Apr 6, 2010 (CIDRAP News) – Despite a rapidly launched range of studies, investigators in Canada are still unable to say—or to rule out—whether receiving a seasonal flu vaccination in the 2008-09 season made it more likely that Canadians would become ill from 2009 pandemic H1N1 flu.

In a lengthy article published today in Public Library of Science Medicine (PLoSMed), researchers detail the results of four supplementary studies that were launched after an April 2009 school outbreak provided the first signal of an association between seasonal flu shots and pandemic flu illness. The studies, which took in about 2,700 people, found overall that the likelihood of needing medical attention for pandemic flu was 1.4 to 2.5 times greater among people who were vaccinated the previous fall.

But the authors warn that, since all four studies were observational, even careful design cannot rule out the possibility that some undetected methodologic bias affected the results. That caution is echoed in a companion editorial, written by US researchers unconnected to the Canadian study, who cite the contradictory results of six other studies conducted in Mexico, Australia, and the United States at the same time as the Canadian ones. Four of those studies found no association between seasonal flu vaccination and pandemic flu illness, while the two done in Mexico paradoxically found that seasonal flu shots may have had a protective effect.

The Canadian researchers add, however, that their results may signal a heretofore-undetected biological mechanism of interaction, one that could occur again in the rare instance of a pandemic strain arising after a flu season has already begun. The 2009 pandemic strain surfaced in the last weeks of the 2008-09 flu season, months after vaccines for that season had been administered.

"Our results may seem counterintuitive, but they cannot be dismissed on the basis that no biological mechanism can plausibly explain them," the Canadian researchers write. "If these observations do reflect a real biological effect . . . they raise important questions that warrant further scientific observation."

The publication of the researchers' data marks the end of a more than 6-month-old mystery that first surfaced at the start of the H1N1 pandemic's second, autumn wave and threatened to disrupt vaccination across Canada. Word of the manuscript's unexpected observations rippled across North America, but with the article in press, its authors were not free to speak.

International media, however, covered the rumored findings, leading officials at the US Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) to weigh in from the unusual position of commenting on data they had not yet seen.

"We have looked at our data at the CDC nationally," Dr. Thomas Frieden, director of the CDC, said on Sept. 25, 2009. "I have looked carefully at the data from New York City where we had a very large outbreak and lots of information about what vaccine was received. The Australians have looked at it and published their information. And in none of those data is there any suggestion that the seasonal flu vaccine has any impact on your likelihood of getting H1N1. If data is published in the scientific literature, by all means, we would love to see it. If there's preliminary data, we would love to see it. But nothing that we've seen suggests that that is likely to be a problem."

The long-awaited paper today describes the genesis of the concern: an indication from Canada's nationwide, nearly real-time monitoring system for flu-vaccine effectiveness that students at a school in rural British Columbia were more likely to have novel influenza-like illness if they had already received the trivalent injectable vaccine for the 2008-09 season.

To test that counter-intuitive finding, researchers from public health agencies in British Columbia, Quebec, Ontario, Alberta and Manitoba and several Canadian universities launched four studies. Three were case-control studies—one drawn from the same national monitoring system and two using lab-confirmed patient data from Ontario and Quebec—and one was a prospective household transmission study from Quebec.

All four studies, the authors say, show that the seasonal flu vaccine was effective in that season, reducing cases of flu needing medical attention. But all four also show an increased risk of illness from pandemic flu among the vaccinated. The risks shown in the studies ranged from 1.19 to 3.20 times greater for those who received the seasonal vaccine than for those who did not.

If that finding is not the result of chance or bias that occurred despite careful study design, the researchers say, then several hypotheses might explain the increased risk. Immunization might block the cross-protective immunity created by an earlier infection. "Original antigenic sin," or immunologic memory dating back to someone's first flu infection, might create antibody responses that are cross-reactive to other flu strains, but not strong enough to be cross-protective, and thus do not neutralize the virus. Or a related phenomenon called "antibody-dependent enhancement" might lead antibodies to inadvertently enhance virus uptake and production.

None of those mechanisms, the Canadian researchers note, could be elucidated by the epidemiologic studies that revealed the apparent vaccination-illness link.

In their commentary, researchers Cecile Viboud of the National Institutes of Health and Lone Simonsen of George Washington University acknowledge the care with which the Canadian teams designed their studies to eliminate as much design and analytical bias as possible. But pointing to the six simultaneous US, Mexican, and Australian studies that found very different effects—along with a seventh study in the US military with findings that echo the Canadian ones—they say that only a prospective randomized trial could produce results trustworthy enough to guide policy.

Organizing a randomized trial amidst the rapid viral spread and political tension of a pandemic would have been challenging, they acknowledge.

"This illustrates the difficulty of making policy decisions in the midst of a public health crisis, when officials must rely on limited and possibly biased evidence from observational data, even in the best possible scenario of a well-established sentinel monitoring system already in place," they write. "This perplexing experience should teach us how to best react to disparate and conflicting studies and prepare us for the next public health crisis, so that we can better manage future alerts for unexpected risk factors."

Skowronski DM, De Serres G, Crowcroft NS, et al. Association between the 2008–09 seasonal influenza vaccine and pandemic H1N1 illness during spring–summer 2009: four observational studies from Canada. PLoS Med 2010 Apr 6;7(4) [Full text]

Viboud C, Simonsen L. Does seasonal influenza vaccination increase the risk of illness with the 2009 A/H1N1 pandemic virus? PLoS Med 2010 Apr 6;7(4) [Full text]