COMPOSITION — All influenza vaccines available in the US this season are trivalent: they contain two influenza A virus antigens and one influenza B virus antigen (see Table 1).3 Influenza A viruses are the primary cause of influenza-related morbidity and mortality, especially in older adults. Illness caused by influenza B viruses is usually more severe in children, especially those <5 years old.4

TIMING — In the US, vaccination against influenza should ideally be offered in September or October and continue to be offered as long as influenza viruses are circulating in the community. In most adults, serum antibody levels peak 1-2 weeks after vaccination. Vaccination in July or August may result in suboptimal immunity before the end of the influenza season, especially in adults ≥65 years old.5

The CDC Advisory Committee on Immunization Practices (ACIP) recommends that pregnant women who are in their first or second trimester during July or August delay vaccination, if possible, until September or October to ensure that their babies are protected throughout the influenza season. Vaccination during July or August can be considered for women who are in their third trimester.1

Children aged 6 months through 8 years who previously received two lifetime doses of an influenza vaccine will only need one dose this season. Those who require 2 doses should receive the first dose as early as possible so that the second dose can be given by the end of October (see Table 2, footnote 3). Vaccination in September or October is preferred for children of any age who need only one dose, but administration in July or August can be considered.

EFFECTIVENESS — Influenza vaccination reduces the incidence of laboratory-confirmed influenza and the risk of serious complications and death associated with influenza illness.6-10 The effectiveness of the seasonal influenza vaccine in preventing influenza illness depends on several factors, including the match between the vaccine and circulating strains and the immunologic response of the recipient. Vaccine effectiveness is greatest when the match is close, but even when it is suboptimal, vaccination can substantially reduce the risk of influenza-related hospitalization and death.11-13 In an observational study in 1,630,328 adults 18-64 years old, the high-dose recombinant vaccine (Flubok Quadrivalent) was significantly more effective than standard-dose vaccines in preventing influenza illness, but not influenza-related hospitalization.14

During the 2023-2024 influenza season in the Southern Hemisphere, vaccination was associated with a 52% reduction in the risk of influenza-associated hospitalization.15

OLDER ADULTS — Older adults are at increased risk for severe influenza illness, hospitalization, and death. Their immunogenic response to influenza vaccination may be reduced compared to that in younger persons, and their antibody levels may decline more rapidly.16

In a cohort study of hospitalized adults ≥60 years old with cardiovascular disease, influenza vaccination was associated with a reduced risk of recurrent hospitalization for ischemic heart disease, respiratory hospitalization, and in-hospital death.17

High-Dose Vaccine – Fluzone High-Dose, an inactivated vaccine that contains 4 times the amount of antigen included in standard-dose inactivated influenza vaccines, is FDA-licensed for use in persons ≥65 years old.

In a randomized, double-blind trial in a total of 31,989 adults ≥65 years old during 2 influenza seasons, Fluzone High-Dose induced significantly greater antibody responses than a standard-dose inactivated trivalent vaccine and was 24% more effective in preventing laboratory-confirmed influenza illness.18 In observational studies and randomized trials in adults ≥65 years old, use of a high-dose inactivated vaccine was associated with a reduced risk of respiratory-related and all-cause hospitalization and death compared to use of a standard-dose inactivated vaccine.19-23

In patients with high-risk cardiovascular disease (recent MI or hospitalization for heart failure), use of a high-dose inactivated vaccine elicited greater humoral responses compared to standard-dose inactivated vaccines, but it did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations.24,25

Adjuvanted Vaccine – Fluad, an adjuvanted inactivated influenza vaccine, is FDA-licensed for use in persons ≥65 years old. It contains MF59, an oil-in-water emulsion of squalene oil that increases the immune response by recruiting antigen-presenting cells to the injection site and promoting uptake of influenza virus antigens.

In a randomized trial in 7082 adults ≥65 years old, Fluad elicited significantly greater antibody responses than a nonadjuvanted, standard-dose inactivated vaccine.26 In observational studies and randomized trials, older adults who received an adjuvanted inactivated vaccine were less likely to develop symptomatic influenza illness or be hospitalized for influenza or pneumonia than those who received a nonadjuvanted, standard-dose inactivated vaccine.27-29

Recombinant Vaccine – Flublok, a recombinant influenza vaccine produced without use of influenza virus or chicken eggs, contains 3 times the amount of antigen included in standard-dose inactivated influenza vaccines. It is FDA-licensed for use in persons ≥18 years old.

In a retrospective cohort study in 12.7 million adults ≥65 years old vaccinated during the 2019-2020 influenza season, the recombinant quadrivalent vaccine was more effective in preventing hospital visits than a nonadjuvanted, standard-dose inactivated quadrivalent vaccine, an adjuvanted trivalent vaccine, or a high-dose trivalent vaccine.30

Choice of Vaccine – In adults ≥65 years old, high-dose, adjuvanted, and recombinant influenza vaccines improved humoral and cell-mediated immune responses and reduced influenza-related medical encounters and hospitalization compared to standard-dose inactivated vaccines.31,32 Few trials have directly compared the high-dose, adjuvanted, and recombinant vaccines in older adults and none have shown that any one is superior to another.

