Flu fallout: what went wrong in 2010, and should we have seen it coming?

Eighteen months ago, Dr Darryl Maher received news that changed his working life. He learnt that the seasonal influenza vaccine made by CSL Biotherapies had been linked to serious adverse reactions in children, such as high fevers and febrile seizures.

“It’s one of those things — I can remember exactly where I was. I was at a departmental off-site meeting with our previous medical director when she received a call. We were quite devastated by it. We were very concerned because it was so uncharacteristic, and they were quite serious events”, says Dr Maher, a haematologist by training and Medical and Research Director at CSL Biotherapies.

Dr Maher was not the only one upset by the increased adverse events. Families across the country were reeling, as their previously healthy children experienced fever, pain, vomiting and prolonged seizures after receiving the vaccine. Most of the adverse events had been reported in Western Australia, the only state to fund a vaccination program for children. Many children required hospital admission — in some cases, admission to an intensive care unit.1

The most severe confirmed case was an 11-month-old girl who spent 11 days in intensive care in Perth suffering a global brain injury and organ damage after receiving the influenza vaccine. After 8 weeks in hospital, she was discharged with permanent neurological damage.2 In Brisbane, a 2-year-old girl died within 24 hours of receiving the vaccine. However, the coroner was unable to confirm or rule out that the vaccine caused her death.2,3

On 23 April 2010, Australia’s Chief Medical Officer, Professor Jim Bishop, made the unprecedented decision to suspend the use of all seasonal influenza vaccines for children 5 years of age and under. At that time, three seasonal trivalent influenza vaccines were licensed for paediatric use in Australia — Fluvax (CSL Biotherapies), Influvac (Solvay Abbott) and Vaxigrip (Sanofi Pasteur).1

Investigations found that the rate of febrile seizures following receipt of the CSL vaccine was about 1 for every 100 doses administered in children aged 6 months to 4 years.4 This is high when compared with a usual paediatric febrile seizure rate following influenza vaccination of 0.16 per 1000 doses, according to data from the United States Centers for Disease Control.1 Later research estimated the rate of febrile convulsions after receipt of the CSL vaccine to be 3.3 per 1000 doses, or more than 200 times the only published population-based estimate.5

The Therapeutic Goods Administration (TGA) found that the brand of vaccine was known in two-thirds of the 99 confirmed cases of febrile convulsions that were determined to be causally linked to influenza vaccines among children under 5 years of age. In all these cases, the brand was Fluvax or Fluvax Junior, manufactured by CSL.1

On 27 July 2010, Professor Bishop announced that influenza vaccination for children under 5 years could resume only with Influvac and Vaxigrip.6

This year, CSL did not seek approval for the use of Fluvax in children under 5 years, and a warning in the product information (PI) states that it is not for use in this age group. The vaccine is licensed for use without restriction in children aged over 9 years, and in adults. It is only recommended for use in children aged between 5 and 9 years when no alternative vaccine is available.7

In general, for inclusion of vaccines on the Australian Register of Therapeutic Goods, data are required that support their quality, safety and efficacy, including clinical trials data. However, clinical trials are not required for seasonal influenza vaccines, because there is insufficient time between the selection of the seasonal influenza strains in October and the start of the vaccination program the following March.1 The strains included in the trivalent vaccine are selected every 6 months, depending on which viruses are circulating, in a process led by the World Health Organization.8

When there are no changes to the manufacturing process apart from the addition of a new strain, the TGA allows manufacturers to submit an application as a “strain change” rather than as a new product application. “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”, the TGA says.1

Influenza vaccines do have a lengthy history in Australia. CSL has been supplying inactivated influenza vaccine since 1968, and the licence for Fluvax was granted in 1992. However, Fluvax was licensed without the need for supporting data: it was “grandfathered” onto the register, like other therapeutic products available at the time. Annual clinical studies have been conduted in adults since the mid 1990s (TGA spokesperson, Department of Health and Ageing, Canberra, ACT, personal communication, Oct 2011).

