Influenza primary prevention

Primary prevention of influenza relies on two complementary strategies: annual vaccination, which is the cornerstone intervention for all persons aged ≥6 months without contraindications, and targeted antiviral chemoprophylaxis, reserved for defined high-risk exposure scenarios rather than widespread use.^[1]

Routine annual influenza vaccination is recommended for all persons aged ≥6 months without contraindications.^[1] Several vaccine platforms are available — inactivated (IIV), recombinant (RIV), and live attenuated (LAIV) — with no preference among age-appropriate options noted by the American Academy of Pediatrics (AAP).^[2] Vaccination should ideally occur by the end of October but should be continued throughout the season as long as viruses are circulating.^[3] For older adults, CDC recommends vaccination in September or October and advises against administering too early due to waning immunity, which may be more pronounced in this population.^[4]

• Adults aged ≥65 years: The Advisory Committee on Immunization Practices (ACIP) preferentially recommends one of three enhanced formulations — high-dose inactivated (HD-IIV), recombinant (RIV), or adjuvanted inactivated (aIIV, MF59-adjuvanted) — over standard-dose IIV. This is due to diminished immune responses to standard vaccination in this population. A network meta-analysis of 32 studies (>71 million vaccinated participants) found enhanced vaccines conferred modestly greater protection against influenza-associated hospitalization than standard-dose vaccine (pooled relative vaccine effectiveness [rVE] of 18%, 95% CI 3–32% from randomized studies; 11%, 95% CI 8–14% from observational studies), with no significant differences among HD, adjuvanted, and recombinant vaccines.^[5] The pooled DANFLU-2/GALFLU (FLUNITY-HD) analysis and subsequent trials have since demonstrated HD-IIV superiority over standard-dose vaccine for hospitalization outcomes in adequately powered individually randomized trials.^[6] A cluster-randomized crossover study found adjuvanted vaccine noninferior to HD-IIV for PCR-confirmed influenza and related hospitalization outcomes.^[7] Reactogenicity (injection-site pain, systemic symptoms) is generally greater with enhanced formulations, but the benefit-risk balance favors enhanced vaccines in this population.^[1][5]
• Solid organ transplant recipients: ACIP recommends that solid organ transplant recipients aged 18–64 years receiving immunosuppressive medications may receive HD-IIV3 or aIIV3 as acceptable options, without preference over other age-appropriate vaccines.^[1]
• Children aged 6 months–8 years: Those requiring 2 doses (per prior vaccination history) should receive the first dose as soon as possible after vaccine becomes available, with the second dose ≥4 weeks later.^[2]
• Immunocompromised patients: Live attenuated vaccine should not be administered; high-dose vaccine is favored in these groups where evidence supports improved immunogenicity.^[3]

Key updates for the 2025–26 season include revised antigenic composition, FDA approval of FluMist for self- or caregiver-administration, expansion of Flublok (RIV) to ages ≥9 years (from ≥18 years), and a new ACIP recommendation that children ≤18 years, pregnant women, and all adults receive only single-dose, thimerosal-free formulations.^[1][4] Interim 2025–26 vaccine effectiveness estimates are lower than recent seasons but remain protective: 38–41% against outpatient visits and 41% against hospitalization in children/adolescents; 22–34% against outpatient visits and 30% against hospitalization in adults.^[8]

ACIP now recommends that all persons aged ≥6 months with egg allergy of any severity, including anaphylaxis, receive influenza vaccine, using any age-appropriate formulation (egg-based or non–egg-based), with no additional safety measures required beyond those for any vaccine recipient.^[1] This recommendation is based on 20 studies with no reported anaphylaxis cases (GRADE certainty: very low).^[1] This supersedes older guidance that distinguished hive-only reactions from more severe egg reactions requiring special observation settings.

True contraindications/precautions include:^[1]

• Severe allergic reaction (e.g., anaphylaxis) to any vaccine component or a prior dose of that vaccine — labeled contraindication.
• LAIV specifically: is not approved for and should not be given to persons aged <2 or >49 years; also contraindicated in pregnancy, immunosuppression, and several other conditions per ACIP beyond the package insert.
• History of Guillain-Barré syndrome within 6 weeks of a prior influenza vaccine dose — a precaution for all influenza vaccines.
• Moderate-to-severe acute illness (with or without fever) — general precaution, defer until resolution.

