Swine flu behaviour revealed

Scientists have published new research exploring the characteristics of the pandemic swine flu strain, including why it appears to affect younger people more severely. The study, which used both lab testing and animal models, suggests that the pandemic strain causes more lung damage and replicates deeper in the lungs than other human H1N1 infections. It is thought that these characteristics could be responsible for the viral pneumonia that seems to be contributing to hospitalisations and fatalities in people without existing health problems.

Key findings at-a-glance

The pandemic declared by the World Health Organisation on June 11 2009 has been caused by the circulation of a new strain of the H1N1 virus.
The genetics of the new strain show that it is most closely related to swine viruses, which will normally cause only mild illness in infected humans.
One of the first US isolates of the new H1N1 strain has been characterised and tested alongside other isolates in a study involving both laboratory experiments and tests in mice, ferrets, pigs and non-human primates.
Swine flu appears to cause more severe lesions in the lungs of infected mice, ferrets and non-human primates than a seasonal H1N1 strain.
The virus can replicate in pigs without causing symptoms, which possibly explains the lack of an outbreak in pigs before the first human cases were seen.
Increased pathogenic properties of the pandemic H1N1 strain, including its more efficient replication, may be responsible for the viral pneumonia that has contributed to hospitalisations and fatalities in otherwise-healthy people. These findings are not directly linked to the two recent swine flu deaths that are still under investigation.

Where was the article published?

This research was carried out by Yasushi Itoh, Yoshihiro Kawaoka and colleagues from the Shiga University of Medical Science, and other academic and medical institutions in Japan and the US. The study was published in Nature and supported by the National Institute of Allergy and Infectious Diseases Public Health Service, ERATO (Japan Science and Technology Agency), departments of the Japanese government and by a grant for Specially Promoted Research.

What kind of study was this?

This was a laboratory study combined with animal research. The researchers isolated and characterised a sample of the new H1N1 virus taken from one patient who had been hospitalised, known as isolate CA04. They also isolated samples from four ‘mild cases’, and compared these with a seasonal H1N1 strain that has recently circulated.

The isolates were initially replicated in canine kidneys to provide a stock of viral particles to investigate through further experiments. Different mice were infected via the nose with CA04 and the other swine flu isolates. The levels of virus in nasal samples and in the lungs of these mice were then compared with the levels seen after infection with the seasonal H1N1 strain. The isolates were also tested in ferrets and macaque monkeys to assess the effects on other mammals.

Usually, the elderly are at greatest risk from the flu virus, but the current H1N1 pandemic appears to be different, and younger people seem more susceptible. To explore the reasons behind this, the researchers looked for antibodies that can neutralise CA04 in the blood samples of two sets of donors. The first set were samples collected in 1999 from residents and staff in a nursing home, while the second set was collected in 2000 from workers and patients in a hospital.

They also exposed the CA04 isolate sample to commonly used antivirals, in order to test its susceptibility to the drugs.

What does the research say?

There were several notable differences between infection with pandemic H1N1 and a non-pandemic, H1N1 strain that was recently circulating.

Mouse testing showed:

The CA04 strain of H1N1 swine flu (isolated initially from a person who was hospitalised) led to significantly more pronounced lung lesions.
At three days after infection, significant bronchitis (infection of the airways of the lung) and alveolitis (infection of the air sacs in the lung) were evident.
While these infections were also seen in the mice infected with seasonal H1N1, there was some evidence that the infections in pandemic H1N1 infected mice were directly caused by the virus, i.e. the presence of viral antigens in the lesions. With the recently circulating H1N1, the viral antigen was rarely detected in the lung lesions.
There was also a more pronounced inflammatory response in the lungs of CA04-infected mice on day 6 after infection.

Macaque tests showed:

Infection with CA04 led to a greater increase in body temperature than infection with non-pandemic H1N1.
The pandemic influenza strain caused more severe lung lesions than the seasonal H1N1.
The pandemic strain also replicated efficiently in the lungs, in a similar way to highly pathogenic influenza viruses. Other human influenza viruses do not replicate easily in primate lungs, so this is a notable characteristic.
As with mice, there was greater lung inflammation following infection with CA04 compared with the recently circulating H1N1 strain.

Ferret testing showed:

More severe lung infection in those infected with CA04 compared with the seasonal strain, however similar levels of virus were detected nasally, and there were no particular differences in body temperature or weight.
The CA04 strain was highly transmissible in ferrets. After three days of close proximity (but no contact) with infected animals, those without the infection had caught the flu.

The authors also concluded:

The genetic make-up of the current H1N1 pandemic virus suggests that it originated in pigs, even though there were no porcine outbreaks of the disease reported before the first cases of human infections.
CA04 isolates were found to efficiently replicate in the lungs of pigs without causing any symptoms. The researchers suggest that this may explain the lack of an outbreak of swine flu in pigs.
CA04-neutralising antibodies were found in many people born before 1918 (the year of the 1918 Spanish flu pandemic), and this suggests that exposure to the human H1N1 viruses that circulated until 1957 (which were closely related to the 1918 Spanish flu virus) could confer some immunity to people aged over 60 years.

What is the implication and importance of this?

Collectively, the findings demonstrate that CA04, an isolate of the H1N1 virus causing the current global pandemic, causes more severe infection than seasonal H1N1 flu in three different animal models.

The authors of this study speculate that these properties may be linked to the viral pneumonia that has so far contributed to hospitalisations and fatalities seen in infected people with no known underlying health problems.