CSL’s flu vaccine leaves a hole in Australia’s pandemic plan

Not being able to give children the locally-manufactured vaccine leaves a hole in our pandemic preparations. Julian Smith/AAP

Facts about Flu - We often hear of an expected pandemic and had a scare in 2009 with the swine flu, but how well are we prepared?

Although no longer considered an immediate risk, the recent outbreak of bird flu (H7N9) in China means pandemic planning is back on national agendas. A cornerstone of these plans is the early availability of vaccines - and Australia may have a problem.

Depending on when it becomes available, a pandemic vaccine should be targeted at those most at risk of a severe outcome from infection or at those who amplify its spread.

For both the seasonal and pandemic flu, the main spreaders are children. So a pandemic vaccine should be safe to give to children. Indeed, children, especially the very young, are one of the groups most at risk of severe outcomes.

During the 2009 flu pandemic, Australia relied on local manufacturer CSL to produce a vaccine. After China, Australia was the second country in the world to have a pandemic vaccine available. It was given to both adults and children.

But CSL’s influenza vaccines are no longer recommended for children younger than five years and doubt exists about their safe use in children up to ten years old.

The change in recommendation by Australia’s National Health and Medical Research Council followed events in 2010, which had their genesis three years earlier.

Questions about safety

In 2007, a number of children in Western Australia died of influenza-related causes. So, the state government started a campaign to provide free flu vaccines to children under the age of five.

CSL and other vaccine manufacturers provided vaccines at no cost. The first year of the campaign (2008) went well and the vaccine was assessed as being about 60% effective, which is pretty much as expected.

No safety problems were recognised in 2008 or 2009, but things went horribly wrong in 2010.

In that year, the CSL flu vaccine – but not other registered vaccines – were found to have caused an unusually large number of high fevers. Some of these fevers were so severe that they led to fits.

What’s more, some of the fits were prolonged and at least one resulted in ongoing disability in a previously healthy child. Following extensive investigation, the CSL vaccines are no longer recommended for children younger than five years old in Australia, the United Kingdom or the United States.

The events of 2010 probably couldn’t have been foreseen because the Fluvax seems to have been safe for children in some years but not others. It’s a problem CSL has yet to fully understand but, in retrospect, it does not appear to be isolated to 2010.

Fevers and children

CSL’s Fluvax was first registered in Australia for adults and children in 1991, at a time when formal studies of efficacy and safety were not routinely required. The vaccine was re-licensed for children in 2002, in a formulation that did not contain the preservative thiomersal, but was otherwise largely unchanged from the vaccine registered 11 years previously.

The regulator, Australia’s Therapeutic Goods Administration, refers to this method of registration as “grandfathering”. This implies the registration is based on confidence arising from widespread use or experience, but it’s not necessarily supported by formal evidence.

But grandfathering of Fluvax for children was done with almost no grandfatherly experience of its use in children. Although used widely in adults for many years, Fluvax was little used in children before the Western Australian campaign.

Because Fluvax was registered for children in Australia, it was registered for use in children in a number of other countries – even though the Australian registration was not based on efficacy or safety data.

The international practice of registering in one country when the vaccine was registered in another country was followed. It was only when Sweden requested safety data on the vaccine formulation without the thiomersal preservative that CSL conducted a safety and efficacy trial in children. This was done over two years in 2005 and 2006.

The results of this trial were not published until 2009. And although not recognised at the time, they foreshadowed the problems of increased fever and related fits that were detected the following year.

At the request of US regulators, in 2009 CSL conducted a head-to-head comparison of Fluvax with another US-registered influenza vaccine in children. Fluvax produced significantly more fevers than the other vaccine.

In another CSL-sponsored trial in Australia published this year, the company’s 2009 southern hemisphere vaccine was found to be associated with high fever in children.

A hole in the plan

Fluvax was no longer recommended for young children after 2010, but it has been inadvertently given to children in Australia since. There was a serious adverse outcome documented in the ACT only last year.

Given these ongoing problems, there may be reluctance to give any future pandemic influenza vaccine manufactured by CSL to children, unless it’s shown that benefits outweighed risks. And this leaves a potentially large hole in Australia’s pandemic plans.

To fill this hole, CSL would need to show it understood why its seasonal vaccines cause high fevers in children, at least in some years. The US Food and Drug Administration has suggested the problem is related, at least in part, to the CSL manufacturing process, and CSL agrees.

Even when the problem (known in the trade as the “root cause”) is identified, understood and fixed, CSL would need to conduct a very large trial of the improved vaccine to demonstrate its safety and efficacy. Only then could Australians once again feel confident about giving Fluvax to children.

Failing that, the nation will need to turn to other vaccine manufacturers to fill the hole in our pandemic plans. But this may mean there are insufficient doses available when the vaccine is most needed.

This is the fifth article in our series Facts about Flu. Click on the links below to read other instalments in the series.

Part one: Of influenza, flu, potions and key opinion leaders

Part two: Influenza vaccine for 2013: who, what, why and when?

Part three: H1N1, H5N1, H7N9? What on earth does it all mean

Part four: The Tamiflu saga shows why all research data should be public

Part six: Should flu shots be mandatory for health-care workers?

Part seven: The Holy Grail of influenza research: a universal flu vaccine

Part eight: Is it really the flu? The other viruses making you ill in winter

Part nine: The heart of the matter: how effective is the flu jab really?

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