As the official flu season begins in the Northern Hemisphere, health officials are looking for ways to stretch limited supplies of vaccine against the novel H1N1 flu virus that leapt from swine to humans earlier this year. A suite of studies published in The New England Journal of Medicine (NEJM) online Thursday and preliminary data from two clinical trials released today offer good news, particularly for the 43 million Americans vaccinated against "swine flu" in 1976.

In particular, a single dose of pandemic vaccine induces protective antibody levels in most adults. Data on children are expected in another two weeks, said Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases (NIAID) in a press conference today.

 One of the NEJM studies also showed that many older Americans as well as recipients of the 1976 swine flu vaccine may already be protected against the new virus. In that study, researchers from the U.S. Centers for Disease Control and Prevention (CDC) report that tests of serum taken from 1976 swine flu vaccine recipients showed a strong protective immune response against today's pandemic virus. The findings may help to explain why the virus sickens children and young adults more than older people, the authors wrote. The preexisting immunity may also prime 1976 vaccinees to respond vigorously to the new pandemic vaccine.

"It would certainly be something very interesting to look at," says Jackie Katz, senior author of the study. "That's why we did these studies originally, to help inform the public health response."

Adults appear protected
Since the new H1N1 virus emerged earlier this year, health officials have noted how it has disproportionately struck children and young adults and conspicuously spared older people worldwide. The disparity is most dramatic in the U.S.: 79 percent of laboratory-confirmed cases have been in people under 30 years old, whereas only two percent of cases have been in adults over 60. The U.S. median age of pandemic infections so far is 12, but somewhat higher in other countries. The median age of confirmed cases in Australia is 21, for example.

Since May, Katz, who is chief of the CDC National Influenza Division's Immunology and Pathogenesis Branch, has been testing stored serum samples to look for existing immunity to the new virus in the U.S. population. Her group's latest report shows that serum from adults born before 1930, including survivors of the 1918 pandemic, possesses antibodies that recognize and respond powerfully to the novel H1N1 virus.

With an antibody concentration of 40 or more considered protective (immunologists describe antibody responses in terms of serum dilution ratios, such as 1:40), the tests showed that 100 percent of subjects born between 1910 and 1929 mounted antibody levels of 80 or more. Only 34 percent of subjects born before 1950 mounted comparable levels, suggesting that exposure to the 1918 pandemic virus or its immediate descendents in the 1920s and 1930s conferred the strongest protection against the new flu.

The original swine flu
The CDC group also started over the summer to test 83 samples of serum drawn in 1976 from adults who received a single dose of the swine flu vaccine as well as a handful of samples from children who got the 1976 vaccine. The study found that the serum from 52 (63 percent) of the adult subjects produced antibody levels of 160 or more when exposed to the novel H1N1 virus. That number was nearly as many (59) of those whose serum demonstrated a strong response when exposed to the 1976 swine flu itself.

The NEJM report notes that a Japanese study recently reported finding protective antibody responses against the novel H1N1 virus in Japanese adults exposed to the 1918 pandemic virus, but not in subjects born after 1920. Serum from older Europeans tested by the CDC also showed lower response levels than the U.S. samples, possibly indicating a greater level of protection among Americans from the 1976 vaccine, which was given only in the U.S.

The study also confirmed previous work showing that infection with the modern seasonal H1N1 virus or exposure to seasonal vaccines in the past 20 years did not confer protection against the pandemic version of H1N1.

Family connection
The genealogy of the H1N1 virus family would explain why exposure to a swine lineage via the 1976 vaccine or to older human lineages offers cross-protection against the new strain. The parent of all H1N1 flu viruses, the virus that caused the pandemic of 1918–1919, jumped into the human population from some as yet unknown source and wrought worldwide havoc for two years, then settled down with considerably less virulence to become the circulating human seasonal flu strain for nearly 40 years. Sometime around 1920, humans introduced it to pigs, and that swine H1N1 lineage remained largely unchanged until the 1990s. The 1976 swine flu strain and early human H1N1 strains are therefore very close siblings.

