Review of the management of adverse events associated with Panvax and Fluvax
5.1 InfluenzaInfluenza is a contagious disease of the respiratory tract caused by influenza viruses which generally circulate in the winter in temperate countries, but year-round in tropical areas. The virus is constantly changing. Most people who get influenza have a self-limiting illness, lasting from a few days to several weeks, but for some people – the elderly, those with poor immune systems and those with certain pre-existing chronic diseases - influenza can be a significant disease, requiring hospitalisation and resulting in death. Serious disease and death can also occur in healthy adults and children. High rates of influenza resulting in hospitalisation occur in infants and young children. Vaccines are available to protect against seasonal influenza infection (see 5.8 Seasonal influenza vaccine).
5.2 Pandemic influenzaInfluenza pandemics occur when a new subtype of influenza virus, which most people have not previously been exposed to, emerges in humans. The virus spreads easily and rapidly in the highly susceptible population, infecting large numbers of people worldwide (Australian Government Department of Health and Ageing 2008). Some pandemics cause severe disease and many deaths but others are mild in the illness and death they cause. The severity of a pandemic can change over its course (WHO 2011).
Pandemics have occurred at irregular intervals throughout history. During the 20th century, the world experienced three pandemics - in 1918-19, 1957-58 and 1968-70. Pandemics have been of varying severity. The 1918-19 pandemic was extremely severe with at least 50 million deaths worldwide, with an unusually high number of deaths in young otherwise healthy people. The other two pandemics were less severe with 2 million and 1 million deaths respectively around the world.
The timing and severity of pandemics are unpredictable; even at the beginning of a pandemic it is not possible to predict its overall severity. Pandemics also have the potential to overwhelm national health systems and cause economic and societal disruption. A high level of preparedness is needed globally to enable rapid and flexible responses to reduce the impact of the pandemic.
5.3 Australia’s preparation for a pandemicAustralia has prepared for an influenza pandemic over the past decade, with the development of plans for both whole of government and health sector responses. For the 2009 H1N1 influenza pandemic (see 5.4 The 2009 H1N1 influenza pandemic), national guidance for the health sector response was provided by the Australian Health Management Plan for Pandemic Influenza 2008 (AHMPPI) (Department of Health and Ageing 2008). This document, which built on two previous iterations and the outcomes of Exercise Cumpston in 2006, was developed following extensive consultation with peak bodies, advisory groups and eminent experts in pandemic influenza. The AHMPPI was endorsed by all Australian Health Ministers in December 2008.
The purpose of Australia’s pandemic planning has been to ensure that we are ready to assess the situation, make decisions quickly and take action whenever a pandemic occurs. Without such planning, Australia would not have been able to act as quickly and effectively as it did in response to the 2009 H1N1 pandemic and the impact of the pandemic could have been a lot more serious.
Pandemic planning and preparation is ongoing. The AHMPPI was updated in December 2009 to reflect the lessons learnt from the response to the 2009 H1N1 pandemic. The updated AHMPPI was endorsed by the Australian Health Ministers’ Council (AHMC) in October 2010. This is an interim revision – a more comprehensive revision will be undertaken once a formal review of the health sector response to the 2009 H1N1 pandemic has been finalised.
A key objective of the AHMPPI is to reduce the transmission of the pandemic virus to decrease the number of people who become infected. The AHMPPI identifies the development and widespread use of a specific customised pandemic vaccine as the best method of protecting individuals against infection and the development of severe illness as well as reducing the spread of the virus in the community. Candidate pandemic (pre-pandemic) vaccines, based on viral strains thought to have pandemic potential, also have a role within the AHMPPI.
This is in keeping with World Health Organization (WHO) advice that influenza vaccines are “one of the most effective ways to protect people from contracting illness during influenza epidemics and pandemics” (WHO 2011).
Customised pandemic vaccines can only be developed once the new pandemic viral strain emerges. As production timelines for influenza vaccine using a standard egg-based method are several months long and global production capacity is limited, the AHMPPI recommends that arrangements be made early for future production and purchase of customised pandemic vaccine.
