Seasonal flu vaccine: Overview of vaccine regulation and safety monitoring and investigation into adverse events following 2010 seasonal influenza vaccination in young children
Since Edward Jenner's creation of the world's first vaccine against smallpox more than 200 years ago, human beings have been benefiting from vaccination. Infectious diseases such as polio, rubella, measles, diphtheria, smallpox and pertussis, leading causes of childhood mortality at the turn of the 20th century, have been contained through the development and widespread administration of vaccines.
Beyond childhood vaccinations, the development of vaccines against communicable diseases such as hepatitis A and B, meningococcal, human papillomavirus and influenza has resulted in improvements in quality of life and longevity to greater numbers in the community. The benefits of disease containment reach beyond the individual to the community through the reduction of the spread of disease, with ensuing economic and social benefits.
Yet despite advances in vaccines and immunisation, seasonal influenza remains a considerable burden, both clinically and economically, through ill health and premature death. It has been estimated that influenza epidemic kills up to 500,000 people worldwide each year. In 2009 the total number of laboratory confirmed influenza cases in Australia was 44,221.1 Between 1997 and 2005 the average number of deaths in children aged 0-4 years due to influenza and pneumonia was 41. For all age groups, the average annual number of deaths due to influenza and pneumonia during this period was 2686.2 In addition, in the first quarter of 2010 the Australian Sentinel Practice Research Network reported an average of 89 influenza-like-illness notifications per week, or 1-9 cases per 1000 consultations a week for influenza-like-illness.3 In a recent Australian study of children hospitalised with influenza, more than 12% developed pneumonia, and over 7% required admission to intensive care. In Australian children aged less than five years, deaths from influenza have been reported at a rate of 0.2 per 100,000 children.4
1 Department of Health and Ageing. Communicable Diseases Intelligence Quarterly Report. December 2009, Vol 33 Number 4
2 Australian Institute of Health and Welfare (AIHW) 2007. GRIM (General Record of Incidence of Mortality) Books. AIHW: Canberra.
3 Department of Health and Ageing. Communicable Diseases Intelligence Quarterly Report. June 2010, Vol 34 Number 2.
4 Brotherton J, Wang H, Schaffer A, Quinn H, Menzies R, Hull B, et al. Vaccine preventable diseases and vaccination coverage in Australia, 2003 to 2005. Commun Dis Intell 2007; 31:Suppl-152.
National Immunisation Program
The National Immunisation Program (NIP) is a collaborative program between the Australian, and State and Territory governments to increase national immunisation rates. The program funds free vaccination for eligible Australians against vaccine-preventable diseases, administers the Australian Childhood Immunisation Register (ACIR), and communicates information to the general public and health professionals. The Office of Health Protection (OHP) within the Department of Health and Ageing (DoHA) is responsible for the development, implementation and evaluation of national immunisation policies and programs including Commonwealth funding of vaccines. The role of the Australian Government is to provide national leadership on the development and implementation of immunisation policy, fund the NIP vaccines, direct and support research into vaccine-preventable diseases and to make resources available for best practice in immunisation. Under the National Healthcare Agreement, the States and Territories are to maintain immunisation rates for vaccines in the national schedule. States and territories are responsible for managing the distribution of vaccines to public and private immunisation providers. States and territories also fund local education and communication activities, run immunisation programs through schools, and contribute to notification payments paid to providers for submitting data to the ACIR. The Australian Government provides funding for Medicare Australia for the ACIR and the General Practice Immunisation Incentives Scheme (GPII) and subsidises individual consultations which involve immunisation through the Medicare Benefits Schedule. The Victorian Cytology Service is also funded by the Australian Government for the administration of the National HPV Vaccination Program Register.
The National Immunisation Committee (NIC) is the peak group responsible for overseeing the development, implementation and delivery of the Immunise Australia Program. The NIC reports to the Australian Health Protection Committee through the Communicable Diseases Network Australia (CDNA).
The Australian Technical Advisory Group on Immunisation (ATAGI) provides advice to the Minister for Health and Ageing on the Immunise Australia Program, the medical administration of vaccines available in Australia, including those on the NIP, and other related issues.
The National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases (NCIRS) was established by the Commonwealth Department of Health in August 1997. NCIRS has partnerships with DoHA, the NSW Department of Health, and the Children's Hospital at Westmead. The Centre's primary function is to perform research aimed at reducing the incidence of vaccine preventable diseases and improving vaccine uptake in children and adults. NCIRS provides independent expert advice on all aspects of vaccine-preventable diseases as well as social and other issues related to immunisation.
The Immunise Australia Program implements the National Immunisation Program Schedule which currently includes vaccines against 16 diseases. The National Immunisation Program (NIP) has significantly reduced the incidence of Vaccine-Preventable Diseases (VPD) in Australia. VPDs prevented by vaccines in the NIP are notifiable through the National Notifiable Diseases Surveillance System (NNDSS).
