that all adults 65 years of age or older should be vaccinated against influenza using influenza virus vaccine inactivated or influenza virus vaccine recombinant.100 ACIP states a preference for the adjuvant-containing quadrivalent inactivated vaccine (Fluad^®), quadrivalent influenza virus vaccine inactivated (Fluzone^® High-Dose), or quadrivalent recombinant influenza vaccine (Flublok^®).100 If none of these 3 vaccines are available, then adults 65 years of age or older may receive any other age-appropriate standard-dose influenza virus vaccine.100,200

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies performed using influenza virus vaccine inactivated (Afluria^®, Fluad^®, Fluarix^®, Flucelvax^®, Flulaval^®, Fluzone^®) have not revealed evidence of harm to the fetus.104,106,107,108,186,190 Animal reproduction studies have not been performed to date with Fluzone^® High-Dose.160

Data are insufficient to assess the risk of administering inactivated influenza vaccines during pregnancy.104,106,107,108,160,186,190

Pregnant and postpartum women are at higher risk for severe influenza and influenza-related complications, particularly during the second and third trimesters, which may lead to adverse pregnancy outcomes including preterm labor and delivery.104,106,107,190

ACIP, ACOG, and AAP recommend that all women who are pregnant or who might become pregnant during the influenza season should receive any licensed, age-appropriate, inactivated influenza vaccine (i.e., influenza virus vaccine inactivated or influenza vaccine recombinant).100,112,118,134 These experts state that influenza virus vaccine inactivated can be administered at any time during pregnancy before or during the influenza season.100,112,118,134 Postpartum women who did not receive such vaccination during pregnancy should be encouraged to receive vaccination (e.g., before hospital discharge).112 In addition to providing potential benefit to the mother, transplacental distribution of antibodies to the fetus following maternal vaccination also may provide some protection in infants.100,112,324,327,328

There are substantial data to date indicating that influenza virus vaccine inactivated does not cause fetal harm when administered to pregnant women,100,112 but data are limited regarding the safety of influenza vaccination during the first trimester.100,112,574 Results of a limited, case-control, observational study using data collected through the Vaccine Safety Datalink (VSD) suggest that women who received influenza virus vaccine inactivated containing influenza A (H1N1)pdm09 during 2 consecutive years (2010-2011 and 2011-2012) had an increased risk of spontaneous abortion during the first 28 days after vaccination.100,112,573,574 However, the US Centers for Disease Control and Prevention (CDC) states that this study does not quantify the risk of miscarriage and does not prove that influenza vaccine was the cause of these miscarriages.574 Other studies that used data from VAERS or other VSD data have not identified any new or unexpected patterns of adverse pregnancy events or fetal outcomes and have not found an association between influenza vaccine and miscarriage.100,112,574

ACIP states that there is no evidence of risk to the fetus if inactivated vaccines are administered during pregnancy.134

To monitor pregnancy outcomes and newborn health status following influenza vaccination of pregnant women, some influenza virus vaccine inactivated manufacturers have established pregnancy registries.104,106,107 Women who receive the vaccine during pregnancy or their health-care providers may contact the manufacturer at 855-358-8966 (Afluria^®),108 888-452-9622 (Fluarix^®, Flulaval^®),106,107 or 800-822-2463 (Fluzone^®).104

Fertility

Animal studies using influenza virus vaccine inactivated (Afluria^®, Fluad^®, Fluarix^®, Flucelvax^®, Flulaval^®, Fluzone^®) did not reveal any effects on female fertility.104,106,107,108,190

Lactation

It is not known whether parenteral influenza virus vaccine inactivated is distributed into milk.104,106,107,108,190 Data are insufficient to assess the effects on the breast-fed infant or on milk production.104,106,107,108,160,186,190

The benefits of breast-feeding and the importance of the vaccine to the woman should be considered along with the potential adverse effects on the breast-fed child from the vaccine or from the underlying maternal condition (i.e., susceptibility to influenza infection).104,106,107,108,190

ACIP and AAP state that breast-feeding is not a contraindication to administration of inactivated vaccines and such vaccines do not pose any unusual risks for the mother or her nursing infant.112,134 These experts state that influenza virus vaccine inactivated may be administered to women who are breast-feeding.112,134

Antiviral Agents

Although no specific studies are available evaluating concomitant use of baloxavir marboxil,410 oseltamivir,407 or peramivir406 with influenza virus vaccine inactivated, the vaccine may be administered concomitantly with or at any time before or after these antivirals.100,134,406,407

Zanamivir does not interfere with the antibody response to influenza virus vaccine inactivated.408 Influenza virus vaccine inactivated may be administered concomitantly with or at any time before or after zanamivir.100

Amantadine122 and rimantadine120 do not appear to interfere with the antibody response to influenza virus vaccine inactivated.