To ensure the government has priority access to pandemic influenza vaccine, the Australian Government has put Influenza Deeds of Agreement in place for the supply of seasonal, candidate pre-pandemic and customised pandemic influenza vaccines. The current Influenza Deeds of Agreement are with both CSL Limited and Sanofi Pasteur. They were initially signed in 2004 following an open tender procurement process conducted by the Department of Health and Ageing. Interim deeds are in place with CSL and Sanofi Pasteur in 2010 and a tender process is nearing completion for supply after 2011. The Office of Health Protection in the Department of Health and Ageing manages the Influenza Deeds.
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5.4 The 2009 H1N1 influenza pandemicThe 2009 H1N1 influenza pandemic was the first human influenza pandemic in 40 years and caused significant human infection and mortality globally.
The pandemic (H1N1) 2009 virus combines genetic components from swine, avian and human influenza virus strains. This genetic form was new and there was very little immunity in the largely naïve Australian population, although there was some evidence of cross protection against the virus in older Australians. The virus itself has proven to be more transmissible between humans than seasonal influenza and spread rapidly during the pandemic. Symptoms have been mild and generally short lived in most cases. In many cases, however, infection has had serious consequences. The groups most vulnerable to poor outcomes have included pregnant women, those with underlying medical conditions and Indigenous Australians.
As at 5 November 2010, a total of 44,403 confirmed cases of pandemic (H1N1) 2009 influenza had been recorded in Australia since the first case in May 2009. Of these, 37,636 cases were reported in 2009 and 6,767 cases were reported in 2010. A total of 213 pandemic influenza-associated deaths had been reported, 22 of which occurred in 2010. Thirteen percent (13%) of the 2009 confirmed cases were hospitalised and 14% of these required admission to an intensive care unit (ICU).
In Australia and around the globe, the highest attack rates were in school children and young people. As with seasonal influenza, there was also a high rate of hospitalisation among children under the age of 5 years in Australia.
Although the pandemic was moderate overall, it was severe in a significant number of people and we could not be complacent about its impact in Australia. There remained a risk that the virus could mutate to a more virulent form and there was also a need to guard against an anticipated second wave of infection. Vaccination remained a key strategy for protecting the population.
Based on expert advice on the number of people requiring vaccination to achieve the dual aims of protecting vulnerable individuals and preventing transmission of the pandemic virus, the Government purchased 21 million doses of Pandemic H1N1 Vaccine from CSL through its existing Deed of Agreement. This was sufficient to vaccinate half the population should two doses be needed to achieve immunity or the whole population should only one dose be needed.
5.5 Pandemic H1N1 Vaccine (Panvax®)The CSL Pandemic H1N1 Vaccine (Panvax®) was a purified, inactivated, monovalent (single strain), split virion (split virus) vaccine, manufactured by the same production method as the seasonal vaccine. The virus strain included in the vaccine was selected by the Australian Influenza Vaccine Committee (AIVC) based on the recommendation of the World Health Organization.
Clinical trials of the CSL adult and paediatric vaccine were undertaken to assess the safety and immunogenicity of the vaccine. Clinical trials are not normally conducted for changes in strains in seasonal influenza vaccine (see 3.2 Premarket assessment and authorisation of seasonal influenza vaccine). The pandemic (H1N1) 2009 virus, however, was a novel virus and clinical trials prior to registration were requested by the TGA. The trials commenced in July 2009 and first reported in September 2009, with children’s data available at the end of November 2009. The trials confirmed that the vaccine was immunogenic and well tolerated, with an adverse effect profile similar to that of seasonal influenza vaccines. A single dose was confirmed to be sufficient for immunity in adults and older children in September. Children under the age of 10 years achieved a good level of immunity after one dose but a second dose was recommended to ensure a sustained response.