VPDs will always remain a threat in Australia as natural disease cycles can result in regular resurgences, such as the recent pertussis outbreak; disease importations have the potential to start outbreaks in Australia, exemplified by the recent measles outbreaks; and many VPDs can cause a range of disease severity amongst the population, mild in most but severe in some, such as influenza. High vaccination coverage rates contribute to herd immunity - suppressing circulation of VPDs and protecting those at risk in our population, including those too young to be vaccinated.
Seasonal influenza vaccines are available through the NIP, to people who meet eligibility criteria, and the private market. Eligibility for free seasonal influenza vaccine is based on a person's health status, not their income / concessional status. During the 2010 influenza season, the following groups of high risk individuals are eligible to receive the free seasonal influenza vaccine:
- individuals 65 years of age and older;
- all Aboriginal and Torres Strait Islander people aged 15 years and older;
- individuals aged 6 months and older with conditions predisposing to severe influenza; and
- pregnant women.
The impact of an influenza season and its severity are difficult to measure due to the nature of the illness, and comparisons between seasons need to be interpreted with caution due to changes in testing practices and surveillance measures. Notifications since 2007 have been affected by heightened media attention due to several paediatric deaths in that year and differing diagnostic testing patterns compared to previous years. Notifications from 2008 and 2010 have been at similar levels to 2007, and substantially lower than during the pandemic season in 2009.
Regulation of vaccines
In Australia, vaccines and other prescription medicines are regulated by the Therapeutic Goods Administration (TGA) in accordance with the provisions of the Therapeutic Goods Act 1989 (the Act). It is a requirement of the Act that therapeutic products imported into, supplied in, or exported from Australia be included in the Australian Register of Therapeutic Goods (ARTG).
In order for a vaccine to be included in the ARTG, a sponsoring company is required to make an application which consists of data to support the quality, safety and efficacy of the product for its intended use, and which is then subject to rigorous evaluation by the TGA. TGA's data requirements are largely based on those applying in the European Union, supplemented by Australia-specific requirements where necessary. Extensive guidance is available to assist with the interpretation of the requirements, including documents relating specifically to the registration of vaccines.
The quality control aspects of an application cover the batch production processes to ensure that the medicine is produced to a consistent standard as defined by the product specification. This quality specification places controls on the purity and potency of the medicine as well as on other aspects necessary to ensure the efficacy of the product.
Recognising the important role of vaccines for public health, the pre-market quality review of vaccine submissions is supplemented by a batch release program operated by TGA in accordance with recommendations of the World Health Organization. Through this program, production and quality control data for each batch of a vaccine are assessed prior to it being supplied in Australia. The TGA also operates a batch testing program for the most widely used vaccines, including influenza vaccines, in which aspects such as the potency and sterility of the vaccine are checked.
The pre-clinical data supplied to TGA for assessment include studies designed to assess the toxicological profile of the medicine. These studies commonly include data on the safety of the product when tested in animals.
The third component of an application to include a vaccine, or other prescription medicine, in the ARTG is the submission of clinical data. This part of a submission consists of clinical trial data in humans. These data are used to support both the safety and efficacy of the product for the indications proposed by the product sponsor. The clinical data requirements vary with different products and different types of submission. In general, well-designed trials conducted in a sufficient number of subjects representing the target population and of a sufficient duration are usually required in order to demonstrate the efficacy and safety of the product for the proposed indication. The clinical evaluators assess the balance of benefits and risks based on the submitted clinical trial data and then recommend approval or rejection of the application based on that overall assessment. Each medicine and vaccine carries the risk of adverse effects in some people; the key issue in the regulatory decision is to determine that the overall balance of risks and benefits is positive in the population in whom the product is intended to be used.
As part of the evaluation process, the TGA delegate will refer an application or a new chemical entity (NCE) or major extension of indication to the Advisory Committee on Prescription Medicines (ACPM). The ACPM is a statutory committee whose members are appointed by the Minister. The Committee meets every two months and considers applications referred to it by TGA delegates, providing advice on a range of issues, but with particular emphasis on NCEs and extension of indications for already marketed prescription products.
Since April 2009, the TGA has required sponsors to submit a formal risk management plan (RMP) with each application for registration or extension of indication of a new medicine or vaccine. RMPs are intended to set out those activities and interventions that will be undertaken to identify, characterise and mitigate known or anticipated risks relating to a new medicine or vaccine, recognising that premarketing trials cannot prospectively identify all safety issues.
The decision-maker with respect to an application for marketing approval is a delegate of the Secretary of the Department of Health and Ageing, within the TGA. The delegate takes into account (but is not bound by) the views of the ACPM before making a decision to approve or reject a product. Approvals may be subject to conditions such as restrictions on the use of a product to certain patient groups, or compliance with an agreed RMP. The Product Information and the Consumer Medicines Information are made available on the TGA website to assist health professionals and consumers to better understand the benefits and risks of medicines.