Immune Globulins

There is no evidence that immune globulins (immune globulin IM [IGIM], immune globulin IV [IGIV], immune globulin subcutaneous) or specific hyperimmune globulins (hepatitis B immune globulin [HBIG], rabies immune globulin [RIG], tetanus immune globulin [TIG], varicella zoster immune globulin [VZIG]) interfere with the immune response to inactivated vaccines.134 ACIP states that influenza virus vaccine inactivated may be given concurrently with (using separate syringes and different injection sites) or at any interval before or after immune globulin preparations.134

Immunosuppressive Agents

Individuals receiving immunosuppressive therapy (e.g., alkylating agents, antimetabolites, certain biologic response modifiers, corticosteroids, radiation therapy) may have reduced immune responses to vaccines, including influenza virus vaccine inactivated.104,105,106,107,108,134,160,186,190

Inactivated vaccines generally should be administered at least 2 weeks prior to initiation of immunosuppressive therapy and, because of possible suboptimal response, should not be administered during and for certain periods of time after immunosuppressive therapy is discontinued.105,134,135 Because the intervals between discontinuance of immunosuppressive therapy and restoration of immune competence vary depending on the type and intensity of immunosuppressive therapy, underlying disease, and other factors, optimal timing for vaccine administration following discontinuance of immunosuppressive therapy has not been identified for every situation.105

ACIP and the Infectious Diseases Society of America (IDSA) recommend that inactivated vaccines be administered at least 2 weeks before initiation of cancer chemotherapy or radiation therapy, if possible, and avoided during such therapy.134,135 Individuals vaccinated during or within 14 days of starting chemotherapy or radiation therapy should be considered unimmunized134 and should be revaccinated at least 3 months after such therapy is discontinued if immunocompetence has been restored.134,135 IDSA states that, if indicated based on the time of the year, influenza virus vaccine inactivated can be administered during cancer chemotherapy or less than 3 months after such therapy is discontinued; however, immunologic responses to the vaccine may be reduced.135

Inactivated vaccines should be administered at least 2 weeks prior to treatment with anti-B-cell antibodies (e.g., rituximab).105,134 The optimal time to administer vaccines in patients who have received treatment with anti-B-cell antibodies is unclear.135 Some experts state that administration of inactivated vaccines should be deferred until at least 6 months after treatment with anti-B-cell antibodies has been discontinued.105,134,135

Inactivated vaccines should be administered at least 2 weeks prior to initiation of therapy with certain other immunosuppressive biologic response modifiers (e.g., colony-stimulating factors, interleukins, tumor necrosis factor [TNF; TNF-α] blocking agents).105,134 Some experts state that, if an inactivated vaccine is indicated in a patient with a chronic inflammatory illness who is receiving maintenance therapy with a biologic response modifier, the vaccine should not be withheld because of concern about exacerbation of the inflammatory illness.105,135

Corticosteroids given in greater than physiologic doses may reduce immune responses to vaccines.134 ACIP and AAP state that inactivated vaccines preferably should be administered at least 2 weeks prior to initiation of corticosteroid therapy that is considered immunosuppressive;105,134 however, if this is not feasible in patients receiving long-term corticosteroid therapy for inflammatory or autoimmune diseases, inactivated vaccines can be administered during such therapy.105 IDSA states that, although it may be reasonable to delay administration of inactivated vaccines in patients treated with high-dose corticosteroid therapy because of possible reduced immune responses, recommendations for use of influenza virus vaccine inactivated in individuals receiving corticosteroid therapy, including high-dose corticosteroid therapy, generally are the same as those for individuals not receiving such therapy.135

Vaccines

Although specific studies may not be available evaluating concurrent administration with each antigen, concurrent administration of influenza virus vaccine inactivated with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit is not expected to affect the immunologic response or adverse reactions to any of the preparations.100,105,134

Immunization with influenza virus vaccine inactivated can be integrated with immunization against diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis A, hepatitis B, human papillomavirus (HPV), measles, mumps, rubella, meningococcal disease, pneumococcal disease, poliovirus, rotavirus, and varicella.105,134 However, each parenteral vaccine should be administered using separate syringes and different injection sites.134

COVID-19 Vaccines

ACIP states that approved or authorized COVID-19 vaccines may be given with influenza vaccines without concern for safety or immune interference.100 Providers should be aware of the potential for increased reactivity such as injection site reactions; therefore, if given at the same time, COVID-19 vaccines and influenza vaccines, including influenza virus vaccine inactivated should be administered in different limbs, if possible.100

An interim analysis of a clinical study of 296 persons ≥65 years of age comparing concomitant administration of HD-IIV4 and a booster dose of an mRNA COVID-19 vaccine (administered in separate upper arm sites) with administration of either vaccine alone did not identify any safety concerns or any evidence of immune interference on influenza hemagglutination inhibition or SARS-CoV-2 binding antibody responses.589 Local reactogenicity up to 21 days postvaccination was similar between the coadministration group and the group that received the mRNA COVID-19 vaccine alone.589 Similar frequency of systemic reactions were reported at in the coadministration and mRNA-1273 groups, but with lower frequencies observed in participants who received QIV-HD alone.589

In a multicenter, randomized clinical study, 679 adult participants were recruited to receive concomitant administration of either an age-appropriate influenza vaccine or placebo along with their second dose of a COVID-19 vaccine (either an adenovirus viral vector COVID-19 vaccine, ChAdOx1, or an RNA COVID-19 vaccine, BNT162b2).590 Injections were administered by IM injection in the upper arm, with one injection on each side for the concomitant administration recipients.590 Analysis up to 21 days after vaccination, did not identify safety concerns or evidence of immune interference on influenza hemagglutination inhibition or SARS-CoV-2 binding antibody responses.590 The study found similar rates of local reactogenicity between the coadministration group and single vaccine administration group; however, systemic reactions were reported at similar frequencies in the coadministration and mRNA vaccine groups, with lower frequencies observed in participants who received QIV-HD alone.590