The most recent Cochrane review on influenza vaccines in children, last updated in 2007, found that the vaccines were effective in children older than 2 years but said the lack of data in children under 2 years was “surprising”. “If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required”, the review concluded.9

Some experts are concerned about this lack of data. Professor Peter Collignon, Professor of Infectious Diseases at the Australian National University, says there has not been enough clinical research on influenza vaccines, particularly in paediatric populations. “For any drug or vaccine, you need prospectively collected data in large studies and that’s just not available for this vaccine. My strong view on this is that we need hard data.”

Despite the lack of baseline data, influenza vaccines had an overall history of safe use in Australia for decades without any substantial safety concerns. Although the National Immunisation Program does not provide nationwide free influenza vaccination for all children, WA has offered a funded influenza vaccination program for all children aged 6 months to under 5 years since 2008. As such, influenza vaccines, produced by CSL and other manufacturers, were used to vaccinate tens of thousands of Western Australian children in 2008 and 2009 without serious incident.5

Was there any way to predict the events that unfolded in 2010? After Fluvax was linked to the febrile seizures in 2010, CSL re-examined its clinical research and has acknowledged that, in retrospect, there were some warning signs.

“We’ve gone back and reanalysed all the clinical trials, including data that became available after the events in 2010, and they do show this tendency to fever in children”, says Dr Maher.

CSL conducted a trial of its 2009 influenza vaccine in almost 2000 Australian children. The unpublished results showed that 424 of the 703 children aged 6 months to less than 3 years (60%) experienced any systemic solicited adverse event, such as fever, headache or myalgia, within 7 days of administration of the vaccine. Fever was reported for 201 children (29%), grade 3 fever was reported for 13 (2%), and one child had a febrile convulsion.10 Professor Collignon says these rates seem high, particularly when compared with the risks of influenza itself. “By my calculations, if more than one child in 1000 has a febrile seizure, the vaccine is doing more harm than good.”

Another unpublished trial looked at almost 1500 children aged 6 months to less than 3 years who received a trivalent seasonal influenza vaccine during the 2009–2010 northern hemisphere winter. Among those allocated to receive a CSL vaccine, 37% experienced fever, compared with only 14% of those who received a US comparator vaccine.11 CSL did not receive the results of this trial until about a month after the adverse events came to light in 2010, but acknowledges their relevance.

Additionally, the rates of paediatric fever seem to vary from year to year. A published Australian trial of CSL trivalent influenza vaccine found that among 151 children aged 6 months to less than 3 years, 22.5% experienced fever after vaccination with the 2005 formulation. This proportion increased to 39.5% among 76 participants who subsequently received the 2006 formulation. Among 272 children aged between 3 and 9 years, the rate of fever increased from 15.6% in 2005 to 27.0% in 2006, including one child who had a febrile convulsion.12

Surprisingly, only the 2005 data from this study were included in the PI for the 2010 Fluvax.13 Professor Collignon says this is concerning, and the TGA should require that the PI includes the most recent data.

“It strikes me that the product information ought to reflect the latest data, particularly when the data show an increase in side effects compared with previous studies.”

Dr Maher says the data from the 2006 season were not included in the PI because the increase in fevers seen in 2006 was not deemed “clinically substantial” at the time. “The fevers did go up in total, but they were mostly mild or moderate; there wasn’t a significant increase in severe fever”, he says.

“But in retrospect, having had the events of last year and the results of the trial [comparing Fluvax with a US comparator], now when you look back on that data you think, well, maybe that was telling us something.” These results were not included in the 2011 Fluvax PI.14 However, Dr Maher says they will be added to next year’s PI.

Unusually, for the 2010 southern hemisphere influenza season, , all three of the influenza strains were changed. “It happens every 20–30 years that all three are changed in one go. That’s something that we thought was a telling point in trying to understand what may have contributed to [the excess adverse reactions].

