Vaccine-associated enhanced disease (VAED)

Background

Vaccine-associated enhanced disease (VAED) is a rare phenomenon where a person who has been vaccinated experiences a (usually) more severe clinical presentation of an infection than would normally be seen in an unvaccinated person. The mechanisms for how VAED occurs are complex and not clearly understood. Mechanisms may include the behaviour of antibodies generated from vaccination and abnormal T-cell responses. With the exception of dengue vaccination, where use is restricted to minimise VAED risk (see below), vaccines that have been associated with VAED are no longer in use.

Diagnosis

It can be difficult to distinguish between breakthrough disease (when disease occurs in a vaccinated individual because of inadequate vaccine protection) and VAED. To identify a case of VAED, it is necessary to have a clear understanding of the clinical presentation and usual course of the natural disease. VAED is identified by comparison to the natural disease; the clinical presentation of VAED is atypical, modified or more severe. Factors to be considered when assessing a possible case of VAED include:

• expected background rates of disease
• age
• sex
• time of symptom onset after vaccination
• duration of disease
• clinical course and progression of disease
• any co-morbidities.

Various laboratory and clinical diagnostic parameters can be used to help assess the possibility of VAED, including detailed review of all cases of possible vaccine failure.

Associations

Vaccines that have been associated with the development of VAED include an inactivated respiratory syncytial virus (RSV) vaccine, an inactivated measles vaccine and a vaccine for dengue fever. (Note that the RSV and measles vaccines associated with VAED are not in use in Australia.)

VAED was observed in the 1960s during clinical trials for an inactivated whole-virus vaccine against RSV. In these trials, some children who had received the vaccine and then were later diagnosed with RSV infection developed more serious disease. As a result, this vaccine was never approved for general use.

People who received an inactivated measles vaccines in the 1960s were found to be more likely to develop an atypical form of measles disease if they were infected. This vaccine is no longer available, and the current measles-containing vaccines are not associated with the same adverse effects.

Dengvaxia, a live-attenuated recombinant dengue vaccine that is currently the only licensed dengue vaccine globally, has also been associated with VAED. If given to someone who has never had dengue infection, Dengvaxia can increase the risk of serious disease if the person is infected with dengue after vaccination. For this reason, Dengvaxia is only recommended in specific groups of people who have already had dengue infection, for prevention of subsequent, more serious secondary infection, within closely defined criteria.

Given the rare possibility of VAED, careful surveillance for potential VAED is an important part of both development of new vaccines, and post-licensure vaccine safety surveillance. 

Implications for future doses

All vaccines currently available through the National Immunisation Program (NIP) are not linked to VAED.
COVID-19 vaccines are not linked to VAED.

Dengvaxia is registered by the Therapeutics Goods Administration (TGA), but is not currently marketed in Australia.

Resources

• Brighton Collaboration Case Definition of the term “Vaccine Associated Enhanced Disease”
• Gartlan C, Tipton T, Salguero FJ, Sattentau Q, Gorringe A, Carroll MW. Vaccine-associated enhanced disease and pathogenic human coronaviruses. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.882972
• CHOP: Antibody-dependent enhancement (ADE) and vaccines
• 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;29(22):3053–3066. doi:10.1016/j.vaccine.2021.01.055 
• ATAGI: Clinical advice of the use of Dengvaxia for Australians
• Bigay J, Le Grand R, Martinon F, Maisonnasse P. Vaccine-associated enhanced disease in humans and animal models: Lessons and challenges for vaccine development. Front Microbiol. 2022;13. doi:10.3389/fmicb.2022.932408