Premarket assessment and authorisation of seasonal influenza vaccine
Seasonal influenza vaccines present particular challenges for registration processes because of the short time between the selection of the seasonal influenza virus strains and the beginning of the next influenza season. Australia proceeds with its annual influenza vaccination program without requiring a clinical trial of the vaccine to ensure timely vaccine availability and based on many years of safe effective use of the seasonal vaccine in several million people. Where there are no changes to the manufacturing process other than the virus strain, the application can be processed as a strain change rather than as an application for new product approval. This pragmatic approach is taken because the manufacturing process for the vaccine varies little from year to year, and there is lengthy experience with influenza vaccination.
In Europe, very small scale studies are conducted with the seasonal trivalent influenza vaccine to confirm immunogenicity (that the vaccine produces an immune response) and gross safety in 50 patients aged between 18 and 60 years, and 50 patients aged 60 years and over. While the results of these studies are available to the TGA, the small number of patients involved means they cannot identify common or rare adverse effects such as the febrile convulsions in young children seen in 2010. Post-market safety monitoring is therefore particularly important for identifying new signals for seasonal vaccines.
TGA's post-market monitoring of vaccines
As noted above, all medicines and vaccines confer a risk of adverse effects in some people. It is therefore extremely important to monitor the safety of vaccines in use in the community. The TGA is responsible for administering the post-market vaccine safety surveillance system as part of its overall function of monitoring the safety of medicines in Australia. Effective systems for the identification, reporting, and evaluation of adverse events following immunisation (AEFIs) are essential to ensuring public confidence in major vaccination programs. National monitoring of the safety of vaccines by the TGA is undertaken in accordance with protocols that include arrangements for the prompt and regular sharing of information between the TGA and state and territory health authorities. Effective monitoring is thus reliant on the cooperation of the states and territories.
The current mechanisms for reporting adverse events following immunisation have been endorsed on several occasions by states and territories, both within the National Immunisation Committee and through the Australian Technical Advisory Group on Immunisation (ATAGI), as recently as 2007. Not only is the TGA best placed to manage the national reporting of AEFIs, the TGA can meet its legislated responsibilities for ensuring the quality, safety and efficacy of vaccines it has registered only if it has confidence in coordinated and cooperative national monitoring and reporting.
The primary function of the AEFI monitoring system is to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of known ones.
Voluntary reporting of AEFIs
The core of the post-market monitoring system is a surveillance framework that relies in large part on voluntarily reporting of AEFIs by immunisation providers and consumers, with mandatory reporting by sponsors of all adverse events of which they become aware.
AEFI reports received from sponsors, vaccination providers and consumers received by the TGA will not necessarily be complete. The reports are promptly triaged as serious or non-serious based on internationally-accepted criteria, and then coded using standard terminology in accordance with the Medical Dictionary for Regulatory Activities (MedDRA), a document endorsed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
Reports received by the TGA are entered into the database within 48 hours of receipt - in most cases within 24 hours. Individual reports of serious AEFIs are reviewed by a medical officer, and medical officers at the TGA also undertake a weekly review of adverse event reports related to vaccines to assist in identifying clusters of reports or unusual reports.
TGA staff may request advice about AEFIs from the TGA's Advisory Committee on the Safety of Medicines (ACSOM), and as potential safety signals are identified, the TGA may also convene an ad-hoc expert advisory committee to augment its in-house and statutory committee expertise. This is an effective way of rapidly undertaking focused assessment of emerging safety signals.
Communication with states and territories
Although the TGA is responsible for administering the national vaccine safety monitoring system, the system involves a coordinated approach from the TGA and the states and territories. AEFIs are notifiable conditions in the ACT, NSW, NT, QLD, SA, VIC and WA and must therefore be reported directly to the relevant health authority. These state and territory health authorities then forward AEFI notifications to the TGA. In Tasmania, immunisation providers report directly to the TGA. The TGA triages and codes reports from state and territory health authorities in the same way as reports received from sponsors, healthcare providers and consumers.
All AEFI reports received by the TGA are forwarded to the relevant health department on a monthly basis. This arrangement ensures that each health department has access to all reports of AEFIs occurring in that jurisdiction irrespective of whether they were reported via the health department or directly to the TGA. In this way, each jurisdiction is at liberty to carry out any analysis it requires for its own purposes using the same dataset that is available to the TGA for that jurisdiction.
Several states in Australia have relatively recently implemented changes to their passive surveillance systems in order to capture a larger proportion of AEFIs, and respond more robustly to AEFI reports within their state. For example, the Victorian system SAEFVIC actively encourages parental reporting and provides flexible and multiple modality reporting. Since 1997, the South Australian government has also implemented an enhanced vaccine surveillance system and a strategy to actively promote and encourage AEFI notification to immunisation providers and members of the public. The National Immunisation Committee members have highlighted that measures such as better access to information for healthcare providers and the public about vaccine safety data and better risk/benefit communication strategies have led to improved satisfaction and improved reporting rates in their states.
