Study: Children, middle-aged most vulnerable to variant H3N2

Aug 10, 2012 (CIDRAP News) – A serologic study from Canada suggests that children and middle-aged adults have little or no immunity to the swine-origin variant H3N2 influenza virus (H3N2v), but about half of adolescents and young adults have some degree of immunity as measured by antibody levels.

The researchers also found that seasonal flu vaccines used in the past two seasons did not improve participants' ability to mount an immune response to H3N2v. Their report was published this week in the Journal of Infectious Diseases.

Given the results, "A specific vaccine would be needed in the event A(H3N2)v establishes epidemic spread," says the study, which was led by Danuta M. Sowronski, MD, of the British Columbia Centre for Disease Control as first author.

The H3N2v strain, which contains the matrix gene from the 2009 H1N1 virus, emerged last summer in the United States, causing a dozen cases. But more than 150 cases of H3N2v illness have been reported in the past few weeks, most of them in children who had contact with pigs, often at county fairs. The illnesses have generally been mild and self-limiting.

A flu expert with the US Centers for Disease Control and Prevention (CDC) said today that the new findings generally agree with those of previous studies by the CDC and others, but the finding of low antibody levels in middle-aged adults emerged more clearly in the new study than in previous ones.

The CDC has prepared a candidate vaccine for the novel virus, and clinical trials are expected this fall.

Samples from all ages
The Canadian researchers looked for cross-reactive antibodies to H3N2v, using 1,116 serum samples that had been collected in 2010 from people across the age spectrum. In addition, they tested sera collected from children and adults before and after receipt of the 2010-11 seasonal flu vaccine and from elderly people before and after receipt of the 2011-12 vaccine.

Hemagglutination inhibition (HI) and, in a subset of cases, microneutralization were used to assess antibodies to H3N2v.

Overall, 25% of the 1,116 participants had an HI antibody titer of at least 40 to the H3N2v strain, the level that's believed to confer some degree of protection. But no children younger than 5 years and fewer than 20% of subjects 14 or younger or over age 40 had this seroprotective level of antibody.

Between the ages of 14 and 40, half of the subjects had a seroprotective level of antibody to the virus, the report says. The proportion peaked at about 60% in adults in their 20s but dropped to about one-third for those in their 30s. Fewer than 10% of those between ages 40 and 69 and about 20% of those older than 69 had seroprotection.

The researchers also looked at cross-reactivity to an H3N2 strain called A/Sydney, which circulated in the late 1990s and was the most closely related and readily available human ancestor strain to H3N2v. Overall, they found a seroprotective level of antibody to A/Sydney in 61% of their samples. More than 90% of teens and adults in their 20s had seroprotection, and for adults overall the prevalence was more than 60%.

To test whether seasonal flu vaccine enhanced protection against H3N2v, the team looked for at least a fourfold increase in antibodies to the novel virus (seroconversion) after vaccination. They found that seroconversion rates were less than 15% in all age and vaccine groups, with little difference by age-group.

Among elderly people who received the 2011-12 seasonal vaccine, 72 received a vaccine containing the MF59 adjuvant. The researchers said the adjuvanted vaccine didn't enhance response to H3N2v compared with the other formulations.

"Our serologic findings suggest substantial protection against A(H3N2)v in late adolescence and young adulthood, but broad susceptibility in children and older adults," the authors say in summary.

The lack of protective antibody levels in middle-aged and older adults contrasts oddly with the fact that there was only one adult among the first 13 H3N2v cases identified, the authors comment. They say this "may reflect limitations in surveillance sensitivity, exposure opportunities or pediatric versus adult hygiene or other protective measures."

The explanation for the age-related variation in seroprotection may have to do with differences in the H3N2 strains that different age-groups were exposed to in childhood, the researchers suggest. They say that the A/Sydney strain circulated a few years after, and is 96.4% similar to, H3N2v's closest human ancestor, A/Wuhan.

Those who were children in the 1990s may have been "primed" by exposure to H3N2v ancestor strains, resulting in robust memory responses to related strains in later years, they write.

The authors note several limitations of their data and say the findings need confirmation elsewhere.

A CDC expert, Jacqueline Katz, PhD, said the Canadian findings generally agree with previous smaller studies conducted by her agency and a group in Norway. But she said the study is much larger and offers greater insight into the age-related differences in seroprotection against H3N2v. Katz is chief of the immunology and pathogenesis branch of the CDC's Influenza Division.

"Overall, the three studies agree that there is negligible cross-reactive antibody to the H3N2v virus detected in younger children," Katz said. The work also confirms previous findings that seasonal trivalent flu vaccine containing an H3N2 strain does not trigger much of a cross-reactive response to the novel virus, she added.

"What's novel about Skowronski's study is it's the largest to date and had the ability to look more closely at different age groups," she said. "They have quite an interesting finding that middle-aged adults, ages 40 to 69, show a substantial reduction in the level of cross-reactive antibody compared with younger adults."

The Norwegian study had a similar finding, but in a tighter age-group of adults, she said, adding that further research is warranted to try to find an explanation for the phenomenon.

Katz concurred with the Canadian team's suggestion that different childhood exposures may be a reason for the age-related differences in seroprotection.

"It may be that that particular group [middle-aged adults] had a different exposure, that they saw an earlier H3N2 virus for the first time, and didn't have the same robustness of response to the viruses from the 1990s that are closest to the H3N2v strain," she said. "We're interested in looking into that a little more."

"When you do genetic and antigenic analysis, you can see that viruses from the early 1990s are genetically most closely related to the hemagglutinin of the H3N2 variant viruses," Katz said. "So it does make sense that individuals who were of an age to be exposed to those in the early 1990s and made a robust response may have the highest cross-reactive antibody response to the variant strain."

Skowronski D, Janjua NZ, De Serres G, et al. Cross-reactive and vaccine-induced antibody to emerging swine influenza A(H3N2)v. J Infect Dis 2012 (Early online publication) [Full text] [Abstract]

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