Summary of investigations into the paediatric adverse events associated with Fluvax® vaccine in 2010
Melbourne, Australia — 20/06/2012
CSL has undertaken an extensive and systematic investigation over a two year period to determine the cause of the unexpected febrile reactions in children following vaccination with Fluvax® in 2010. The investigation comprised three distinct but interlinking components:
|1. ||Clinical safety investigations to characterise the safety concern, identify risk factors and at-risk populations. |
|2.||Manufacturing and Quality investigations, reviewing all aspects of the manufacturing process from raw material through to finished product. |
|3.||Scientific investigations to identify the molecular mechanism and review the feasibility for predictive tests to assist in future vaccine production.|
SH = Southern Hemisphere
NH = Northern Hemisphere
Fluvax® is marketed in the Northern Hemisphere as Afluria® (US and Germany) and Enzira® (UK)
Read More about the investigationsClinical Safety Investigation including key findings >>Manufacturing Investigation including key findings >>Scientific Investigation including key findings >>Ongoing Studies including key findings >>
Clinical Safety Investigation
The Clinical Safety Investigation comprised reviews and analyses of:
- All cases from the CSL worldwide safety database adverse events reports, including by batch
- Safety data from all studies using CSL’s seasonal and pandemic influenza vaccines
- Cumulative adverse event reports from the 2010 SH season and 2010/11 NH season
- Published literature and epidemiology data pertaining to febrile convulsions in children
- Historical data relating to the quality, production and use of CSL’s influenza vaccine
- Observational studies following administration of CSL’s seasonal influenza vaccine in the SH 2011
- Cumulative adverse events reports, including by batch number, every 3 months from NH 2010/11
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- The safety issue of febrile convulsions was identified specifically in children aged less than 5 years.
- There were increased reports of febrile reactions (predominantly fever) in the 5 to less than 9 year age group, but the overall number of reports was substantially lower than in the younger age group.
- Safety concerns were not identified in individuals aged 9 years and over.
- Fluvax® vaccine had not been previously linked to a significant risk of febrile convulsion.
- Data that emerged after the events of 2010 showed that Fluvax® vaccine is associated with a higher rate of fever in young children than another marketed vaccine, but that these data were not predictive of the febrile convulsion signal in 2010.
The Manufacturing Investigation comprised a thorough review of every step of the CSL manufacturing process, including all raw material and utility inputs, comparing 2009 and 2010 SH seasons:
|Solution Preparation ||Formulation|
|Equipment preparation and sterilisation||Dispensing and packing|
|Hen’s eggs||Quality Control testing|
|Influenza virus seeds||Environmental monitoring|
|MPH step 1: pre-treatment||Process services|
|MPH step 2: Egg inoculation||Facility, equipment, process validation|
|MPH step 3: Incubation, candling, chilling||Preventative maintenance & calibration|
|MPH step 4: Harvest of Allantoic Fluid ||Operations |
|MPH step 5: Allanotic Fluid Filtration||Aseptic qualification|
|MPH step 6: Zonal centrifugation||Cold chain|
|MPH step 7: Viral inactivation||Stability|
|MPH step 8: Splitting and sterile filtration ||Raw materials|
|MPH step 9: Concentration and diafiltration ||Product contact consumables|
The Manufacturing Investigation also included an extensive Quality review of:
- All in-process tests, batch records, deviations, release tests and specifications for the 2010 formulation of Fluvax®
- Comparison of stability data for the 2009 and 2010 SH formulations of Fluvax®
- Comparison of quality characteristics for the 2008, 2009 and 2010 SH formulations of Fluvax®
- Comparison of change controls for the formulation of CSL’s 2010 SH and 2009/2010 NH influenza vaccines and the 2009 pandemic vaccine
- Qualification status and performance of suppliers and materials used in the manufacture of the 2010 formulation of Fluvax®.