AEFI reports received by the TGA are routinely passed in de-identified form to the National Centre for Immunisation Research & Surveillance (NCIRS) for various analyses, including the preparation of regular national AEFI surveillance reports, national immunisation program evaluations, reports to ATAGI, and ad-hoc analyses. Annual surveillance reports have been prepared by NCIRS in collaboration with the TGA and published in Communicable Diseases Intelligence since 2003.
Adverse events following 2010 seasonal influenza vaccination in young children
The investigation of a series of adverse events associated with the use of the 2010 seasonal influenza vaccine provides an example of the way in which the Australian vaccine program and its attendant monitoring framework operate effectively to respond to emerging safety issues, even when a vaccine is being utilised outside the nationally recommended guidelines.
Since 2008, Western Australia (WA) has funded a seasonal influenza vaccination program for all WA children aged 6 months to less than 5 years. WA Health suspended the 2010 program on 22 April 2010 following reports of an apparent increase in febrile reactions following vaccination during March-April over the number that would be expected from records for 2008 and 2009, despite a similar uptake of seasonal vaccine in 2009 and 2010.
On 23 April the Chief Medical Officer, Professor Bishop, suspended the use of seasonal influenza vaccine in children 5 years and under pending an investigation of the safety signal. At that time a joint working party of ATAGI and the TGA was established to consider the reports of febrile convulsion in children and to provide advice around the possible resumption of the program. The working party returned its findings in July 2010, with the result that the Chief Medical Officer recommended Fluvax Junior not be used in children under five years of age, and that the other seasonal influenza vaccines available in Australia (Vaxigrip and Influvac) be used instead.
To investigate the cause of this safety signal, the TGA has undertaken an extensive investigation including:
- working closely with ATAGI and NCIRS in undertaking epidemiological investigations;
- conducting a detailed case review of each report of febrile convulsion;
- reviewing paediatric clinical trial data for the monovalent pandemic H1N1 (PANVAX) vaccine;
- reviewing and analysing distribution data, clinical trial data, manufacturing process information and information about the experience of other countries using the various brands of the southern hemisphere 2010 trivalent influenza vaccine (TIV);
- auditing vaccine manufacturing facilities;
- undertaking extensive laboratory analyses, guided by a special expert panel chaired by Professor Peter Doherty, to assist in the interpretation of the results and to advise on methods for further testing.
A timeline of the investigation is at Attachment A. An interim report of this investigation was published on the TGA website on 2 July 2010. Public advisories issued by the TGA and the Department of Health and Ageing are listed at Attachment B.
The investigation focused on addressing the following key questions:
- Is there a real excess of fever/febrile convulsions attributable to 2010 Southern Hemisphere TIV?
- Is the apparent signal in WA also apparent in other states? If not, are there factors specific to the conduct of the immunisation program in WA that would account for different rates of Adverse Events Following Immunisation (AEFIs) in WA than in other states?
- Is the situation in 2010 different to previous years?
- If there is an excess of fever/febrile convulsions, is it attributable to a specific vaccine brand? If so, can any definitive conclusions be drawn about the relative safety of the other TIVs?
- Are there any clinical or other contributing factors that could contribute to an apparent excess of fever/febrile convulsions?
- Are there any vaccine quality or compositional issues that could account for the observed pattern of febrile reactions?
Summary of adverse events following immunisation (AEFIs) reported to TGA
There are currently four 2010 trivalent seasonal influenza vaccines approved for use in Australia, three of which have paediatric indications. They are FLUVAX/FLUVAX JR (sponsor CSL), INFLUVAC (Solvay/Abbott) and VAXIGRIP (Sanofi-Pasteur). [A fourth brand, INTANZA (Sanofi-Pasteur), is only approved for use in adults and is not included in the NIP.]
As at 4 June 2010 the TGA had received a total of 1,729 AEFI reports concerning 2010 TIV. The summary data are presented in Table 1, listed by vaccine type.
It is important to note that these data reflect all cases reported to the TGA as suspected reactions to influenza vaccination, prior to detailed case review.
Table 1: Summary of AEFI reports initially received by TGA to 04/06/2010
|Vaccine Type||Total||0-5 age group||Fever||Convulsion|
|Influenza vaccine not specified||257||194||182||26|
Table 2 presents the regional distribution of those AEFIs reported in relation to FLUVAX or FLUVAX JR, or where the vaccine type was not specified.
Table 2: Breakdown of AEFIs reported post FLUVAX/FLUVAX JR, or vaccine not specified
|S/T not known||48||35||29||7|
Each of the febrile convulsion case reports underwent careful review and case ascertainment within the TGA, using de-identified clinical data provided by states and territories.
