Adverse Events of Special Interest (AESI) and related risks: Vaccine-associated enhanced disease (VAED)


Vaccine-associated enhanced disease (VAED) falls within the immunological category of AESI. VAED occurs when an individual who has received a vaccine develops a more severe presentation of that disease when subsequently exposed to the virus, compared to when infection occurs without prior vaccination. This assumes that the vaccine recipient has not previously been exposed to the disease and is seronegative at the time of immunization. In particular, vaccine-associated enhanced respiratory disease (VAERD or simply ERD) refers to disease with predominant involvement of the lower respiratory tract, or as part of a systemic process.  

The case definition for VAED presents three levels of diagnostic certainty:  

  • Level 1 (definitive case): A definitive case of VAED cannot be ascertained with current knowledge of the mechanisms of pathogenesis of VAED.
  • Level 2 (probable): Ascertainment is based on confirmed infection, with known criteria of previous serological status (2A, highest level of certainty) or without previously known (2B, lower certainty) serostatus, clinical and epidemiologic criteria, and available histopathology.
  • Level 3 (possible): Ascertainment is based on confirmed or suspected infection, known (3A higher level of certainty) or unknown (3B lower level of certainty) serostatus, clinical and epidemiologic criteria, but no histopathology findings.

VAED risk factors:

Diseases and other factors: Severe disease has been documented resulting from infection in individuals primed with non-protective immune responses against the respective wild-type viruses. VAED typically presents with symptoms related to the target organ of the infection pathogen.  

Vaccines in general: VAED or VAERD may occur at any time after vaccination. The timing of occurrence of clinical manifestations of VAED or VAERD after vaccination will be dependent on the mechanism or pathophysiologic pathway leading to disease enhancement after natural infection. VAED or VAERD may present within 2–4 weeks of natural infection, if the expected initial antibody responses are inadequate; or may present at a later time (>1 month or longer) after natural infection if antibody waning is noted or if the mechanism is not exclusively antibody mediated. Classic examples of VAED are atypical measles and enhanced respiratory syncytial virus (RSV) occurring after administration of inactivated vaccine for these pathogens. No single or combination of specific confirmatory tests is available to diagnose VAED. As the clinical manifestations of VAED lies within the spectrum of natural disease – occurring more frequently and/or severely in vaccinated individuals – it is also difficult to separate vaccine failure (also called breakthrough disease) from VAED in vaccinated individuals. All cases of vaccine failure should be investigated for VAED. Vaccine failure is defined as the occurrence of the specific vaccine-preventable disease in a person who is appropriately and fully vaccinated, taking into consideration the incubation period and the normal delay for the protection to be acquired as a result of immunization.


Brighton Collaboration. Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data [Internet]. BC; 2020 [cited 29 Oct 2021]. Available at:

Munoz FM, Cramer JP, Dekker CL, et al. Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021;39(22): 3053–3066.

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