A retrospective analysis of self-reported vaccine data (v-safe [CDC's voluntary smartphone-based monitoring system]) from 92,023 patients 12 years of age and older that were registered as receiving a Moderna or Pfizer booster dose (monovalent) at the same time as an influenza vaccine, found that patients were slightly more likely to report any systemic reaction within 7 days of administration.592 However, most reactions reported in this time period were generally mild (fatigue, headache, myalgia).592

Hepatitis B Vaccines

Safety and efficacy of concomitant or sequential administration of adjuvant-containing influenza virus vaccine inactivated (Fluad^®) and adjuvant-containing hepatitis B vaccine recombinant (Heplisav-B^®) have not been evaluated.100 Because of limited data regarding concomitant use, ACIP recommends that use of a non-adjuvant-containing influenza virus vaccine inactivated (not Fluad^®) be considered in individuals receiving adjuvant-containing hepatitis B vaccine recombinant concurrently.100 However, vaccination against influenza should not be delayed if a non-adjuvant-containing influenza virus vaccine inactivated is not available.100

Pneumococcal Vaccines

Influenza virus vaccine inactivated may be administered concomitantly with pneumococcal 13-valent conjugate vaccine (PCV13; Prevnar 13^®) or pneumococcal 23-valent polysaccharide vaccine (PPSV23; Pneumovax^® 23) using separate syringes and different injection sites.105,112,134

Concomitant administration of PCV13 (Prevnar 13^®) and parenteral influenza virus vaccine inactivated (using separate syringes and different injection sites) in adults 50 years of age or older resulted in similar frequencies of local reactions at the injection site compared with administration of PCV13 (Prevnar 13^®) alone.181 However, there was an increase in some solicited systemic reactions when PCV13 (Prevnar 13^®) and parenteral influenza virus vaccine inactivated were administered concomitantly compared with administration of the influenza vaccine alone (headache, chills, rash, decreased appetite, muscle and joint pain) or the pneumococcal vaccine alone (fatigue, headache, chills, decreased appetite, joint pain).181

There have been some reports of an increased incidence of adverse local and systemic effects when PPSV23 (Pneumovax^® 23) was administered concomitantly with influenza virus vaccine inactivated (at a different injection site) compared with administration of influenza virus vaccine inactivated alone, but these reactions generally are mild and well tolerated and do not preclude concurrent administration of the vaccines at different sites.146,246 ACIP states that concomitant administration of PPSV23 (Pneumovax^® 23) and parenteral influenza virus vaccine inactivated results in satisfactory antibody responses without increasing the incidence or severity of adverse reactions.134

Respiratory Syncytial Virus (RSV) Vaccine

ACIP states that RSV vaccine may be administered concomitantly with other adult vaccines during the same visit, but might increase local or systemic reactogenicity.601 Concomitant administration of RSV and seasonal influenza vaccines met noninferiority criteria for immunogenicity with the exception of the FluA/Darwin H3N2 strain when the GSK RSV vaccine was administered concomitantly with adjuvanted quadrivalent inactivated influenza vaccine.601 RSV and influenza antibody titers were somewhat lower with concomitant administration; however, the clinical significance of this is unknown.601

Rotavirus Vaccine

Concomitant administration of rotavirus vaccine live oral and influenza virus vaccine inactivated has not been studied;167 however, ACIP and AAP state that inactivated vaccines may be administered concurrently with or at any time before or after a live vaccine (e.g., rotavirus vaccine).105,134,167

Zoster Vaccines

Zoster Vaccine Recombinant

Data from an open-label, randomized study in adults 50 years of age or older indicate that concurrent administration of quadrivalent influenza virus vaccine inactivated (Fluarix^®) and zoster vaccine recombinant (Shingrix^®) does not interfere with the immune response to either vaccine106,117 and is not associated with any safety concerns.117 Although the rates of solicited systemic adverse effects (i.e., fatigue, headache, myalgia, shivering, fever) in those receiving the vaccines concurrently were similar to those observed when zoster vaccine recombinant was given alone, the rates were higher than those observed when quadrivalent influenza virus vaccine inactivated was given alone.106

Safety and efficacy of concomitant or sequential administration of adjuvant-containing influenza virus vaccine inactivated (Fluad^®) and zoster vaccine recombinant have not been evaluated.100,117 Because of limited data regarding concomitant use, ACIP recommends that use of a non-adjuvant-containing influenza virus vaccine inactivated (not Fluad^®) be considered in individuals receiving zoster vaccine recombinant concurrently.100 However, vaccination against influenza should not be delayed if a non-adjuvant-containing influenza virus vaccine inactivated is not available.100

Pharmacology

Influenza virus vaccines stimulate active immunity to influenza virus infection by inducing production of specific antibodies;100 protection is provided only against those strains of virus from which the vaccines are prepared and possibly closely related strains.100

In healthy young adults, seasonal influenza virus vaccine inactivated has been shown to induce rapidly and simultaneously both a systemic (i.e., in serum)159,222,252,253,254 and, to a lesser extent, local (i.e., in the upper respiratory tract)222 immune response.