The Therapeutic Goods Administration (TGA) approved the registration of Panvax H1N1 pandemic vaccine for use in adults and children 10 years and older on 18 September 2009 and in children aged 6 months to 9 years on 3 December 2009.
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5.6 The National Pandemic (H1N1) 2009 Vaccination ProgramThe national Pandemic (H1N1) 2009 Vaccination Program commenced in adults and children 10 years and over on 30 September 2009 and in children aged 6 months to less than 10 years on 4 December 2009. The vaccine remained available until the final batches reached their expiry date on 31 December 2010.
The program was delivered through general practice and other primary care immunisation services, hospitals, state run clinics and workplaces. In addition, some jurisdictions ran community based vaccination clinics, for example, at schools on several weekends in Queensland and at various public events (festivals) in Tasmania. By the end of the program, 9.4 million doses of Panvax had been distributed to immunisation providers. The number of doses administered is not known but, based on serosurvey and telephone survey results, it has been estimated that about 18% of the population of all ages and 21% of adults had been vaccinated by February 2010, noting that uptake continued until the end of December 2010.
5.7 Pharmacovigilence arrangements for the National Pandemic (H1N1) 2009 Vaccination ProgramAn intensive pharmacovigilence program, based on EMEA recommendations (2009), was implemented to monitor the pandemic vaccination program. TGA’s routine pharmacovigilance mechanisms and processes (see 3.0 The Australian Regulatory System for Drugs and Vaccines) were enhanced with the establishment of a dedicated call centre within TGA to receive telephone reports of adverse events through the Pandemic hotline. A simplified web reporting form was developed and made directly accessible from the TGA website homepage. Information materials about the vaccination program for health professionals and consumers encouraged the reporting of adverse events and provided information about how to make a report. TGA worked with international regulatory agencies to establish agreed case definitions and follow up tools for assessing cases of adverse events. The agreed case definitions and clinical follow up forms for adverse events of special interest (AESIs) were circulated to all jurisdictions. All AESIs, such as anaphylaxis, convulsions or Bell’s palsy, were followed up to determine the relationship between the event and the use of the vaccine. The Adverse Drugs Reaction Advisory Committee (ADRAC) undertook weekly review of the adverse events reports until the end of 2009. ADRAC was replaced by the Advisory Committee on the Safety of Medicines (ACSOM) in January 2010, after which TGA continued regular review of the AE reports and referred cases to ACSOM when further advice was needed. An expert pharmacoepidemiology panel was established to provide advice on methods of further evaluation for any safety signals.
Additional activities included:
- CSL undertook fortnightly signal detection and provided the TGA with monthly simplified Periodic Safety Update Reports (PSURs) outlining all serious adverse events associated with the vaccine reported to CSL in Australia and internationally.
- Where a report of exposure of pregnant woman to the vaccine was made, CSL followed up the case to pregnancy outcome and reported this to TGA.
- CSL established active surveillance for Guillain Barré Syndrome (GBS)
- TGA exchanged information about pandemic H1N1 vaccine pharmacovigilence activities with its international counterparts and established a mechanism for the rapid sharing of safety data.
5.8 Seasonal Influenza VaccineThe seasonal influenza vaccines currently available in Australia are inactived, split virion or subunit vaccines, produced using virus strains propagated in fertilised hens’ eggs. The process involves various steps, including purification, inactivation and disruption of the virus. There are some differences in the order in which these steps are carried out and in the chemical agents used for the different brands of the vaccine.
Seasonal influenza vaccines are trivalent ie they protect against three strains of influenza, two A strains (an H1 and an H3) and a B strain. As influenza viruses are continually subject to antigenic change, annual adaptation of the influenza vaccine composition is needed to ensure the vaccine provides protection against the virus strains likely to be circulating during the influenza season.
Information on the circulating strains and epidemiological trends is gathered by the WHO Global Influenza Surveillance Network (GISN), to which the WHO Collaborating Centre for Reference and Research on Influenza, based at the Victorian Infectious Diseases Reference Laboratory in Melbourne, is an important contributor. Twice a year the WHO organises a consultation with representatives from the Network to review the results of their laboratory and clinical studies and make recommendations on the composition of the influenza vaccine (February: northern hemisphere; September: southern hemisphere).