On the basis of this detailed review, the TGA concluded that there were 100 confirmed cases of febrile convulsions in children under the age of 5 years across Australia, 58 of which were reported from WA. Of the 100 cases, 99 are considered causally related to vaccination with seasonal influenza vaccine and one case is considered unrelated because of the lack of a temporal association with vaccine administration.
Of the 99 cases considered causally related, 74 are considered very likely to be related to influenza vaccination because no other potential causative factors have been identified. The remaining 25 cases are only possibly causally related to the vaccine because they could also be explained by the concomitant administration of one or more other vaccines and/or a concurrent infection.
FLUVAX or FLUVAX JUNIOR was used in all 66 cases where the brand of the seasonal influenza vaccine was reported.
Of the 100 cases of febrile convulsion, 25 were directly observed by a medical or allied health practitioner. Of these 25 cases, 17 are considered very likely to be causally related to vaccination with the seasonal influenza vaccine and 8 are only possibly causally related to the vaccine because they can also be explained by the concomitant administration of other vaccines and/or concurrent infection.
In the remaining 75 cases the diagnosis of febrile convulsion was made by a health care professional on the basis of a history obtained after the event. Of these, 57 are considered very likely to be causally related to vaccination with the seasonal influenza vaccine, a further 17 are considered possibly causally related to the vaccine because they can also be explained by the use of concomitant vaccines and/or concurrent infection, and one was considered causally unrelated.
Detailed accounts of the process and outcomes of the case ascertainment and review undertaken by the TGA are at Attachments C and D.
A number of epidemiological analyses were undertaken by ATAGI in conjunction with NCIRS and also by individual jurisdictions. A summary of those analyses is presented here.
The data indicate that CSL's 2010 trivalent influenza vaccine (TIV) products FLUVAX and FLUVAX JUNIOR were associated with febrile reactions in the 4-24 hours following vaccine administration at higher rates than documented following seasonal TIV administration in previous years in Australia. This higher frequency of early fever responses was associated with substantially higher rates of TIV-associated febrile convulsions in children 6 months to less than 5 years of age, particularly in WA, where the highest numbers of children in this age group were vaccinated in 2010, but also in other states.
While there is no clear literature-based estimate for expected rates of influenza vaccine-attributable febrile convulsions, rates of febrile seizures in children 6 months to 3 years, identified by the US CDC Vaccine Safety Datalink (VSD) project over the period 2005-06 to 2009-10 were 0.16/1,000 in the 7 day period post TIV administration and 0.03/1,000 for day 0 (day of administration of vaccine).
While caution must be used in the interpretation of AEFI data in a stimulated reporting environment there is an apparent rate of febrile convulsions following TIV of approximately 7 per 1,000 doses in WA and approximately 5 per 1,000 doses in other jurisdictions, compared with 0.06 per 1,000 doses for PANVAX at the time of suspension of the program. Subsequent analysis of adverse events associated with PANVAX has shown the rate of febrile convulsions associated with this vaccine in Australia at between 0.08/1,000 and 0.17/1,000.
The clinical pattern of vaccine-associated and non-vaccine-associated febrile convulsions is similar, and in keeping with historical experience of febrile convulsions.
There are no apparent clinical or epidemiologic factors that would point to a plausible explanation for the observed rates of fever and febrile convulsion.
These conclusions have been drawn from the following epidemiological analyses summarised here:
- A vaccine-specific, uncontrolled cohort study from WA using denominator data directly obtained by surveying vaccinating GPs showed that in 2010:
- For children aged less than 3 years, the rate of febrile convulsions per 1,000 doses administered were approximately 7/1,000 for FLUVAX (adult) vaccine; 10/1,000 for FLUVAX JUNIOR; and 0 for INFLUVAC from 1,450 doses administered. Only 48 doses of VAXIGRIP were administered, with no febrile convulsions.
- For children aged 3-4 years, the rates of febrile convulsions were substantially lower at 1.5 (95% Confidence Interval 0.6 to 3.5) for FLUVAX adult, slightly higher at 14.0 (95% CI 5.5 to 35.5) on a smaller denominator for FLUVAX JUNIOR, while the rate was again zero (95% CI 0 to 2.1) for INFLUVAC in 1,800 doses given,
- Rates of febrile reactions in children under 3 years of age were approximately 50/1,000 for FLUVAX, 40/1,000 for FLUVAX JUNIOR, and 5 for INFLUVAC. Rates were substantially lower in 3-and 4-year-olds, but still 10 to 20-fold higher for FLUVAX or FLUVAX JUNIOR than for INFLUVAC.
- A controlled cohort study using denominator data inferred from 2009 Australian Childhood Immunisation Register (ACIR) records showed risk ratios for febrile convulsions in vaccinees vs non-vaccinees of approximately 5, both in children 6 months to < 3 years, and in those aged 3-4 years. By contrast, the estimated rates for 2009 were 0.3/1,000 and zero for vaccinees, and 0.6 and 0.1 for non-vaccinees, in those aged 6 months to < 3 years and 3-4 years, respectively.