Local mucosal immunity in the respiratory tract (e.g., in tonsils) confers the initial line of defense against influenza.222,252,253,254 It has been suggested that migration of activated B cells, particularly IgA-committed B cells, via lymphatic drainage from the injection site to the mucosal surfaces of the tonsils is responsible for the local immune response after influenza vaccination.222 It also has been suggested that stimulation of local secretory IgA antibodies may be proportionately greater following intranasal influenza vaccination compared with parenteral vaccination, potentially resulting in an increased and broad mucosal and systemic immune response with the intranasal route of vaccination.100,321,322,371 Intranasal influenza vaccination with a live, attenuated (cold-adapted) influenza virus vaccine also may provide greater cross-protection against variant strains, possibly secondary to superior mucosal IgA and T-cell-mediated immune responses, but comparative trials employing parenteral vaccination with currently available inactivated vaccines are necessary to provide definitive information on relative protective efficacy.371,372 Cytotoxic T cells may be cross-reactive against different subtypes of influenza A because of their recognition of internal viral antigens expressed on the surfaces of infected cells that are shared among influenza A viruses, despite antigenic differences between the hemagglutinin molecules.371 The live, attenuated intranasal vaccine also may induce the production of more broadly cross-reactive humoral antibodies.371 Influenza-specific antibodies are predominantly IgG and IgM in serum and IgA in oral fluids.159,222,252,253,254,371

Efficacy of seasonal influenza virus vaccine inactivated in preventing or attenuating illness is variable, depending principally on the age and immunocompetence of the vaccinee and on the degree of similarity between the virus strains included in the vaccine formulation and those circulating during the influenza season.100,480

Although postvaccination antibody titers initially may remain stable (e.g., hemagglutination-inhibition [HI], IgG) or decrease (e.g., IgA) with repeated annual vaccination against seasonal influenza, prevaccination titers of HI, IgG, and IgA prior to the subsequent annual dose are increased overall.380 Thus, repeated annual vaccination against seasonal influenza results in an increase in and maintenance of antibodies to seasonal influenza A (H1N1) and (H3N2) strains over time, which is beneficial for protection of vaccinees.380 Even in individuals in whom a decrease in antibody titers occurs with repeated vaccination, an increase in avidity of the antibodies for influenza antigens could prevent a decline in immune competence.380 Annual vaccination against seasonal influenza is recommended because of the constant development of antigenic variants via antigenic drifts, which is the virologic basis for seasonal epidemics and the reason for annual review and periodic reformulation of the antigenic composition of influenza virus vaccine inactivated.100

Influenza Virus and Infection

Influenza viruses are spread from person to person, principally through the coughing or sneezing of infected individuals in close proximity to susceptible individuals.166 Influenza usually is transmitted by direct deposition of virus-laden large droplets onto mucosal surfaces of the upper-respiratory tract during close contact (within 3 feet) of an infected individual; transmission also may occur through direct or indirect contact with respiratory secretions as the result of touching surfaces contaminated with influenza virus and then touching the eyes, nose, or mouth.166 Adults can transmit influenza virus from the day before their symptoms begin to approximately 5 days after symptom onset.166 Children can transmit influenza to others from several days before their symptoms begin to 10 days or more after symptom onset.166

The typical incubation period for seasonal influenza is 1-4 days (usually 2 days).166 The severity of influenza illness depends on the individual's prior immunologic experience with antigenically related virus variants.166 Influenza illness can vary from asymptomatic infection to severe illness.166 In general, about 50% of infected individuals develop classic symptoms of influenza characterized by abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, nonproductive cough, sore throat, rhinitis, ocular symptoms such as eye pain and light sensitivity).166 Systemic symptoms and fever typically last 2-3 days and the illness usually resolves within 5-7 days, although cough and malaise can persist for more than 2 weeks, especially in geriatric individuals.115,166 Influenza can also exacerbate chronic conditions (e.g., pulmonary or cardiac disease), and/or lead to secondary bacterial pneumonia, sinusitis, or otitis media; or contribute to coinfections with other viral or bacterial pathogens.100,115,166 Influenza-related deaths can result from pneumonia, as well as from exacerbations of cardiopulmonary conditions and other chronic diseases.100,115,166

Influenza viruses can cause disease among persons in any age group, but infection rates are highest among children.100 Rates of complications, hospitalizations, and death are highest among adults 65 years of age and older, children younger than 5 years of age (particularly those younger than 2 years of age), and individuals of any age who have medical conditions that place them at increased risk for complications from influenza.100,166

Antigenic Characteristics of Influenza Viruses

Influenza A viruses are classified into subtypes based on 2 surface antigens, hemagglutinin (H) and neuraminidase (N).100,166 Three subtypes of hemagglutinin (H1, H2, H3) and 2 subtypes of neuraminidase (N1 and N2) have been identified among influenza A viruses that have caused widespread disease in humans.166 Immunity to these antigens, especially hemagglutinin, reduces the likelihood of infection and the severity of disease if an individual does become infected.100 However, there may be sufficient antigenic variation (antigenic drift ) within the same subtype over time, so that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype.100,166