The ACIP recommends that adults ≥65 years old receive either a high-dose, adjuvanted, or recombinant influenza vaccine; if none of these vaccines are available, any age-appropriate influenza vaccine should be given.1

PREGNANCY — Vaccination protects pregnant women against influenza-associated illness, which can be especially severe during pregnancy, and protects their infants for up to 6 months after birth (influenza vaccines are not approved for use in infants <6 months old). Protection is greatest in infants born to mothers who were vaccinated during the third trimester.33

The ACIP and the American College of Obstetricians and Gynecologists (ACOG) recommend vaccinating pregnant women against influenza (see Timing section).34,35 The live-attenuated intranasal vaccine (FluMist) should not be used during pregnancy.

Most studies have not found an association between influenza vaccination and adverse pregnancy outcomes, but data demonstrating the safety of vaccination during the first trimester are limited.36 In one prospective study of women who were pregnant or planning on becoming pregnant, exposure to an influenza vaccine before or during pregnancy was not associated with an increased rate of miscarriage.37

EGG ALLERGY — The recombinant vaccine (Flublok) and the cell culture-based inactivated vaccine (Flucelvax) do not contain egg protein. Other available influenza vaccines may contain trace amounts of egg protein (ovalbumin), but numerous studies have found that persons with a history of egg allergy are not at increased risk for an adverse reaction to influenza vaccines that are propagated in eggs.38

The ACIP, American Academy of Pediatrics (AAP), and Joint Task Force on Practice Parameters of the American Academy of Allergy Asthma and Immunology and the American College of Allergy Asthma and Immunology state that persons with a history of egg allergy of any severity can receive any age-appropriate influenza vaccine without the need for additional safety measures.1,2,39 The AAP adds that it is not necessary to inquire about egg allergy before administration of any influenza vaccine.2

IMMUNOCOMPROMISED PERSONS — The live-attenuated intranasal influenza vaccine (FluMist) should not be used in immunocompromised persons. Inactivated and recombinant vaccines are generally considered safe for use in such persons, but the immune response may be reduced. In two randomized trials in solid-organ transplant recipients, the high-dose vaccine induced significantly greater immune responses than standard-dose vaccines.40,41 The ACIP states that the high-dose inactivated and adjuvanted inactivated influenza vaccines are acceptable options for solid organ transplant recipients 18-64 years old who are receiving immunosuppressive therapy. Separating the time of influenza vaccination from that of an immunocompromising intervention could be considered.

USE WITH OTHER VACCINES — Any influenza vaccine can be given at the same time as a COVID-19 vaccine, but the vaccines should be administered in separate arms. The ACIP states that coadministration of a respiratory syncytial virus (RSV) vaccine with other adult vaccines during the same visit is acceptable; RSV and influenza antibody titer levels are somewhat lower with coadministration than with sequential administration (~1 month apart).42

Inactivated and recombinant influenza vaccines can be administered concomitantly or sequentially with live, inactivated, or recombinant vaccines. The live-attenuated intranasal influenza vaccine can be given simultaneously with inactivated or other live vaccines; other live vaccines not administered simultaneously should be given at least 4 weeks later. Because of limited safety data on concurrent use of 2 or more adjuvanted vaccines, use of a nonadjuvanted influenza vaccine may be considered when another adjuvanted vaccine (e.g., Shingrix, Heplisav-B) is administered concurrently.

USE WITH INFLUENZA ANTIVIRALS — Any inactivated or recombinant influenza vaccine can be administered to persons receiving antiviral drugs for treatment or chemoprophylaxis of influenza. Use of oseltamivir (Tamiflu, and generics) or zanamivir (Relenza) within 48 hours before, peramivir (Rapivab) within 5 days before, or baloxavir marboxil (Xofluza) within 17 days before administration of the live-attenuated intra-nasal influenza vaccine could inhibit replication of the vaccine virus, reducing its effectiveness. Persons who receive any of these antiviral drugs during these specified times and through 2 weeks after administration of the live-attenuated vaccine should be revaccinated with an inactivated or recombinant influenza vaccine.

ADVERSE EFFECTS — Influenza vaccination has been associated with Guillain-Barré syndrome, but the absolute risk is very low (about 1-2 additional cases per million persons vaccinated) and influenza infection itself has been associated with the syndrome (about 17 cases per million patients hospitalized with influenza).43 In a prospective cohort study in patients with diabetes, influenza vaccination was associated with hyperglycemia, but serum glucose levels returned to baseline 2 days after vaccination.44

Except for soreness at the injection site, adverse reactions to inactivated influenza vaccines are uncommon. In clinical trials, the high-dose vaccine (Fluzone High-Dose) caused more injection-site reactions than standard-dose influenza vaccines. Pain and tenderness at the injection site also occurred more frequently with an adjuvanted vaccine (Fluad) than with a nonadjuvanted vaccine. Delivery of Afluria by needle-free jet injector has resulted in more mild to moderate local reactions than delivery by standard needle and syringe.

The most common adverse reactions associated with the live-attenuated intranasal vaccine are runny nose, nasal congestion, fever, and sore throat. The vaccine may increase the risk of wheezing, especially in children <5 years old with recurrent wheezing and in persons of any age with asthma. Persons who receive the live-attenuated vaccine may shed the vaccine-strain virus for a few days after vaccination, but person-to-person transmission has been rare, and serious illness resulting from transmission has not been reported. Nevertheless, the ACIP recommends that persons who care for severely immunocompromised patients in protected environments should not receive the live-attenuated vaccine or should avoid contact with such patients for 7 days after receiving it.

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