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Encephalitis caused by influenza vaccine — Clinical Guidelines

Overview

Influenza remains a significant public health concern despite the availability of licensed vaccines 3. Various influenza vaccine formulations, including high-dose, mRNA-based, and recombinant vaccines, are being developed and evaluated for improved efficacy and immunogenicity 2 3 9.

Diagnosis

Management

High-dose inactivated influenza vaccine (QIV-HD) has shown superior efficacy against laboratory-confirmed illness compared to standard-dose quadrivalent influenza vaccine (QIV-SD) in older adults 4.

QIV-HD demonstrated a relative vaccine effectiveness (rVE) of 43.6% against hospitalization for influenza compared to standard-dose vaccine in older adults 1.

QIV-HD reduced pneumonia and influenza (P&I) hospitalizations (rVE: 23.5%) and all-cause hospitalizations (rVE: 7.3%) compared to standard-dose influenza vaccine (SD-IV) in adults ≥65 years in randomized trials 10.

mRNA-based seasonal influenza vaccines encoding hemagglutinin (HA) and neuraminidase (NA) have shown promising immunogenicity and an acceptable safety profile in phase 1/2 trials 2.

Modified mRNA influenza vaccines have shown promising immunogenicity against influenza and an acceptable safety profile in phase 3 trials 3.

Special Populations

High-dose inactivated influenza vaccine has shown superior efficacy against laboratory-confirmed illness compared to standard-dose quadrivalent influenza vaccine (QIV-SD) in older adults 4.

High-dose inactivated influenza vaccine (QIV-HD) demonstrated a relative vaccine effectiveness (rVE) of 5.9% against hospitalization for influenza or pneumonia compared to standard-dose vaccine in older adults (≥65 years) 1.

QIV-HD reduced P&I hospitalizations (rVE: 23.5%) and all-cause hospitalizations (rVE: 7.3%) compared to SD-IV in adults ≥65 years in randomized trials 10.

Inactivated quadrivalent influenza vaccine (IIV4) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) demonstrated non-inferior immunogenicity and safety when administered simultaneously or separately in individuals aged ≥60 years with chronic diseases 7.

Obesity has been associated with altered inflammatory profiles that may influence vaccine responses, though specific associations with influenza vaccine immunogenicity require further evaluation 8.

Pregnant women are at high risk for severe influenza, and maternal influenza vaccination reduces morbidity and mortality in pregnancy and provides passive immunity to newborns 20.

Key Recommendations

High-dose inactivated influenza vaccine (QIV-HD) reduces the incidence of pneumonia and influenza (P&I) and all-cause hospitalizations compared to standard-dose influenza vaccine (SD-IV) in adults aged ≥65 years 10. (Evidence: Strong)

High-dose inactivated influenza vaccine (QIV-HD) demonstrated a relative vaccine effectiveness of 43.6% against hospitalization for influenza compared to standard-dose vaccine in older adults 1. (Evidence: Moderate)

mRNA-based seasonal influenza vaccines have shown promising immunogenicity and an acceptable safety profile in early-phase trials 2. (Evidence: Moderate)