Antiviral chemoprophylaxis is not recommended for routine or widespread seasonal/pre-exposure use, to limit emergence of antiviral resistance and preserve treatment availability for high-risk or severely ill patients. It is reserved for specific postexposure scenarios:^[9][10]

• High-risk persons exposed to an infectious contact during the first 2 weeks after vaccination (before immunity develops).
• Persons with severe immunodeficiency or others unlikely to respond to vaccination (e.g., on immunosuppressive therapy) after exposure.
• High-risk persons with a vaccine contraindication after exposure.
• Outbreak control in institutional settings (e.g., long-term care facilities).

A 2024 systematic review and network meta-analysis supporting WHO guideline development found moderate-certainty evidence that oseltamivir, zanamivir, and baloxavir probably reduce symptomatic influenza risk in high-risk individuals but have little important effect in low-risk populations.^[10]

Evidence base for chemoprophylaxis agents:

• Oseltamivir (oral) and zanamivir (inhaled): Efficacious in randomized placebo-controlled household-contact studies.^[9]
• Baloxavir: FDA-approved for post-exposure prophylaxis of influenza in patients aged ≥5 years.^[11] A single dose within 48 hours of exposure to a symptomatic household contact reduced influenza incidence to 2% versus 13% with placebo (aRR 0.14) in a Japanese RCT (household members ≥5 years of age).^[9]
• IV peramivir: No chemoprophylaxis data exist; FDA-approved indication is limited to treatment of acute uncomplicated influenza in patients aged ≥6 months symptomatic for ≤2 days.^[11]

Practical points: Chemoprophylaxis should generally not be initiated if >48 hours have elapsed since exposure. When used, once-daily prophylactic dosing (oseltamivir/zanamivir) must be distinguished from higher treatment dosing. Close monitoring with early treatment initiation if symptoms develop is a reasonable alternative to prophylaxis in many exposed persons.^[9]

• Egg allergy, including anaphylaxis, is no longer a reason to withhold or specially observe influenza vaccination.^[1]
• Enhanced vaccines (HD, adjuvanted, recombinant) are now preferentially recommended for adults aged ≥65 years.^[1]
• Solid organ transplant recipients aged 18–64 years on immunosuppressive medications may receive HD-IIV3 or aIIV3 as acceptable options.^[1]
• Baloxavir is now FDA-approved for post-exposure prophylaxis in patients aged ≥5 years.^[11]

• Whether HD-IIV, adjuvanted, or recombinant vaccine is superior for older adults remains unresolved; head-to-head data show no consistent superiority of one over another across seasons.^[5][7][12]
• Interim 2025–26 vaccine effectiveness estimates (22–41% depending on age group and outcome) are lower than in recent prior seasons, underscoring year-to-year variability tied to antigenic match.^[8]
• Optimal timing of vaccination in older adults is debated given concerns about waning immunity if given too early in the season.^[3]

• Egg allergy of any severity is not a contraindication to any influenza vaccine — this is a frequently missed update in practice.^[1]
• For adults aged ≥65 years, reach for HD-IIV, RIV, or aIIV first; if unavailable, give any age-appropriate vaccine rather than delaying.^[1]
• LAIV is not approved for children <2 years or adults >49 years.^[1]
• Baloxavir is FDA-approved for post-exposure prophylaxis in patients ≥5 years; oseltamivir and zanamivir are used off-label for this indication.^[11]
• Antiviral chemoprophylaxis window closes at 48 hours post-exposure — after this, favor close symptom monitoring plus early treatment-dose therapy if illness develops.^[9]
• Never use once-daily prophylactic antiviral dosing to treat a symptomatic patient — this constitutes under-dosing.^[9]

• Withholding LAIV or IIV from egg-allergic patients or requiring extended observation — no longer indicated.^[1]
• Using antiviral chemoprophylaxis broadly/indiscriminately, risking resistance and depleting supply needed for treatment of high-risk or severely ill patients.^[9]
• Giving LAIV to contraindicated groups (age <2 years, >49 years, pregnancy, immunosuppression).^[1]
• Delaying vaccination while awaiting “ideal timing” — vaccination should proceed as soon as vaccine is available and continue throughout the season.^[3]