Influenza B viruses also demonstrate antigenic variation, although less rapidly and to a lesser extent than influenza A viruses.100,166 Circulating influenza B viruses are separated into 2 distinct genetic lineages (Yamagata and Victoria) and, unlike influenza A viruses, influenza B viruses are not divided into subtypes.100

Because of the antigenic variation associated with both influenza A and B viruses, major epidemics of respiratory disease caused by new variants of influenza virus continue to occur.100,166 Therefore, the antigenic characteristics of current strains of seasonal influenza virus identified by ongoing surveillance are used as the basis for selecting influenza virus strains to be included in each year's seasonal influenza vaccine.100

The current practice of surveillance and periodic incorporation of new antigenic variants into the annual seasonal vaccine formulation generally has been effective in addressing antigenic drifts in the virus.100,166,239,241,293,480 Of additional concern are antigenic shifts in which major changes in the nucleotide sequence of the hemagglutinin or neuraminidase occur resulting in new subtypes with the potential for causing worldwide pandemics.100,166,241,316,317,318 Antigenic shifts occur far less frequently than antigenic drifts100,166 (reported at irregular intervals of 10 to greater than 40 years)166 and generally are the result of genetic reassortment or recombination between influenza A viruses that affect humans and/or animals.100,166 Because viral strains with major antigenic differences from prevalent subtypes appear and because the population does not have protective antibody against these new antigens, pandemics can occur.100,166 Antigenic shifts that resulted in influenza pandemics occurred in 1889-1891, 1918-1920, 1957-1958, 1968-1969, and 2009-2010.166

During 2009, a new influenza A (H1N1) virus, previously referred to as the novel 2009 influenza A (H1N1) virus or swine-origin influenza A (H1N1) and now referred to as influenza A (H1N1)pdm09, emerged and was associated with a global pandemic.100,166,513,514,515,516,517 This virus contained a unique combination of gene segments not previously reported among human or swine influenza A in the US or elsewhere514,517,522 and appeared to be a triple-reassortant swine influenza virus containing genes from human, swine, and avian influenza A viruses.517,522

There have been reports of human infection with a swine influenza virus, influenza A (H3N2) variant (H3N2v).544,549,550,551,557,559,561,562,572,576 Human cases were initially reported in the US during the summer of 2011.544,549,550 Since then, at least 352 human cases of influenza A (H3N2v) infection have been confirmed in the US.561 Direct contact with swine has been documented for the majority of human cases of H3N2v infection (e.g., prolonged exposure to pigs at agricultural fairs);551,557,561,572 although limited human-to-human transmission was detected, sustained community spread of H3N2v has not been identified to date.551,557 This novel H3N2v virus contains the matrix (M) gene from the influenza A (H1N1)pdm09 virus.544,549,550,551,557,561,572

During recent years, there have been more than a dozen cases of human infection with influenza A (H1N1) swine variant (H1N1v) and several cases of human infection with influenza A (H1N2) swine variant (H1N2v) in the US.561 A fatal infection with influenza A (H1N1v) was reported during the 2014-2015 influenza season, but no ongoing human-to-human transmission was detected.561

There also are influenza A subtypes that occur mainly in birds but also have rarely caused infection in humans (H5N1, H7N2, H7N3, H7N7, H7N9, H9N2).150,431,432,433,434,445,453,551,557,559,576 Future epidemics or pandemics could involve avian influenza viruses or new influenza subtypes, and monitoring avian and animal populations and humans closely associated with poultry and animals provides important information regarding new strains.115,241,312,316,317,318,431,432,433,551

Response to Influenza Virus Vaccine Inactivated

Children and Adolescents

Infants and children 6 months of age or older usually can develop protective levels of antibody after vaccination with the recommended number of doses of IM seasonal influenza virus vaccine inactivated.100 Estimates of the efficacy or effectiveness of influenza virus vaccine inactivated among children 6 months of age or older vary by the specific influenza season and study design, and only limited efficacy data are available for children from studies that used culture- or reverse transcription-polymerase chain reaction (RT-PCR)-confirmed influenza virus infections as the primary outcome.100

In a randomized trial conducted in the US during 5 influenza seasons (1985-1990) that included children 1-15 years of age, vaccination with influenza virus vaccine inactivated reduced culture-confirmed influenza by 77-91%.100 In a single-season placebo-controlled study that included children 3-19 years of age, efficacy of the inactivated vaccine was 56% among healthy children 3-9 years of age and 100% among healthy children and adolescents 10-18 years of age.100

Studies using seasonal influenza virus vaccine inactivated indicate that 2 vaccine doses provide better protection than a single dose during the first season that a child is vaccinated.100 Vaccine effectiveness is lower in children younger than 5 years of age who were not previously vaccinated or who received only 1 dose of vaccine the first year they were vaccinated compared with children who received 2 doses of vaccine the first year they were vaccinated.100 In a case-control study that included children 6-59 months of age conducted during the 2004-2005 influenza season, effectiveness of influenza virus vaccine inactivated in preventing laboratory-confirmed influenza was 57% in those who were fully vaccinated (i.e., received the recommended number of doses); a single dose was not significantly effective.100