Circulating human H1N1 disappeared in 1957 and only reemerged in 1977. Since then it has evolved sufficiently so that the modern seasonal H1N1 is more of a distant cousin to the older strains.

Although the new virus contains pieces from a variety of human and animal flu lineages, it retains the hemagglutinin protein—the H1—from the classical swine strain. Hemagglutinin is a viral protein that enables the flu virus to enter host cells. Because the protein is on the surface of the viral particles, it is a primary target for immune system cells and antibodies to recognize the viruses. Genetic analyses of the new virus's H1 protein and the classical swine H1 show them to be nearly identical.

Booster shots
"Basically, it's a 1931-like swine virus," says Brian Murphy, co-chief of the respiratory viruses laboratory at NIAID. Murphy supplied most of the 1976 serum samples used in Katz's study. He retrieved them once he learned of the genetic similarity between the new swine flu and classical swine virus. "We had them in our repository," he recalls of the samples taken from NIAID workers in 1976, "because we were doing a variety of experimental studies at the time. We used the licensed vaccine to immunize workers in the lab, to make sure people working with the virus had been immunized, and we obtained sera pre- and post-vaccination to make sure they had a satisfactory response."

Many of the lab workers showed a "tremendously vigorous" antibody response to the 1976 vaccine at the time, Murphy recalls. "We really don't know if people who had good titers [antibody levels] then [also] have them now, but I presume they would," or at least a good percentage of them would, he says. That presumption leads Murphy to conclude that when it comes to the pandemic H1N1 virus, "I would say, yes, there will be resistance in some percentage of those 40 million subjects."

Katz also cautions that the serum samples taken from 1976 vaccinees shortly after being vaccinated may not represent the level of response those same subjects would muster 33 years later. On the other hand, she adds, "As was observed in both 1976 and 1978 H1N1 vaccine clinical studies, individuals primed by prior exposure to H1N1 viruses through infection or vaccination made an antibody response to the new H1N1 vaccines after one dose."

If previous exposure to older H1N1 lineages primed 1976 vaccinees to produce good immune activity after a single dose of vaccine, then priming by the 1976 vaccine may yield a robust response to the new pandemic vaccine following a single dose, Katz acknowledges. "I think hopefully that information is being gathered and will be very interesting to see." The preliminary U.S. trial results released today did not examine trial subjects’ prior vaccine history or break down responses by age to determine possible preexisting immunity.

Stretching the vaccine supply
Pandemic planners had expected individuals to require two doses of vaccine in the fall, but if a significant portion of the population requires only one dose, vaccine supplies could be stretched. In the U.S. trials of two vaccines made by Sanofi Pasteur and CSL Limited, more than half of adults over 65 showed a strong immune response to a single vaccine dose, and 80 percent to 96 percent of adults between 18 and 64 mounted a robust response. “This is good news,” said Health and Human Services director Kathleen Sebelius at today's press conference, “but there is still critical research going on. We will assess the data further and make critical distribution decisions.”

CDC has already released updated recommendations for vaccine distribution, urging health care workers to concentrate on providing a single vaccine dose to at-risk groups and not to hold back vaccine supplies in order to provide a second dose to each individual.

The two other flu vaccine studies published in yesterday's NEJM also described responses to a single vaccine dose. An Australian test of a novel H1N1 vaccine showed that a single dose, containing an amount of virus antigen typical of seasonal flu vaccines, produced protective levels of antibodies in 96.7 percent of trial subjects.

Meanwhile, a U.K. trial of a pandemic vaccine containing MF59, an immunity-boosting vaccine additive that is approved in Europe, produced protective responses with half the usual amount of virus antigen in three quarters of trial subjects. Two doses of the adjuvanted vaccine generated protective antibody levels in more than 90 percent of the subjects.

Earlier this summer, estimates of this year's death toll from the H1N1 strain reached into the tens of thousands. This week's good news about vaccination could go a long way to cut that number sharply.