16 August 1957: a nurse at Montefiore Hospital gets the first Asian flu vaccine shot in New York (Image: Associated Press)

Six months ago, swine flu emerged as a massive threat to global health. It seemed to come out of nowhere, but our timeline explains how the origins of the H1N1 pandemic go back more than a century

1889

Prior to 1889, the main flu virus circulating in humans has been from the H1 family. But this year, a new strain of H2 flu emerges in Russia and spreads around the world, killing about 1 million people. Afterwards, H2 replaces H1 in humans. Such replacements seem to be a regular feature of flu pandemics.

People born before 1889, who have been exposed to H1 flu, have some immunity to it. This affords them some protection in the deadly H1N1 epidemic of 1918. Those born after 1889 do not have any immunity to H1.


1918

The “Spanish flu” epidemic of 1918 kills at least 50 million people worldwide. It is caused by an H1N1 virus which evolves directly from a bird flu into a human flu.

After a mild wave of infections in the summer, the epidemic goes global: one-third of the population eventually get sick. Although most cases are mild, many sufferers develop a rapidly fatal infection deep in their lungs. People born before 1889 are less susceptible, thanks to their previous exposure to H1N1.

Most deaths are caused by bacterial lung infections that move in after the virus. Modern antibiotics might mean that a re-run of the 1918 pandemic would be less dangerous.

After 1919, the descendants of the H1N1 virus continue to circulate and cause seasonal flu outbreaks in humans – and pigs.

1931

Swine flu is first isolated from a pig in Iowa.

1933

The first human flu virus is isolated at Mill Hill in London. When given to ferrets, it produces a disease whose symptoms are all but identical to the Iowan pig virus. But ferrets that have had the human virus are not fully immune to the pig virus, showing that the two viruses have already started to evolve apart.

1957

An H2N2 virus causes the “Asian” flu pandemic, completely displacing the H1N1 viruses that have been circulating in humans since 1918. The pandemic is fairly mild, killing 1 to 1.5 million people worldwide.

The virus is produced by a reassortment, in which human-adapted H1N1 swaps genes with an H2N2 bird flu. The new H and N surface proteins mean most people do not have antibodies to the virus, allowing it to go pandemic. However, its human-adapted genes mean it is not as lethal to humans as the 1918 virus, which came, with few changes, from birds.

People tend to mount the best immune response to the first kind of flu virus they experience. Because of this, people born before 1957, whose first experience of flu would have been the H1N1 viruses then in circulation, have some immunity to the 2009 H1N1 strain causing the current pandemic. People born after the 1957 pandemic do not have this immunity.

1968

An H3N2 virus causes the “Hong Kong” flu pandemic, which is even milder than the Asian flu, killing an estimated 0.75 million to 1 million people worldwide.

The virus only differs from H2N2 in one of its surface proteins, the H; since many people still have antibodies to the unchanged N2 protein, its effects are less severe. But because H3N2 completely replaces H2N2 in people, no one born since 1968 has any immunity to H2.

1972

Researchers Graham Laver and Robert Webster discover that waterfowl are the natural hosts of influenza viruses. The birds harbour strains unknown in humans that could reassort with human strains and give rise to new human pandemics.

1976

An H1N1 virus jumps from pigs to humans and kills a US army recruit. However the virus does not spread beyond the army base and fizzles out without triggering a pandemic.

Nevertheless, fears of a replay of the 1918 pandemic lead to 48 million people being hastily vaccinated against the swine flu virus. The vaccine is associated with an unusual number of cases of Guillain-Barré syndrome: 532 people get it, and 25 die.

1977

An H1N1 virus appears in north-east China and starts circulating in humans. It causes seasonal flu in every subsequent year. No one knows where it came from, though it looks like an H1N1 that circulated in the Soviet Union in 1950 and some suspect it escaped in a laboratory accident.

The virus causes a mild flu pandemic, which mainly affects people born after H1N1 flu disappeared in 1957. However, the real surprise is that it does not displace the previous, and more virulent, seasonal flu, H3N2. Instead, it continues circulating alongside it.

The antibodies people produce after being infected by this new seasonal H1N1 do not protect against 2009 H1N1. However, infections also trigger another reaction called cell-mediated immunity, in which certain white blood cells target and destroy infected cells. Tests of the 2009 H1N1 pandemic vaccine show that, unlike antibodies, cell-mediated immunity to seasonal H1N1 may help protect against the pandemic virus. This does not prevent disease altogether, but can reduce its severity

1998

The predecessor of the 2009 H1N1 swine flu virus emerges in the US. It is a hybrid of human, bird and swine flu viruses, and by 1999 it is the dominant flu strain in US pigs.

US pig farms try to control it with vaccines, but these attempts are largely ineffective because the virus evolves too rapidly, changing the surface proteins targeted by the vaccine while keeping its internal genes unchanged. The 2009 pandemic virus is a variant on this 1998 flu, and behaves the same way.

2004-2006

H5N1 flu, first identified as a threat to humans in Hong Kong in 1997, spreads from Asia around the world, apparently carried by wild birds. While this “bird flu” proves deadly to humans, killing more than half of its victims, it is kept in check by its inability to spread readily from human to human. H5N1 is also found in pigs in Indonesia, raising fears that it might reassort with other human flu viruses that pigs can harbour.