“Perhaps the way we make the vaccine is more inclined to cause fever in children, and maybe last year’s strain combination then tipped them over the edge and led to severe fevers and febrile convulsions. That’s our current thinking”, Dr Maher says.

The 2010 seasonal influenza vaccine program was suspended almost 18 months ago, and there is still no definitive answer as to what caused the increased rate of adverse events. However, ongoing investigations by CSL and the TGA, in collaboration with the US Food and Drug Administration (FDA), the United Kingdom National Institute for Biological Standards and Control and other authorities, have identified a number of possible contributing factors (Box).

One factor that is still under investigation, according to the TGA and CSL, is the way the virus was split during the manufacturing process. “That is still an element of intense investigation”, Dr Maher says. Split-virion vaccines, such as Fluvax, use a detergent or solvent to “split” the virus and inactivate it.13

A recent MJA report stated that CSL is one of only a few manufacturers worldwide to use deoxycholate as a splitting agent. Deoxycholate use has been linked to previous clusters of adverse events, particularly in Canada in 2000–2001.15 “We hypothesise that suboptimal virus splitting or other mechanisms relating to the use of deoxycholate may have played a role in adverse events linked to the 2010 CSL trivalent influenza vaccine”, the MJA authors said.15

Dr Alan Hampson, a virologist with over 40 years’ experience working with the influenza virus, says when it became clear that the febrile convulsions were linked specifically to the CSL vaccine, his first thoughts were that it was somehow related to splitting conditions. “The splitting process is what detoxifies the vaccine for young children”, says Dr Hampson, who is chairman of the Influenza Specialist Group.

Dr Maher from CSL says his company used sodium taurodeoxycholate, a slightly different form of chemical from that used in Canada, and had been using the same splitting process for decades. “We have been doing it this way for a long time without a problem . . . nevertheless, it’s a hypothesis that has been included in our investigations over the past 18 months.”

The FDA also raised concerns about the splitting process in a warning letter to CSL in June this year. “You failed to determine the optimal splitting conditions for new virus strains before the strains are used in production”, the letter stated.16

The FDA letter raised several other concerns. For instance, it states that some batches of sodium taurodeoxycholate failed identification tests but were still used, and that CSL failed to investigate the potential impact of these failed tests. CSL said these particular batches were not those used in the vaccines that caused the adverse events in 2010; however, they were still accepted for use.

The FDA continues to work with the TGA to monitor CSL’s compliance on some of the issues raised in the letter.

In the aftermath of the 2010 influenza season, several experts and reports have called for improvements to Australia’s post-marketing surveillance system for adverse events following immunisation. Australia’s current system is based on state-by-state passive surveillance, which relies on voluntary reporting of adverse events.

A review prepared for the Department of Health and Ageing by Professor John Horvath outlined the multitude of avenues for reporting adverse events and the variation between the states.6 “Each jurisdiction has its own report form, and data collection differs across the states”, he wrote. Professor Horvath called for improved governance and more timely reporting of adverse events, but said the system had several strengths. It “was able to detect the safety signal associated with the use of the 2010 seasonal influenza vaccine, take appropriate action and undertake a rigorous investigation”, he wrote.6

In contrast, a review prepared for WA Health by Professor Bryant Stokes, published in August 2010, described “a serious deficiency” in current adverse-event reporting mechanisms. Professor Stokes described the system as “confusing”, “not timely” and “cumbersome”.3

Dr Paul Effler, Medical Coordinator, Prevention and Control Program at WA Health, says Australia needs to develop a nationally consistent system because “denominators matter”. “Typically, adverse events for vaccines are so low that if you have a tiny denominator you won’t pick up the signal as fast as you could have if you had a large population.”