Although there is some evidence that antibody responses to influenza virus vaccine inactivated might be lower among children at high risk for influenza-related complications (i.e., children with chronic medical conditions) than among healthy children, one study found that antibody responses among children with asthma are similar to those in healthy children and are not substantially altered during asthma exacerbations requiring short-term prednisone treatment.100

Influenza virus vaccine inactivated is less immunogenic in infants younger than 6 months of age† than in those 6-18 months of age,295,302,326 and safety and efficacy of the currently available vaccines have only been established for children 6 months of age or older.104,106,107

Adults 18 through 64 Years of Age

A single IM dose of seasonal influenza virus vaccine inactivated is highly immunogenic in healthy adults younger than 65 years of age.100 Efficacy is substantially lower when vaccine formulations are antigenically dissimilar to the majority of circulating strains.100 A 2010 meta-analysis of randomized clinical trials among healthy adults 16 through 65 years of age suggested that efficacy against influenza symptoms was 73% when influenza virus strains represented in the seasonal vaccine were well matched with circulating influenza virus strains; efficacy was only 44% when the strains were not well-matched.100

When compared with healthy young adults, patients with certain chronic diseases may develop lower postvaccination antibody titers and remain susceptible to influenza-related upper respiratory tract infection.100,322 In addition, there is some evidence that vaccine effectiveness may be lower in adults younger than 65 years of age who are at higher risk for influenza-related complications compared with healthy adults.100 In a case-control study conducted during the 2003-2004 influenza season, when the vaccine was a suboptimal antigenic match to many circulating influenza strains, effectiveness of the vaccine in preventing laboratory-confirmed influenza among adults 50-64 years of age with high-risk conditions was 48% compared with 60% in healthy adults in this age group.100

Immunogenicity of Flucelvax^® (quadrivalent), a cell culture-derived inactivated influenza vaccine, was compared to immunogenicity of trivalent cell culture-derived inactivated influenza vaccines (no longer available in the US) in a randomized, double-blind study in adults 18 years of age or older.190 Results indicated that the quadrivalent formulation was noninferior to trivalent formulations based on antibody responses and seroconversion rates at 3 weeks after the vaccine dose.190

In a study in adults 18 years of age or older, Flucelvax^® was noninferior to Agriflu^® (an egg-derived inactivated influenza vaccine no longer available in the US) based on hemagglutination-inhibition (HI) antibody responses to all 3 vaccine strains for both postvaccination geometric mean titer (GMT) ratios and seroconversion rates.190

Geriatric Adults 65 Years of Age or Older

Geriatric individuals may have decreased antibody responses and develop lower postvaccination antibody titers following a single IM dose of seasonal influenza virus vaccine inactivated than healthy younger adults.100,190 Although influenza vaccine may be less effective in preventing influenza illness in geriatric adults 65 years of age or older, it may be effective in preventing complications and death.166

In a study in adults who received trivalent influenza virus vaccine inactivated (no longer available in the US), seroprotection (defined as an hemagglutination inhibition antibody [HAI] titers of 40 or greater) to the 3 vaccine antigens (influenza A(H1N1), influenza A(H3N2), and influenza B) was 69, 74, and 67%, respectively, in older adults compared with 83, 84, and 78%, respectively, in younger adults.166

Efficacy of IM seasonal influenza virus vaccine inactivated in preventing hospitalization for pneumonia and influenza has been reported to range from 27-70% among geriatric individuals residing outside nursing homes or similar chronic-care facilities.100,168,218,219,285,363,374 Among elderly nursing home residents, it has been estimated that the vaccine is 20-40% effective in preventing respiratory illness.100 Outbreaks have occurred among well-vaccinated nursing home populations, suggesting that vaccination may not be effective when circulating influenza strains differ from vaccine strains.100

In a large cohort study in geriatric individuals (65 years of age and older) living in the community, influenza vaccination during epidemic and nonepidemic years was associated with a 48-57% reduction in the hospitalization rate for pneumonia and influenza and in 27-39 and 37% reductions in the rates of hospitalization for acute and chronic respiratory conditions and for congestive heart failure, respectively.164 Vaccination also was associated with a 39-54% reduction in all-cause mortality in this geriatric population during the last 3 influenza seasons (1990-1993) of the cohort study.164 Pooled data from this study and subsequent continued study for 3 additional influenza seasons (1993-1996) showed that seasonal influenza vaccination was associated with overall (over all 6 seasons) reductions in hospitalizations for pneumonia, all respiratory conditions, and congestive heart failure of 39, 32, and 27% respectively, and in all-cause mortality of 50%.363 This study also confirmed that both healthy geriatric adults and those with underlying medical conditions are at risk for serious complications of influenza and benefit from vaccination.363

Immunogenicity of Fluad^® standard-dose adjuvant-containing inactivated influenza vaccine (quadrivalent) in adults 65 years of age or older was evaluated in a multinational, randomized, non-influenza comparator-controlled study conducted during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons.186 At 21 days after a dose of Fluad^® (quadrivalent), hemagglutination inhibition (HI) antibody titers were 1:40 or greater in 79-96% and seroconversion was reported in 61-85% of these adults.186