The threat posed by bird flu leads to the first real efforts to be made at pandemic planning: governments start to stockpile antiviral drugs, and the world’s drug companies start doing serious research on pandemic vaccines. These plans are made with the highly lethal H5N1 in mind, meaning that they are not always appropriate for the 2009 pandemic.

Read more: Bird Flu

2007-2008

Pandemic fears boost spending on flu research. European scientists start organising to track flu in wild birds, Vietnamese scientists find that antibodies from bird flu victims can cure other cases of the virus (a technique used in Hong Kong in 2009), the risk of dying of flu is found to be partly genetic, and it turns out that your mother was right to warn you about catching the flu when it’s cold out.

However, Indonesia, where most H5N1 outbreaks are happening, refuses to share samples of the virus, arguing that it will not benefit in return from any vaccines developed as a result. This means scientists cannot monitor the virus’s evolution.

But worries about H5N1 subside as it fails to become contagious in people – although virologists continue to warn that it is not the only threatening flu virus out there. Viruses from the H9, H7 and H2 families all give cause for concern.

March 2009

The first cases of a new type of swine flu are reported in California and Texas in late March. Subsequent genetic analysis suggests that it may have started circulating in humans in January.

April 2009

On 27 April, with 900 cases of suspected swine flu reported in Mexico, the World Health Organization (WHO) upgrades the pandemic warning level from 3 to 4 on a six-point scale. Intensive efforts to understand the virus and develop a vaccine begin immediately.

The US government advises against travel to Mexico, although research suggests that travel bans will not stop the virus spreading.

May 2009

Although swine flu seems to be spreading slowly, it is still progressing quickly enough to justify preparing for a pandemic. However, the WHO delays declaring a pandemic, partly because there is not enough evidence that the virus is spreading in the general population outside the Americas, where it originated.

New Scientist reveals that Europe is not testing people with flu symptoms unless they have recently travelled to an affected area in the Americas, or have had close contact with someone who did. As a result, Europe cannot detect spread in the general population. These restrictions may be making the pandemic “invisible” to the monitoring authorities.

As concerns mount, it transpires that many countries are poorly prepared for this scenario and that supplies of H1N1 vaccine cannot be prepared in time to catch the second wave.

June 2009

The UK and other countries change their rules and start testing people who have flu but no North American contacts. Cases of swine flu are soon detected.

On 11 June the WHO officially declares swine flu to be a pandemic. This is the signal for the vaccine industry to start making pandemic vaccine (paid for by governments), rather than conventional flu vaccine (paid for by ordinary health services).

July 2009

Treatment plans are shaken by the discovery of swine flu that is resistant to the antiviral drug Tamiflu and the realisation that the H1N1 vaccine is growing only half as fast as the ordinary flu vaccine.

The US decides to use its standard formulation for flu vaccine, so no new regulatory tests will be needed. This will allow it to authorise pandemic vaccine before September, when a renewed wave of the pandemic is expected. But this formulation uses a lot of virus, and so reduces the number of doses that can be made.

Researchers discover that the swine flu virus binds far deeper in the lungs than ordinary flu, possibly explaining why it is sometimes fatal. However, the majority of cases are still mild, and it appears that many of the people with severe cases have an underlying health problem – although some of these “problems” are no more remarkable than being overweight, pregnant or unborn.

In the southern hemisphere, where it is winter, swine flu apparently replaces the usual seasonal flu. This suggests that the pandemic virus will displace the two previous seasonal flu strains, as previous pandemics have done. However, after the experience of 1977, when this did not happen, scientists do not rule out the return of H3N2 after the autumn wave of swine flu.

August 2009

A New Scientist poll reveals widespread concern about swine flu among public health officials and epidemiologists, many of whom have obtained supplies of antiviral drugs for their own families.

September 2009

Four major vaccine manufacturers report that their swine flu vaccines work with only one shot. This is good news, given that vaccine is in short supply despite researchers’ success in finding faster-growing strains. The vaccine’s effectiveness suggests there must be pre-existing cell-mediated immunity, possibly because of similarities between the surface proteins on swine flu and the seasonal H1N1 flu that emerged in 1977.

As autumn arrives in the northern hemisphere, experts are on tenterhooks: a particular worry is that swine flu will hybridise with bird flu to create a readily contagious human flu armed with a lethal H5 surface protein. At time of writing, the virus had not become more severe, causing mild disease in most sufferers but making a small number – probably less than 1 per cent – extremely ill.

October 2009

Vaccination programmes begin in the US and Europe, but many healthcare workers are reluctant to have the vaccine, even though it is virtually identical to the seasonal vaccines used in previous years, which have a good safety record.

Production delays also continue to plague the deployment of vaccine. By 22 October, the US has only 27 million doses available, compared with the expected 45 million. Researchers show that this much vaccine will reduce the number of cases in the second wave by less than 6 per cent – but that is still enough to save 2000 lives.

Six months after swine flu first shot to world attention, US President Barack Obama declares the virus a national emergency.

Read more: Swine flu: The pandemic of 2009