The strain composition of influenza vaccines for use in Australia is determined each year by the TGA’s Australian Influenza Vaccine Committee (AIVC) based on the information and recommendations provided by the WHO. The AIVC decision is published on the TGA website.
In some years there are no changes in strain composition, with the same strains being used in two consecutive years. Other years can involve changes in one, two or all three strains. In the 2010 vaccine, all three strains changed, with the seasonal A(H1N1) strain being replaced with the pandemic (H1N1) 2009 strain, the H3N2 component being replaced with the Perth 16 strain and the B/Florida/4 (Yamagatta lineage) virus being replaced with the B/Brisbane/60 (Victoria lineage) virus. The same strains were recommended and used in the 2010/11 Northern Hemisphere vaccine. The pandemic (H1N1) 2009 strain change was managed as a normal seasonal influenza vaccine strain change (see 3.2 Premarket assessment and authorisation of seasonal influenza vaccine) and it is now considered to be a seasonal influenza virus.
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5.9 Seasonal influenza vaccination in AustraliaThe Australian Immunisation Handbook (AIH) (NHMRC 2008) strongly recommends annual seasonal influenza vaccination for any person ≥6 months of age who is at increased risk of severe influenza or complications from influenza or who is likely to transmit the infection to those at increased risk. It also recommends annual influenza vaccination for any person ≥6 months of age who wishes to reduce the likelihood of becoming ill with influenza.
Seasonal influenza vaccines are available free through the National Immunisation Program (NIP) for people who meet eligibility criteria. In 2010, eligibility for NIP funded influenza vaccine was broadened to cover individuals at high risk of complications from influenza, including: those aged 65 years and older; 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.
Seasonal influenza vaccines are also available on the private market and some employers offer subsidised influenza vaccination to their staff. States and Territories provide health care worker vaccination programs and, since 2008, WA has been providing a seasonal influenza vaccination program for all children aged 6 months to less than 5 years.
Approximately 6.3 million doses of seasonal influenza vaccine were distributed in Australia in 2010, of which 3.9 million doses were NIP funded vaccines.
5.10 Febrile reactions and convulsions following immunisationFebrile convulsions are relatively common in young children, with approximately 3% of children having at least one between the ages of 6 months and 6 years. Although distressing to parents and other family members, they generally have an excellent prognosis. Febrile convulsions occur most commonly with high or rapidly rising fevers caused by typical childhood infections but can be associated with any condition that results in fever.
Influenza infection can cause high fevers and febrile convulsions. Children with severe influenza are at particular risk with up to 1 in 5 children hospitalised for influenza having a febrile convulsion in Hong Kong based studies (Chiu et al 2001; Chung and Wong 2007).
Fever is common following immunisation, especially in young children. In most cases the fever is mild but high fevers can occur. Febrile convulsion is a rare but recognised adverse event following immunisation with a number of vaccines, including measles-mumps-rubella (MMR), diphtheria-tetanus-whole cell pertussis (DTPw) and, more recently, measles-mumps-rubella-varicella (MMRV) as well as influenza vaccines (Barlow et al 2001; CDC ACIP 2008).
A Joint ATAGI/TGA Working Group found no clear literature-based estimate for expected rates of influenza vaccine- attributable febrile convulsions. They noted that the US CDC VSD project data over the period 2005-06 to 2009-10 indicated a rate of febrile seizures following trivalent seasonal influenza vaccine in children 6 months to 3 years of 0.03 per 1,000 doses on the day of administration and 0.16 per 1,000 doses in the 1-7 days post-vaccination. They also noted that febrile convulsions had been reported in influenza vaccine post marketing data at a rate between 0.1 in 1,000 and 1 in 1,000 persons vaccinated (TGA 28 September 2010; TGA 8 October 2010).