- Rates of febrile convulsions in PANVAX and FLUVAX recipients in 2010 in Queensland children aged less than 5 years showed a risk ratio of approximately 7 for FLUVAX (based on approximately 80,000 doses of PANVAX and 18,000 doses of FLUVAX administered).
- Time series data from WA show a marked increase in febrile convulsion presentations to ED immediately following TIV vaccination commencement on 8 March 2010, no presentations on Sundays and over the Easter holiday period (when it would be expected that minimal vaccination would be undertaken) and a prompt return to pre-vaccination period levels following cessation of the WA vaccination program on 22 April 2010. Data for the same period in 2008 and 2009 do not show similar phenomena.
- A cohort study from three NSW hospitals using retrospective data obtained via parental report on children aged under 5 years who received FLUVAX, PANVAX or INFLUVAC found that fever was reported in 46% of children who received FLUVAX, 16% following PANVAX, and 7% following INFLUVAC. Parents were unaware of the brand of TIV that had been administered to their child. The risk ratios for fever following FLUVAX vs PANVAX and FLUVAX vs INFLUVAC were approximately 3 (CI 1.8 to 4.3) and 6.5 (CI 3.1 to 13.9) respectively.
No available clinical or epidemiologic factors offer a plausible explanation for the observed fever or febrile convulsion rates. WA data show that the presence of associated respiratory symptoms was less common (p<0.001) in post-vaccination febrile convulsion patients than in other febrile seizure patients. Viral studies were not undertaken in most of the febrile convulsion cases, and this together with the short time to onset of symptoms following vaccination (mean 7.2 hours; range 5.9 to 8.4 hours) suggests that concomitant infection is not a likely explanation for the majority of vaccine-associated febrile events. Approximately one in four vaccinees with a febrile convulsion had an underlying medical condition. The mean age of post-vaccination febrile seizure patients was the same as that in febrile seizure patients who had not been vaccinated (2 years). About 30% of post-vaccination febrile convulsion patients had received a TIV in the previous year.
An analysis of primary care presentations showed significant increases (rate ratios of 1.5-1.9) in numbers of visits day 1 post receipt of FLUVAX in 2010 compared with rates in 2008 or 2009 in both WA and other jurisdictions, with similar denominators in 2009 and 2010. Similar increases were not seen for PANVAX.
Additional analyses of paediatric clinical trial data
To explore whether the observed increase in reactogenicity was the result of the inclusion of a novel strain of H1N1 in the 2010 seasonal TIV, the TGA reviewed data from CSL's two clinical studies of trivalent seasonal influenza vaccines and two clinical studies of monovalent pH1N1 (2009) vaccine.
Additional analyses of the data from the trials were undertaken to determine the relationship, if any, between baseline serological status and febrile reactions, and between prior exposure to TIV and the occurrence of fever. In both Study 060 (Australia) and Study 062 (USA) there were numbers of subjects showing H1N1 seropositivity at baseline. In Study 060, 18% of subjects in Cohort A (6-35 months) had titres >1:10 at baseline and 6.7% had titres > 1:40 at baseline and in Cohort B ( 3-9 years) 45% had titres > 1:10 at baseline and 30% had titres > 1:40 at baseline. In Study 062 the proportions with baseline seropositivity were lower but still around 11% for titre > 1:10 in the younger age cohort and 18% for titre > 1:10 in the older age cohort.
These analyses showed that baseline seropositivity to H1N1 was associated with significantly lower likelihood of a febrile response to vaccination. Logistic regressions of the occurrence of fever following Dose 1 and following Dose 2 versus age group, dosage, and baseline seropositivity to pH1N1 found that baseline seropositivity was associated with a significantly reduced odds ratio of fever following Dose 1, (OR 0.24; CI 0.14 to 0.40), but not following Dose 2 (OR 0.89;CI 0.48 to 1.57). Frequency and intensity of fever also tended to be lower among those who had had previous influenza vaccination (OR 0.64; CI 0.52 to 0.79).
This suggests that rather than a "priming effect" arising through prior exposure to H1N1 (and/or prior TIV), children previously unexposed to TIV antigens or H1N1 (either wild virus or via vaccination) are at greater risk of a febrile response to TIV. This is consistent with the finding that only 30% of the cases of febrile convulsions reported in association with 2010 TIV had received a prior seasonal influenza vaccination.
TGA inspection of CSL manufacturing facilities
All manufacturing facilities of therapeutic goods are assessed for compliance with international standards of Good Manufacturing Practice (GMP). GMP audits are undertaken to ensure manufacturers have suitable facilities and equipment, quality systems and procedures, and trained personnel to consistently manufacture therapeutic goods to approved specifications of quality, safety and efficacy. The TGA audits CSL's vaccine manufacturing facilities annually.
