Fewer senior swine flu cases may hint at protection

May 6, 2009 (CIDRAP News) – A lab test currently under development at the Centers for Disease Control and Prevention (CDC) could answer one of the novel H1N1 swine flu outbreak's most intriguing questions: why older people seem less likely to catch the new disease.

The test, called an antigenic assay, will not be completed for several weeks and then will go through several rounds of double-checking. But when it can be put into use, it should also help determine who should receive a vaccine against the novel flu strain if vaccine manufacturing goes forward.

Wherever there is surveillance for the new flu, it shows that the virus strikes young adults the hardest. In Mexico, according to data released Tuesday by the country's Ministry of Health, 51% of the 866 cases are younger than 20. On Wednesday, according to the CDC, 58% of the confirmed US cases were younger than 18.

To date there has been no way of distinguishing whether the skewed age distribution is due only to who may have first been exposed to the strain—American high school and college students on spring break, for example—or whether some other factor is at work.

"One of the questions which came up is whether most of the people traveling right now … tend to be younger people," Dr. Keiji Fukuda, assistant director-general for health, security, and environment at the World Health Organization said in a briefing Tuesday. He added: "One of the alternate possibilities of course is that it is an infection that is primarily going to younger people because there may be something about older people which is preventing them from being infected."

Scientists at the CDC have been working since the epidemic's earliest days to identify that something. They have glimpsed what are, in effect, its footprints: evidence that people aged 60 and older have a preexisting immune-system component that reacts to the novel strain of flu.

The phenomenon, called cross-reactive antibody, does not mean that older people were infected in the past by  this exact strain of flu. Rather, their blood contains proteins that were produced by their immune systems when they were infected by a different strain of H1N1, and that also react more weakly to the current strain.

The reaction may be so weak that it represents only a laboratory result and not any real-world protection, Dr. Carolyn Bridges, associate director of epidemiologic science in the CDC's influenza division, cautioned in an interview.

"We don't know how well that matches with clinical effectiveness; those are two different things," she said. "The antibody studies are suggestive, but we can't make that leap with confidence."

Older people would have had ample chance to be infected by some variant of H1N1, which is named for the varieties of hemagglutinin (the "H" portion) and neuraminidase (the "N") proteins on the surface of the virus. H1N1 was the dominant strain of seasonal flu from 1918 to 1957, when it was replaced by the H2N2 strain that caused the 1957-58 pandemic.

The 1976 swine flu epidemic was caused by a different H1N1 flu, which circulated briefly and then disappeared behind the H3N2 strain that has been dominating seasonal flu since the 1968 pandemic began. In 1977, an H1N1 strain that was identical to the 1950s version suddenly appeared again—almost certainly as the result of a Russian laboratory accident—and has been part of the seasonal mix ever since.

The novel H1N1 swine flu resembles none of those prior strains. Yet in tests on blood samples that have been stored in CDC freezers from a variety of serologic surveys, as well as ones hastily contributed by academic researchers, serum from people older than 60 seems consistently to be showing a faint protective response to the new flu.

Those results have provided the impetus for the assay now being worked on at the CDC, which, when it is completed, should be able to identify people who have an immune response to the current flu. That is important because evidence of infection is the best, though most labor-intensive, indicator of how far an epidemic has spread and what ages and risk groups are most vulnerable.

But the test could be vital for determining future actions even more than past spread. A positive response could determine who might not need to be vaccinated against the new flu, if a vaccine is achieved—or more likely, who would need only a single dose because their immune system has already been primed by the prior infection. That would save a dose for another recipient, because medicine assumes that vaccination against a new strain of flu requires two doses—and that could be critical, because any vaccine that is made will likely be in limited supply.

A number of logistical challenges are holding up the test's development. Chief among them: The outbreak is too new to allow collection of the blood samples that its developers most need. "For influenza, you really need what are called 'paired serum samples'—collected from the same person, ideally 7 to 10 days from the onset of symptoms and then 2 to 3 weeks after that," Bridges said. "We are just barely at the convalescent point for the earliest cases."

There are other challenges as well. Antibody assays must be precisely tuned to a specific infection. Otherwise, they may deliver a false result by reacting to what immunologists call "original antigenic sin"—the fact that someone's immune system retains the strongest evidence of reaction to the first version of a pathogen it came in contact with, even if the person is subsequently infected with other strains of the same organism.

And no one yet can say how much the persistent presence of yet another swine flu H1N1 strain in pigs—which has been there since 1918 and over the decades has occasionally infected farm workers—might complicate the results the CDC achieves.

But in developing the test, the CDC researchers at least have a path to follow. They performed almost the exact same steps, carving out a new assay, when 18 people fell ill in Hong Kong in 1997. Their account of the process, published in the Journal of Clinical Microbiology in 1999, details the painstaking precision necessary to develop the first reliable test for what came to be known as avian influenza H5N1.

That blueprint is not only guidance; it also serves as validation for the flu scientists who have listened to weeks of suggestions that they spent a decade chasing the wrong bug. "The fundamentals are absolutely the same," Bridges said. "Encountering this new strain, we have benefitted a tremendous amount, in too many ways to name, from all the work done in preparation for H5N1."

See also:

Ministry of Health, Mexico: Situacion actual de la epidemia, May 5, 2009 [pdf]

Rowe T, Abernathy RA, Hu-Primmer J. et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol. 1999 Apr;37(4):937-43. [Full text]

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