18 May 2018

Flu virus impact: No telling how it will go

Heatmap of incidence of 2017 flu season, from FluTracking.
Your participation welcomed in the joint Australia - New
Zealand flu tracking survey: join here
by Anne Crawford

With winter approaching and the influenza (flu) season hovering health authorities and others are wondering if this year’s flu season will be a repeat of the deadly one that occurred last year. It’s a question being asked a lot lately of Professor Allen Cheng, infectious diseases expert at The Alfred Hospital. 

Indeed, Professor Cheng, who runs part of Australia’s hospital-based flu surveillance system FluCAN, is perennially asked if he can predict what will happen in the upcoming season. His answer is the same every year: no, he can’t.

Professor Cheng has co-written a paper in ‘Respirology’ about the complex factors, and difficulty involved in forecasting the timing, size and intensity of an approaching season. The paper touches on the kaleidoscope of changing factors that can coincide in any given year to shape a season. These factors affect the transmissibility, severity (numbers of people in hospital, intensive care and who die from the disease) and the ‘impact’ of the flu, which embraces such ideas as effects on the workforce and hospital capability.

Among the myriad factors cited are: which viruses were circulating previously and currently; prior infection and vaccination history in the community; virus evolution and antigenic drift; climatic factors such as temperature, humidity and UV levels; population density, and travel patterns.

'Antigenic drift' refers to the changes in genetic material that occur because RNA cannot repair its own genetic errors, making the flu virus genetically unstable and altering it slightly between generations.

Temperature is an interesting one. “No one really knows what it is about temperature,” Professor Cheng said. “At this stage we think it’s an interaction between temperature and humidity but no-one’s come up with a convincing model of this.”

The effect of climate change on viruses, while the subject of much interest among infectious disease scientists, is also speculative.

The paper outlines why the virus is so unpredictable. Influenza viruses can be separated into four types A, B, C and D, (influenza A and B cause most human disease), 18 subtypes (only two of which cause most human infections – A(H1N1) and A(H3N2)) and two lineages (only for B viruses; B/Victoria and B/Yamagata). So up to four different influenza viruses can, and often do, circulate in a country at the same time.

One virus type or subtype usually predominates for an extended period. Which virus this is also determines the most susceptible age groups. For example, if an influenza A(H3) virus circulates widely it usually affects older age groups, in contrast to influenza H1 which mainly affects children and adults and less so the elderly.

This difference also influences the severity of the season; A(H3) has a higher mortality in seasons when it predominates, as it infects more elderly people, who have more co-existing diseases and are more prone to having secondary bacterial infections that can lead to pneumonia and hospitalisation or death, as seen in Australia in the 2017–2018 season.  A(H3N2), which tends to affect elderly people more, was the predominate virus last year. Ninety per cent of the 745 people who died in last year’s influenza season in Australia were elderly.

The flu vaccine was apparently less effective than expected last season. Data suggests it offered only 23 per cent protection rather than the average over the past seven years of 40 to 50 per cent.

The mutable nature of the flu virus has meant it has been exceptionally difficult to find a vaccine that protects against all types, and to plan preventative measures such as encouraging vaccination, stockpiling antivirals and having sufficient hospital beds available, for example by cancelling elective surgery.

Every year around September a WHO committee in Geneva estimates a probable flu vaccine composition for the following season based on information from collaborating centres around the world, including one in Melbourne, to which FluCAN feeds data. Vaccines are then manufactured globally and vaccinations started from the end of the following March.

Several million eggs hatched in poultry farms in undisclosed locations in Australia are injected with the virus to produce the vaccine ¬– a process that has changed little since the days in the 1940s when researchers, including Melbourne Nobel Prize winner Macfarlane Burnet, developed techniques that would allow mass-production of vaccines.  

But contrary to common misconception, there’s no live virus in flu vaccines so it’s not possible to contract influenza from a jab, Professor Cheng said. “Most reactions usually go away in a day or so – it’s a good sign that the vaccine does elicit an immune response.”

People who feel they have respiratory symptoms after vaccination are most likely to have caught the respiratory syncytial virus (RSV) virus, which circulates at the same time, he said.

The Australian Government this year introduced for the first time vaccines for the elderly on FluCAN’s recommendation: FluZone High Dose and FluAd, enhanced vaccines that stimulate the immune system more than the standard one.

“Showing that the existing vaccine wasn’t that good in the elderly was the most important thing we did last year,” Professor Cheng said.

“There are good data supporting both these vaccines suggesting that they around 20 to 25 per cent better than the standard vaccines. These are far from a perfect vaccine, but should still be better at protecting the elderly,” he said.

A campaign to promote paediatric flu vaccine will also be run this year. “Flu is a major source of illness in children, the most common cause of vaccine-preventable disease death,” Professor Cheng said. “Flu vaccine does seem to work in kids but the coverage now is very low,” he said. Several children were reported to have died during last year’s epidemic.

Children aged under three years will continue to receive a smaller dose and those aged older than this, the standard dose. 

Elsewhere, researchers are trying to predict flu season activity using mathematical models and Big Data systems. (Big Data is that which is routinely collected for other reasons, such as hospital admissions or people using credit cards to buy cold and flu tablets.)

Google Flu Trends, which trawled words connected to flu to try to predict trends, was “a bit of a disaster” and was discontinued, Professor Cheng said.

“Big data is quite interesting but are so many unknowns – what it’s measuring, how accurate are the other influences that might throw the calibration out – it’s not reliable at the moment,” he said.

“An ideal system will tell you what’s going on right now, how many people have the flu.”

The Centers for Disease Control and Prevention (CDC) in the US crowd-sourced the idea of forecasting in an annual competition ‘Predict the Influenza Season Challenge’. But the conclusion from the early results was that ‘further efforts’ were needed to improve forecast accuracy before policy makers could reliably use the information, the paper says.

“There really aren’t any systems that can cope with new real-time data other than nurses walking the wards talking to patients and doing active surveillance."

Professor Cheng was recently the first author of another paper investigating vaccine effectiveness in people who had vaccines every season. The study of nearly 13,000 people, conducted over 2010-2015, showed that those vaccinated in both the current and previous seasons had higher protection than people vaccinated in either single season, reinforcing recommendations for annual influenza vaccination, particularly for those at greatest risk of the disease.
 
“There’s been a concern that if you vaccinate people over and over they might not respond as well as if you vaccinate them less,” he said.  “In contrast, we found that it’s more protective against severe disease if you get the vaccine repeatedly.”

The first paper was co-written with Professor Ian Barr from the Peter Doherty Institute and World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza.

References

Barr IG, Cheng AC. Difficulties of predicting the timing, size and severity of influenza seasons. Respirology. 2018 Apr 11. doi: 10.1111/resp.13310. [Epub ahead of print]

Cheng AC, Macartney KK, Waterer GW Kotsimbos T, Kelly PM, Blyth CC; Influenza Complications Alert Network (FluCAN) Investigators. Repeated vaccination does not appear to impact upon influenza vaccine effectiveness against hospitalization with confirmed influenza. Clin Infect Dis. 2017 Jun 1;64(11):1564-1572. doi: 10.1093/cid/cix209.
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