As part of the investigation into the occurrence of febrile reactions following administration of 2010 seasonal TIV, an onsite audit of the CSL vaccine manufacturing facility at Parkville was conducted by TGA inspectors on 12-13 May 2010.
Initial discussions identified that CSL had made three changes to its manufacturing process since the 2009 seasonal influenza campaign to increase the virus yield in order to maximise production of the 2009 pandemic H1N1 vaccine. The onsite audit was undertaken to assess these changes and the overall effectiveness of the quality system to manage non-conforming product, process deviations and change control. Review of the validation data demonstrated that the changes had no impact on the quality of the vaccines produced.
At the time of the TGA audit, the TGA was aware that the US FDA's Centre for Biologics Evaluation and Research (CBER) had concerns regarding the facility's manufacture of multi-dose influenza vaccine vials supplied to the US. The TGA had contacted the US FDA regarding its inspection findings as soon as it became aware of the fact that an FDA audit team had visited the CSL facility to seek information that may have informed the investigation of adverse events in Australia.
As the US audit findings related only to multidose vaccine vials supplied in the United States, the TGA and FDA were able to jointly establish that the matters raised in the April 2010 FDA audit did not relate to the single dose influenza vaccine associated with febrile reactions in Australia, and thus were not directly relevant to the investigation of the cause of adverse reactions in Australia. The FDA audit found no evidence that the drugs manufactured at the Parkville site failed to meet their quality specifications and did not identify any safety issues associated with products currently available. The FDA has subsequently accepted CSL 's response in addressing the identified manufacturing deficiencies relating to the US supplied products.
The TGA undertook a further, more detailed annual audit of CSL's facilities on 18 and 21-23 June 2010. The audit team included microbiologists, chemists, biotechnology and vaccine specialists and a laboratory specialist involved in the TGA's vaccine testing program. The audit covered the full manufacture of influenza vaccines from seed lot to filling of vials and syringes and reviewed CSL's investigations and corrective actions arising from the US FDA inspection. The audit included detailed visual inspection, examination of batch records, review of manufacturing procedures, and a thorough inspection of test records. Equipment qualification, calibration and facility maintenance was reviewed, and process validations and other scientific studies were examined. The TGA conducted a detailed review of CSL's investigations into deviations, out-of-specification products and customer complaints, including its investigation of discolouration reported in multi-dose vaccine vials.
A number of inconsistencies with Good Manufacturing Practices were observed at the CSL audits. This is not uncommon during larger, longer and more complex inspections. The observations largely related to inadequate investigations and the physical inspection process for filled syringes and vials. The TGA completed a risk assessment at the conclusion of its most recent audit and was satisfied that the observations did not present an increased risk to the quality, safety or efficacy of CSL's vaccine products. CSL has provided the TGA with details of its corrective actions and the TGA is monitoring these actions, with an on-site follow-up audit planned for November 2010.
Based on findings from the two TGA audits and information from the US FDA audit, no manufacturing deficiency has been identified that is causally linked to the occurrence of a higher than expected rate of febrile reactions to influenza vaccination.
TGA laboratory testing of 2010 seasonal TIV
The TGA has undertaken extensive testing of both retention and field samples of influenza vaccines and this has been informed and guided by a special panel of experts chaired by Nobel laureate Professor Peter Doherty. The TGA is also working collaboratively with other regulatory agencies and laboratories in Australia and around the world, including Melbourne University and Monash Institute of Medical Research in Australia, the US Centers for Disease Control and Prevention (CDC) and the UK National Institute for Biological Standards and Control (NIBSC).
Generally, the virus in influenza vaccines marketed in Australia is inactivated, broken up and filtered so that the vaccine contains non-viable components of the virus and is predominantly 'split' i.e. without any significant numbers of whole virus particles. Pharmacopoeial monographs document the specifications and requirements the vaccine must meet in order to be considered safe, effective and of suitable quality.
Testing by the TGA found no abnormalities in pharmacopoeial parameters, such as the presence of endotoxins (bacterial chemicals that can cause fever) and potency in either retention or field samples, and additional testing has not shown any significant presence of whole virus particles, viable virus or contamination in the finished product.
The capacity of the vaccines to be pyrogenic (produce fever) is being extensively investigated. Preliminary analyses of results from pyrogenicity studies in ferrets suggest that there may be significant differences in changes to body temperature following inoculation with different vaccines. These studies are being conducted by the US CDC and are ongoing.
Cytokines are chemicals in the body that are signalling molecules used for communication between cells. Stimulation of the release of certain cytokines is associated with pyrogenicity; as a result the capacity of the different vaccines to induce particular cytokine responses is also being investigated. Results from studies at the laboratory bench suggest that there may be differences in the production of some cytokines between the different influenza vaccines. Further studies are now being conducted in animal models to try to characterise the nature and degree of cytokine responses to different influenza vaccines.