- Animal and laboratory pyrogencity testing for CSL’s 2009 SH, 2009/10 NH and 2010 SH influenza vaccines
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- Animal studies and laboratory testing ruled out chemical and bacterial contamination
- All batches of Fluvax® in 2010 were released to specification and there was no evidence of batch-specific issues
- There was no change in the amount of sodium taurodeoxycholate (TDOC) used to split each virus strain between the 2009 and 2010 formulations of Fluvax®
- The results from the test used to measure the degree of virus splitting for the 2009 and 2010 formulations of Fluvax® were comparable.
- There were no process changes, manufacturing deviations or raw material issues identified that could explain higher rates of febrile reactions associated with Fluvax® in 2010.
- The most significant change identified in CSL’s manufacturing process was the replacement of all three virus strains in the 2009 SH vaccine formulation with new strains for 2010 SH.
- As no other manufacturer’s influenza vaccine was associated with increased rates of febrile reactions in 2010, the possible contribution of CSL’s method of manufacture together with the strain changes became the primary focus of the scientific investigations
The scientific investigations compared Fluvax®
2010 to the following influenza vaccines:
- Previous season’s influenza vaccines made by CSL
- 2010 and previous season’s influenza vaccines made by other manufacturers.
- Bulk lots of the individual strains used in Fluvax® 2010.
- A new engineered version of Fluvax® 2010 (first with a new A strain, then with a new B strain)
Comparisons were also undertaken after these influenza vaccines had been treated with heat and chemicals.
The parameters compared in these scientific studies were:
- Fever response
- Genetic signatures
- Stimulation of specific immune-response hormones (cytokines)
The experimental systems developed and used to undertake the scientific comparisons were:
- Animal models, including rats, ferrets, rabbits and non-human primates
- Human blood assays (tests) using blood samples from adults and children
- A novel cell culture assay (test) from a cell line expressing a master immune-response regulator protein
In animal models and in vitro systems:
- CSL’s influenza vaccines, as a class, trigger a greater immune gene response and induce higher levels of immune-stimulating hormones (cytokines) compared to other manufacturer’s influenza vaccines
- Fluvax® 2010 induces higher levels of immune-stimulating hormones (cytokines) compared to previous season’s formulations of CSL’s influenza vaccine
- The B strain followed by the H1N1 strain used in Fluvax® 2010 induces the strongest activity in the paediatric blood samples.
CSL’s method of manufacture preserves more short gene fragments and lipids from the virus than other manufacturers.
The particular characteristics of the gene fragments and/or lipids from the swine flu strain and the B strain used in Fluvax® 2010 may have led it to being more reactive in some young children in 2010 compared to CSL’s vaccines in previous seasons.
The gene fragments and lipids appear to be from split virus, but residual whole virus or clusters of both may have also contributed, and are under further investigation.
Increasing the amount of splitting agent (TDOC) reduces the amount of short gene fragments and lipids in the CSL vaccine, and also reduces the reactivity of the CSL vaccine (in vitro).
The scientific studies indicate that the root cause of the severe febrile response seen in some young children after vaccination with Fluvax® in 2010 is complex and multi-factorial.Back to Top
CSL is undertaking further studies to confirm its preliminary conclusion and to investigate potential process changes that will control the reactive characteristics of the CSL influenza vaccine in children.
- CSL has commenced studies to confirm the role of gene fragments and lipids from the virus, and to directly assess the role of split virus complexes, residual whole virus and clusters of both
- CSL has also commenced further laboratory studies to determine the potential effects that manufacturing process variations may have on the reactivity of the CSL vaccine in children.
- These studies mainly focus on the conditions associated with the virus disruption (splitting) process ahead of formulating it.
Until this further work is completed, and because the risk-benefit profile of Fluvax® remains in positive in children aged 9 years and above, CSL is not making any immediate changes to its manufacturing process.Back to Top
CSL will continue to fully support the restricted use of Fluvax® in children until it can generate strong evidence to show that manufacturing changes can consistently produce a safe and effective influenza vaccine for children while also retaining the current safety profile and protective benefits of Fluvax® in adults and the elderly.