Although the swine flu outbreak of 2009 is still in full swing, this global influenza epidemic, the fourth in 100 years, is already teaching scientists valuable lessons about pandemics past, those that might have been and those that still might be. Evidence accumulated this summer indicates that the novel H1N1 swine flu virus was not entirely new to all human immune systems. Some researchers have even come to see the current outbreak as a flare-up in an ongoing pandemic era that started when the first H1N1 emerged in 1918.

As soon as the newest H1N1 virus burst onto the scene in the spring, it conspicuously assaulted the young and left the old mostly unscathed. To date, 79 percent of confirmed U.S. cases have been in people younger than 30 years and only 2 percent in people older than 65. In light of that lopsided attack pattern, investigators at the Centers for Disease Control and Prevention quickly started testing hun­dreds of human serum samples stored between 1880 and 2000, looking for evidence of past human experience with the novel H1N1 virus.

Data published in May showed a power­ful antibody response to the new virus in a third of the samples from subjects older than 60 and in a smaller number (6 to 9 percent) of samples from younger adults. The authors theorized that exposure to post-1918 H1N1 human flu viruses had primed the oldest subjects’ immune system to recognize the novel H1N1.

The CDC group procured serum samples collected from 83 adults and a handful of children who had received the vaccine against swine H1N1 that was given in 1976 to 43 million Americans. More than half of the samples from adults who received a single shot of that vaccine displayed a powerful immune response to the 2009 H1N1 virus, whereas little recognition of the new virus was seen in the serum of inoculated children, all younger than four at the time.

The discrepancy was an important clue, according to senior author Jackie Katz of the CDC’s influenza division, who published those particular findings in September. The adults, who were between 25 and 60 years old in 1976, would have been exposed to H1N1 flu before 1957, the year it stopped circulating for the next two decades. “We assume that by the age of five a person would have had at least one exposure to influenza,” Katz explains. That prior encounter with H1N1 seemed to be the key to a robust recognition of the 1976 vaccine virus, just as having had the 1976 vaccine seems to produce a strong response to the 2009 H1N1 virus. The very young children, in contrast, represent the responses of immune systems that have no past history with H1N1.

Katz cautions that high antibody levels in serum do not guarantee immunity from infection, but they serve as good indicators of protection when testing vaccines and are a fairly sure sign of earlier exposure to the pathogen. For people with some measure of previous immunity, a subsequent vaccine could act as a “booster shot.” Indeed, trial results published in September surprised health officials by showing that a single shot of vaccine against the new H1N1 produced a strong response, even among some children older than six, hinting at broad recognition of the vaccine virus by the trial subjects’ immune system.

Analyses of infection rates in modern seasonal flu epidemics suggest that with age comes a subtle buildup of immunity to flu viruses in general. Although the external viral proteins hemagglutinin and neur­a­minidase (the H and N that designate a flu strain) are the main targets of vaccines, the human immune system may also recognize other viral parts. The resulting responses may not prevent infection, but they may reduce symptoms to a degree that people do not even realize they are infected.

Indeed, the seasonal flu peaks in kids and “then sort of declines with age,” says Jeffery Taubenberger, a virus expert at the National Institute of Allergy and Infectious Diseases. “The elderly have the highest mortality because they often have underlying conditions,” he adds, “but you find that people in their 40s and 50s get a lot less clinical flu than kids, so one possibility is that there’s a slow accrual of a wide variety of flu immunity.”

Taubenberger, who isolated the full 1918 pandemic virus in 1997, notes that even 20th-century seasonal strains such as the H2N2 virus that appeared in 1957 and the H3N2 pandemic strain that began circulating in 1968 are built on the chassis of the original H1N1, as is the 2009 H1N1 virus. In effect, every human flu strain in the past 90 years has been a member of a dynasty founded by the 1918 virus, he concludes.

Those family ties are likely contributing to the relative mildness of the current pandemic. Avian flu viruses bearing H5, H7 or H9 hemagglutinins, widespread in domesticated poultry, have not yet managed to gain traction in the human population. If they did, they might produce a flu as ferocious as the one induced by the H1N1 virus in 1918, when it was truly new to people and killed at least 40 million worldwide.

Long-standing fears of that worst-case scenario engendered pandemic-planning efforts that are paying off today. They also prompted the 1976 vaccination campaign, which has been called a fiasco for the adverse events that accompanied the mass inoculations against a pandemic that never materialized. But even that brush with a version of H1N1, it seems, is paying an unexpected dividend now.