Fluzone^® High-Dose (quadrivalent) contains 4 times the amount of antigen contained in standard-dose Fluzone^® (quadrivalent); the high-dose formulation contains 60 mcg of hemagglutinin of each of the 4 influenza antigens compared with 15 mcg of hemagglutinin of each antigen in the standard-dose formulation.160 The comparative safety and efficacy of Fluzone^® High-Dose (trivalent; no longer available in the US) and standard-dose Fluzone^® (trivalent) were evaluated in a multicenter, double-blind trial in adults 65 years of age or older that was conducted over 2 influenza seasons (2011-2012 and 2012-2013).100,160 Results indicated that Fluzone^® High-Dose (trivalent) was superior to standard-dose Fluzone^® (trivalent) for prevention of laboratory-confirmed influenza in this age group (relative efficacy was 24.2% for the high-dose vaccine compared with the standard-dose vaccine).100,160 There is evidence from a study in adults 65 years of age or older that Fluzone^® High-Dose (quadrivalent) is as immunogenic as Fluzone^® High-Dose (trivalent) based on GMTs and seroconversion rates against the 3 influenza strains common to both vaccines and, based on a prespecified superiority criterion, the quadrivalent high-dose vaccine induced a superior immune response with respect to the additional influenza B strain than that induced by the trivalent high-dose vaccine that did not contain the additional influenza B strain.160

Individuals with Altered Immunocompetence

The response to IM seasonal influenza virus vaccine inactivated in individuals immunosuppressed as the result of disease or immunosuppressive therapy generally is less than that in healthy individuals.100,105,248,261,290,310,377 There is some evidence that administration of an additional (i.e., booster) dose of influenza vaccine may not improve immune response in immunosuppressed individuals (e.g., transplant recipients receiving immunosuppressive drugs, individuals with human immunodeficiency virus [HIV] infection).116,124,232,248,290,310

HIV-infected Individuals

Vaccine-induced antibody levels generally are lower in individuals with HIV infection than in healthy individuals and may be inversely correlated with the severity of manifestations associated with HIV infection.100,116,232,233,310,376,377,414 IM seasonal inactivated influenza vaccine has induced protective antibody titers in HIV-infected children and adults who had only minimal or no acquired immunodeficiency syndrome (AIDS)-related symptoms and mean CD4⁺ T-cell counts of 400/mm³.100,230,232,233,310 In those with advanced disease and low CD4⁺ T-cell counts (e.g., less than 100/mm³), the vaccine may not induce adequate antibody titers.100,232,310 Use of an additional (i.e., booster) dose of the vaccine (e.g., administered 4 or more weeks after the first dose) does not appear to improve the immune response in HIV-infected individuals.116,124,232,310

Some evidence indicates that the antibody response to IM seasonal influenza virus vaccine inactivated correlates directly with the CD4⁺ T-cell count232,376 and inversely with the plasma HIV-1 RNA level,376 being particularly impaired with CD4⁺ counts less than 100/mm³100,232,376 and HIV-1 RNA levels exceeding 100,000 copies/mL.376 In several studies in HIV-infected adults, almost no HI antibodies were measurable in those with CD4⁺ T-cell counts less than 100/mm³, and counts of 100-300/mm³ correlated with a suboptimal antibody response; those with T-cell counts of 300 or more per mm³ were most likely to develop protective titers.232 Results of a small, randomized, placebo-controlled study indicate that influenza virus vaccine is highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected individuals with mean CD4⁺ T-cell counts of 400/mm³.100

Duration of Immunity

The duration of immunity following vaccination with seasonal influenza virus vaccine inactivated usually is less than 1 year.166 Because immunity declines during the year after vaccination100,166 and since circulating strains of influenza virus change from year to year,100,414,482 annual vaccination with seasonal influenza vaccine is needed.100

Vaccine from a previous influenza season should not be used in an attempt to provide protection during a subsequent influenza season.100,112

Chemistry and Stability

Chemistry

Inactivated influenza virus vaccines used for prevention of seasonal influenza contain noninfectious, sterile preparations of suitably inactivated influenza virus types A and B subunits.100,104,106,107,108,160,186,184,190 Most seasonal inactivated influenza virus vaccines commercially available in the US are split-virus preparations (purified subvirion or purified surface antigen) prepared from formaldehyde- or propiolactone-inactivated influenza viruses harvested from allantoic fluids of chick embryos infected with the viruses (egg-based seasonal influenza virus vaccine inactivated).100,104,106,107,160,186 In addition, a subunit inactivated influenza virus vaccine is commercially available in the US that is prepared from propiolactone-inactivated influenza virus propagated in Madin Darby Canine Kidney (MDCK) cells (cell culture-based seasonal influenza virus vaccine inactivated).190

Vaccines used for prevention of seasonal influenza are formulated annually.100 Each year, seasonal influenza vaccines commercially available in the US are formulated as specified by the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) to contain influenza type A and type B antigens representative of the strains of influenza virus likely to circulate in the US in the upcoming (current) influenza season.100,578 The specific vaccine antigens are selected based on data obtained from global influenza virologic and epidemiologic surveillance, antigenic and genetic characterization of circulating influenza viruses, and candidate vaccine viruses available for production.578