In addition, he recommends the development of a prospective, active surveillance system. He says data from the Australian Childhood Immunisation Register (ACIR) — which collects information on all vaccinated children under 7 years of age — could be linked to medical records from some or all hospitals nationwide. For example, this system could detect if children were admitted to hospital for febrile seizures within a week or two of receiving a vaccine. “Australia is positioned to be the leader in vaccine safety with [the ACIR]”, he says.

The Horvath report highlighted problems with the way the “denominator data” — the number of vaccines administered — was collected by the ACIR in 2010, which made calculating adverse events rates difficult. Nevertheless, Professor Horvath agreed that the ACIR dataset could prove “very useful in signal investigations”.6

The review also called for greater transparency of TGA investigations, to improve access to vaccine safety data. In the US, for example, adverse events data that are reported passively are available online to the public in deidentified form. Dr Effler says he finds this amount of openness “refreshing”. “It also inspires confidence because people think, ‘well they’re not hiding anything’.”

Professor Collignon from the ANU also calls for the establishment of an active surveillance system and says it is particularly important for influenza vaccines. “The vaccine changes its formulation each year. And for people who say, ‘Oh well that doesn’t matter’ — look at the CSL vaccine problems. It shows that it does matter.”

“The trouble with a passive surveillance system is that it takes a long time to find a problem and it really underestimates the size of the problem”, he says.

He suggests that, for example, 50 to 100 general practitioners around Australia could be paid to collect data on the first 200 patients they vaccinate each season, through a system funded by a levy on vaccines. Patients and their families could keep a diary of any adverse events experienced within 7 days of receiving the vaccine. “You would suddenly have a lot of data, without really a huge expense”, he says.

Some changes to Australia’s adverse-event reporting system have been made since 2010. The TGA now reviews adverse events reports weekly (rather than monthly), and state and territory health departments are provided with a weekly summary of adverse events related to their jurisdiction. A working group has been established to move towards implementing the Horvath report’s recommendations.

“In addition, work has commenced on refining case definitions and standardised reporting between the TGA and state and territory health departments”, said a TGA spokeswoman.

This year, the TGA required that CSL conduct active surveillance of Fluvax among children, which is almost complete. As the vaccine was not licensed for use in children under 5 years of age, and was not recommended for use in children aged under 9 years, there were very little data in these age groups. However, CSL says that no safety signal has been detected among children aged between 9 and 18 years, or among adults.

In WA, a new website was launched before the start of this year’s influenza season, allowing health providers and the public to directly report adverse events online. Dr Effler says a very low rate of adverse events was recorded on the website in 2011. “We could reassure the public and providers that things were different this year.”

Perhaps the biggest legacy of the 2010 influenza season is diminished public confidence in vaccine safety. However, experts emphasise that the serious adverse events have been clearly linked to one manufacturer’s vaccine, only in children aged under 5 years, and that that vaccine is no longer indicated for use in this age group.

Dr Alan Hampson says the episode has “absolutely not” shaken his confidence in the importance of seasonal influenza vaccination. “We really shouldn’t be asking the question of whether the paediatric influenza vaccine program is valuable: that’s a given . . . to confuse the overall program with that one-off event is counterproductive.”

Dr Effler from WA Health believes that improving adverse events surveillance is one way of building public confidence in what is usually a very safe and effective program. “Advocating for robust adverse events surveillance, to me, doesn’t imply a lack of confidence in vaccines. Really, it’s the other way. We want adverse events surveillance because the vast majority of times it will show that there’s not a problem . . . it ultimately builds confidence in the vaccine programs”.

In the end, though, it is unlikely there will be much confidence in CSL Fluvax until there is a clear explanation of what went wrong. As Professor Collignon says, “If you don’t know what the problem is, how do you fix it?”

At this stage, CSL is not making any promises about when — or even if — the vaccine will be available to children aged under 5 years in the future: “At the end of the day, if there’s not a resolution, it wouldn’t be responsible for us to market the product for that age group”.