| dc.description.abstract | Background
An adverse event following immunisation is any untoward medical occurrence that follows
immunisation and does not necessarily have a causal relationship with the usage of the vaccine.
Seizures, ranging from the common and mostly benign febrile seizure to the life-threatening status
epilepticus, that occur following immunisation are considered adverse events following immunisation.
Febrile seizures have been observed to occur in defined periods following vaccination when a fever is
most likely to occur. The magnitude of risk attributed to specific vaccines varies, with no known
increased risk seen for some vaccines. Status epilepticus, continuous seizure activity for 5 minutes or
more without return of consciousness, or recurrent seizure activity without a return to baseline
consciousness in between, has also been reported following vaccination, though the magnitude of
attributable risk is unclear. Both seizure types are rare, but serious adverse events, that can follow
and sometimes be triggered by immunisation. Because of the potential risk of neurodevelopmental
sequalae, seizures can affect both provider and consumer confidence in vaccine safety and therefore
immunisation coverage.
Knowledge gaps on seizures following vaccination include their clinical severity, developmental
outcomes, genetic risks and revaccination outcomes. In my thesis, I aimed to address these gaps to
better inform immunisation providers about the risks and outcomes of these potentially serious
adverse events following immunisation, to improve guidance on their assessment and management,
and ultimately to improve parent and consumer confidence in vaccine safety.
Febrile seizures following vaccination
In this thesis, I set out to assess the clinical severity, neurodevelopmental outcome and genetic risk of
febrile seizures following vaccination, to supplement the known attributable risk of febrile seizures
following specific vaccines. Vaccine proximate seizures were defined as VPS was defined as a
seizure within 14 days of a vaccination encounter, based on previous studies on the timing of fever
and febrile seizures following specific vaccines. I examined the clinical severity of vaccine-proximate febrile seizures through a multi-site prospective cohort study. I discovered that febrile seizures most
commonly occurred following the first dose of measles-containing vaccine, and were not clinically any
different to febrile seizures due to another cause such as a viral illness. The only factor that prolonged
hospitalisation in children with a vaccine-proximate febrile seizure was the presence of concomitant
laboratory-confirmed infection. A subsequent prospective case-control study was conducted to assess
developmental and behavioural outcomes, and to identify the presence of genetic variants in children
with vaccine-proximate febrile seizures compared to children with non-vaccine-proximate febrile
seizures and no history of seizures. Using standardised developmental tests administered by certified
assessors blinded to the child’s medical history and standardised parent-completed questionnaires,
this study found no increased risk of developmental or behavioural problems in children with vaccineproximate
febrile seizures compared to children with non-vaccine-proximate seizures or no history of
seizures. Genetic variants in the sodium channel gene, SCN1A, associated with a severe form of
epilepsy were only identified in children with prolonged vaccine-proximate febrile seizures.
Status epilepticus following vaccination
Prior to this thesis, there were only case reports and case series on vaccine-proximate status
epilepticus, presenting an incomplete and potentially biased picture of the risk and severity of vaccineproximate
status epilepticus that may not be generalisable to the whole population. Using a
retrospective, population-based, record-linked cohort linking birth, immunisation, hospitalisation and
death data, I was able to determine that less than 4% of first episode status epilepticus in children
was vaccine proximate. Similar to vaccine-proximate febrile seizures, status epilepticus was found to
occur most commonly following the first dose of measles-containing vaccine, but at a rate 35 times
lower than that of vaccine-proximate febrile seizure for the same risk window. There was no difference
in clinical severity, measured by duration of hospitalisation, intensive care unit admission or death,
between vaccine-proximate and non-vaccine-proximate status epilepticus cases. The predictor for
ongoing seizures subsequent to the first status epilepticus was seizure onset prior to the status
epilepticus episode. Importantly, vaccination uptake decreased following status epilepticus,
regardless of the proximity of the status epilepticus episode to vaccination. These findings were
confirmed in a second retrospective cohort study I conducted using medical record review to validate
the findings from the larger population-based retrospective study that relied on hospital administrative data. The retrospective cohort study also found morbidity following vaccine-proximate status
epilepticus was associated with the presence of an underlying genetic epilepsy, where the seizures
are the result of a known or presumed genetic defect.
Revaccination outcomes following vaccine-proximate seizures
Following the identification of the risk and outcome of seizures following vaccination, the next logical
clinical question to address was can these children safely proceed with subsequent vaccinations and,
if so, how? I, therefore, examined the risk of seizure recurrence following revaccination in children
with a previous vaccine-proximate seizure. Through a 5-year multi-site retrospective cohort study, I
reviewed the clinical management and outcomes of children with a history of vaccine-proximate
seizures who presented to a Specialist Immunisation Clinic, a specialist clinic at tertiary paediatric
hospitals where children with a vaccine proximate seizure are provided specialised medical
assessment and management for subsequent vaccinations. Vaccine-proximate seizure recurrence
was found to be more likely in children with an underlying genetic epilepsy, in particular Dravet
syndrome. Reassuringly, the risk of seizure recurrence decreased with the use of prophylactic
benzodiazepine with vaccination in these children.
Conclusions
Vaccination is one of the most effective public health measures for reducing the burden of infectious
diseases. However, the success of vaccination programs has been threatened by vaccine hesitancy,
that is, the reluctance or refusal to vaccinate despite vaccine availability. Concerns regarding the
safety of vaccines and their potential long-term neurological sequalae are amongst the complex
reasons why people choose not to vaccinate.
My doctoral research has contributed to vaccine safety knowledge globally, specifically in the
understanding of seizures, specifically febrile seizures and status epilepticus, as severe acute
neurological events following vaccination. In this thesis, I not only identified the children most at risk of
neurological sequelae following a vaccine-proximate seizure, but also a revaccination management
plan that would allow these children to continue vaccinations without placing them at risk of further vaccine-proximate seizures. These are children aged <12 months, whose underlying genetic epileptic
encephalopathy is unmasked by a vaccination event. These children typically present with status
epilepticus following vaccination, and are most likely to have further seizures with revaccination if it is
given without additional precautions in the form of prophylactic benzodiazepine. My thesis finding
highlights the importance of, and future work required to better understand, adversomics – the
immunogenetics and immunogenomics of vaccine adverse events at the individual and population
level, respectively – and its implications on vaccine safety, confidence and uptake.
Finally, my thesis incorporates a variety of research methods, from retrospective record-linked cohort
studies to examine whole-of-population risk, retrospective multi-site clinic-based cohort studies to
examine detailed clinical management and outcomes, and prospective case-control studies to test
hypotheses. I have demonstrated the unique contribution of each of these research methods and the
strength in combining these to form a broader pharmacovigilance program of research that can help
inform both risk and outcome at a population and individual level. By applying the doctoral research
skills I have acquired, I aim to continue my work as a vaccine safety clinician researcher in the
monitoring and investigation of vaccine safety signals for novel vaccines, including the multiple
COVID-19 vaccines currently in early use globally, to ensure the continued safe and effective use of
vaccines in the years to come. | en_AU |