Seasonal influenza virus vaccine inactivated (egg- or culture-based) is available as various quadrivalent vaccines containing 2 influenza type A antigens (H1N1 and H3N2) and 2 influenza type B antigens (B/Yamagata lineage and B/Victoria lineage).100,104,106,107,108,160,186,190

Egg-based Seasonal Influenza Virus Vaccine Inactivated

Influenza virus vaccine inactivated prepared using viruses propagated in chick embryos (egg-based) is available as various quadrivalent vaccines for use in individuals ≥6 months of age(Afluria^®, Fluarix^®, Flulaval^®, Fluzone^®; IIV4)104,106,107,108 and as a quadrivalent vaccine for use in individuals ≥65 years of age (Fluzone^® High-Dose; IIV4).160 These inactivated influenza vaccines occur as clear and/or slightly opalescent suspensions.104,106,107,108,160

Afluria^® (quadrivalent) is commercially available in 0.5-mL prefilled single-dose syringes as a preservative-free formulation and in multiple-dose vials that contain thimerosal as a preservative (12.25 mcg of mercury per 0.25-mL dose and 24.5 mcg of mercury per 0.5-mL dose).108

Fluarix^® (quadrivalent) is commercially available in 0.5-mL prefilled single-dose syringes as a preservative-free formulation.106

Flulaval^® (quadrivalent) is commercially available in 0.5-mL prefilled single-dose syringes as a preservative-free formulation.107

Fluzone^® (quadrivalent) is commercially available in 0.5-mL prefilled single-dose syringes and in multiple-dose vials as a formulation containing thimerosal as a preservative (25 mcg of mercury per 0.5-mL dose).104

Fluzone^® High-Dose (quadrivalent) is commercially available as a preservative-free formulation in 0.5-mL prefilled single-dose syringes.160

Adjuvant-containing Egg-based Seasonal Influenza Virus Vaccine Inactivated

Adjuvant-containing influenza vaccine is available as a quadrivalent vaccine (Fluad^®; aIIV4).186 The adjuvant in the vaccine is MF59C.1 (MF59^®), a squalene-based oil-in-water emulsion.186 The virus strains contained in the vaccine are propagated in the allantoic cavity of embryonated hens' eggs (egg-based) and harvested, concentrated, and purified and then combined with the adjuvant.186 Fluad^® (quadrivalent) vaccine occurs as a milky white emulsion and has a pH of 6.9-7.7.186 Each 0.5 mL of the vaccine contains at least 15 mcg of hemagglutinin from each of 4 influenza strains and MF59C.1 adjuvant (9.75 mg squalene, 1.175 mg of polysorbate 80, 1.175 mg of sorbitant trioleate, 0.66 mg of sodium citrate dihydrate, and 0.04 mg of citric acid monohydrate).186 This adjuvanted vaccine may contain trace amounts of neomycin (0.02 mcg or less by calculation), kanamycin (0.03 mcg or less by calculation), and hydrocortisone and residual amounts of egg protein (less than 1 mcg), formaldehyde, and cetyltrimethylammonium bromide.186

Fluad^® (quadrivalent) is commercially available as a preservative-free formulations in 0.5-mL prefilled single-dose syringes.186

Cell Culture-based Influenza Virus Vaccine Inactivated

Influenza virus vaccine inactivated derived from viruses propagated in MDCK cells (cell culture-based) is available as a quadrivalent vaccine (Flucelvax^®; ccIIV4).190 The MDCK cells, a continuous cell line, are adapted to grow freely in suspension in culture medium.190 The viruses are inactivated with β-propiolactone, disrupted using cetyltrimethylammonium bromide detergent, purified, and standardized.190 Flucelvax^® occurs as a slightly opalescent suspension in phosphate buffered saline.190 The vaccine may contain residual amounts of MDCK cell protein, MDCK cell DNA, polysorbate 80, cetyltrimethylammonium bromide, and β-propiolactone from the manufacturing process.190

Flucelvax^® (quadrivalent) is commercially available in 0.5-mL prefilled single-dose syringes as a preservative-free formulation and in multiple-dose vials as a formulation containing thimerosal as a preservative (25 mcg of mercury per 0.5-mL dose).190

Stability

Influenza virus vaccine inactivated (quadrivalent) should be refrigerated at 2-8°C and should not be frozen.104,106,107,108,160,186,190 If freezing occurs, the vaccine should be discarded.104,106,107,108,160,186

Influenza virus vaccine inactivated should be protected from light.106,108,186,190

In between uses, multiple-dose vials of influenza virus vaccine inactivated should be returned to 2-8ºC.104,108,190 The manufacturer of Afluria^® states that any vaccine remaining in multiple-dose vials should be discarded after a total of 20 doses have been removed from the vial and that multiple-dose vials should be discarded if not used within 28 days after they were first entered.108

Single-dose syringes and single-dose vials of influenza virus vaccine inactivated are preservative-free.104,106,107,108,160,186,190 Multiple-dose vials contain thimerosal as a preservative.104,108,190

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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