References

1 Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS et al.. High-Dose Influenza Vaccine Effectiveness against Hospitalization in Older Adults. The New England journal of medicine 2025. link 2 Rudman Spergel AK, Lee IT, Koslovsky K, Schaefers K, Avanesov A, Logan DK et al.. Immunogenicity and safety of mRNA-based seasonal influenza vaccines encoding hemagglutinin and neuraminidase. Nature communications 2025. link 3 Fitz-Patrick D, McVinnie DS, Jackson LA, Crowther G, Geevarughese A, Cannon KD et al.. Efficacy, Immunogenicity, and Safety of Modified mRNA Influenza Vaccine. The New England journal of medicine 2025. link 4 Bonduelle O, Delory T, Franco-Moscardini I, Ghidi M, Bennacer S, Wokam M et al.. Boosting effect of high-dose influenza vaccination on innate immunity among elderly. JCI insight 2025. link 5 El Sahly HM, Anderson EJ, Jackson LA, Neuzil KM, Atmar RL, Bernstein DI et al.. Anti-neuraminidase and anti-hemagglutinin stalk responses to different influenza a(H7N9) vaccine regimens. Vaccine 2025. link 6 Yegorov S, Brewer A, Cyr L, Ward BJ, Pullenayegum E, Miller MS et al.. Hemagglutination-Inhibition Antibodies and Protection against Influenza Elicited by Inactivated and Live Attenuated Vaccines in Children. The Journal of infectious diseases 2025. link 7 Tang W, Lu X, Zhu Z, Yu D, Liu H, Song Y et al.. The immunogenicity and safety of an inactivated quadrivalent influenza vaccine and a 23-valent pneumococcal polysaccharide vaccine in individuals with chronic diseases. Frontiers in immunology 2025. link 8 Clarke M, McMillan M, Giles LC, Riley K, Andraweera P, Richmond PC et al.. The impact of obesity on influenza Vaccine immunogenicity: A systematic review. Vaccine 2025. link 9 Ferdinands JM, Blanton LH, Alyanak E, Chung JR, Trujillo L, Taliano J et al.. Protection against influenza hospitalizations from enhanced influenza vaccines among older adults: A systematic review and network meta-analysis. Journal of the American Geriatrics Society 2024. link 10 Skaarup KG, Lassen MCH, Modin D, Johansen ND, Loiacono MM, Harris RC et al.. The relative vaccine effectiveness of high-dose vs standard-dose influenza vaccines in preventing hospitalization and mortality: A meta-analysis of evidence from randomized trials. The Journal of infection 2024. link 11 Bliss CM, Nachbagauer R, Mariottini C, Cuevas F, Feser J, Naficy A et al.. A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein. EBioMedicine 2024. link 12 Zhong S, Ng TWY, Skowronski DM, Iuliano AD, Leung NHL, Perera RAPM et al.. Influenza A(H3N2) Antibody Responses to Standard-Dose Versus Enhanced Influenza Vaccine Immunogenicity in Older Adults and Prior Season's Vaccine Status. The Journal of infectious diseases 2024. link 13 Nauta J. Estimand for non-inferiority influenza vaccine immunogenicity trials. Vaccine 2024. link 14 Motaghi S, Pullenayegum E, Morgan RL, Loeb M. The role of influenza Hemagglutination-Inhibition antibody as a vaccine mediator in children. Vaccine 2024. link 15 Garai R, Jánosi Á, Krivácsy P, Herczeg V, Kói T, Nagy R et al.. Head-to-head comparison of influenza vaccines in children: a systematic review and meta-analysis. Journal of translational medicine 2024. link 16 Johansen ND, Modin D, Nealon J, Samson S, Salamand C, Loiacono MM et al.. A Pragmatic Randomized Feasibility Trial of Influenza Vaccines. NEJM evidence 2023. link 17 Chen C, Liu X, Yan D, Zhou Y, Ding C, Chen L et al.. Global influenza vaccination rates and factors associated with influenza vaccination. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2022. link 18 McMenamin ME, Bond HS, Sullivan SG, Cowling BJ. Estimation of Relative Vaccine Effectiveness in Influenza: A Systematic Review of Methodology. Epidemiology (Cambridge, Mass.) 2022. link 19 Veronese N, Demurtas J, Smith L, Michel JP, Barbagallo M, Bolzetta F et al.. Influenza vaccination reduces dementia risk: A systematic review and meta-analysis. Ageing research reviews 2022. link 20 Adeyanju GC, Engel E, Koch L, Ranzinger T, Shahid IBM, Head MG et al.. Determinants of influenza vaccine hesitancy among pregnant women in Europe: a systematic review. European journal of medical research 2021. link 21 Lee JKH, Lam GKL, Shin T, Samson SI, Greenberg DP, Chit A. Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: An updated systematic review and meta-analysis. Vaccine 2021. link 22 Kohli MA, Maschio M, Mould-Quevedo JF, Drummond M, Weinstein MC. The cost-effectiveness of an adjuvanted quadrivalent influenza vaccine in the United Kingdom. Human vaccines & immunotherapeutics 2021. link

Encephalitis caused by influenza vaccine