Viral proteins such as haemagglutinin and neuraminidase play a major role in the immunogenicity and possibly the pyrogenicity of the influenza vaccines. These proteins are found at varying levels in vaccine preparations. A vaccine manufactured by the same method by the same manufacturer will have a particular chromatographic protein profile that can be used as a signature for that particular vaccine product.
Protein analysis, using size exclusion HPLC techniques, has shown anticipated differences in characteristic protein profiles for the different vaccines. However, the profiles suggest that the content of one of the proteins in the 2010 seasonal influenza vaccine may be higher than in previous years.
Further studies, using mass spectrometry techniques, suggest that the neuraminidase content of the H1N1 component of this year's seasonal influenza vaccine is higher than in previous seasonal influenza vaccines. Reports from manufacturers also indicate that the enzyme activity of neuraminidase is higher in this year's vaccine compared to previous years. Studies into the content and activity of neuraminidase and its contributory role as a pyrogen are ongoing.
Current working hypothesis
The content of neuraminidase appears to be higher in the H1N1 strain used in the 2010 seasonal vaccine. Excess neuraminidase enzyme activity may be pyrogenic and may thus be contributing to the increase in febrile reactions in young children receiving the vaccine for the first time. While the different brands of seasonal influenza vaccines are utilising the same strains of virus, there are differences in manufacturing processes that may result in different levels of activity of the neuraminidase enzyme, which in turn may result in different cytokine responses and degrees of pyrogenicity.
Although the extensive analyses undertaken to date have generated this working hypothesis, further investigation is required to confirm that this is in fact the biological basis for the excess cases of fever and febrile convulsions seen during the 2010 influenza season.
A detailed report of the TGA's laboratory investigation is at Attachment E.
TGA regulatory actions to date
From its investigations to date the TGA has concluded that although there was an excess of fever and febrile convulsions in children 6 months to 5 years following vaccination with FLUVAX or FLUVAX Junior, the overall risk benefit balance of both products remains positive for most people for whom influenza vaccine is indicated, and both remain on the Australian Register of Therapeutic Goods.
However, despite extensive analyses the biological basis for the excess cases of fever and febrile convulsions remains unclear, and it is therefore important to effectively mitigate the risks by limiting exposure to those at greatest risk.
The TGA therefore considers it appropriate that the use of TIV be limited to those children under 5 in whom the risks of a possible febrile reaction or other AEFI are considered to be outweighed by the benefits of vaccination.
TGA's proposed actions regarding 2011 seasonal trivalent influenza vaccine
Consistent with the NIP recommendations, in 2011 the TGA will limit the approved use of FLUVAX in children under the age of 5 to those considered at high risk of complications of influenza, in whom the benefits of influenza vaccination are considered to outweigh the risks of an adverse reaction. In addition, the FLUVAX product will carry a boxed warning advising immunisation providers of the risks of febrile reactions in young children. The TGA is also currently in discussion with influenza vaccine providers regarding the development of an active surveillance program for influenza vaccination in children 9 and under.
The TGA will be working with consumers, healthcare providers and state and territory health authorities to raise the level of awareness of the existing mechanisms of reporting adverse events to the TGA.
It is an unfortunate fact that all medicines have the potential to cause side effects. In the case of the 2010 seasonal influenza vaccine an increase in the expected rate of febrile convulsions led to Commonwealth and State authorities launching a rapid and far reaching investigation that prevented further harm once the problem had been identified.
There are important lessons for vaccine programs arising from this investigation:
- There is a need to ensure prompt reporting of adverse events to the TGA to allow an effective and timely national response.
- There is a need for state authorities to have well-considered and specific monitoring programs in place well before embarking on any large scale trial vaccine programs.
- There is a need to ensure the public are provided with accurate, factual information to allow them to make informed decisions about the use of vaccines.
- There needs to be greater public awareness of the mechanisms to report adverse events, and of the effective mechanisms in place in Australia to respond rapidly to emerging safety signals with any medicine.
The investigation of the febrile convulsions associated with the use of the 2010 seasonal vaccine in children provides support for the effective vaccine monitoring framework that has been established by the Commonwealth in partnership with States and Territories. The TGA will be working with consumers, healthcare professionals and relevant government health authorities to ensure that the lessons learned from this event are utilised to prevent similar events in future.
- Attachment A: Timeline of the investigation into febrile reactions in young children following 2010 seasonal trivalent influenza vaccination
- Attachment B: TGA and DoHA public advisory statements about adverse events associated with 2010 seasonal trivalent influenza vaccine
- Attachment C: Analysis of reports from Western Australia of convulsion following administration of seasonal trivalent influenza vaccine 2010
- Attachment D: Analysis of Australia-wide reports of convulsion following administration of seasonal trivalent influenza vaccine 2010
- Attachment E: TGA influenza seasonal trivalent influenza vaccine laboratory investigation program